Clinical Practice Guideline
for Dementia 2017

Publication of the English Version of“Clinical Practice Guideline for Dementia 2017”
The first “Treatment Guideline for Dementia” was released in 2002. This was followed by publication of the “Treatment
Guideline for Dementia 2010” using the Clinical Question (CQ) format in 2010. In 2014, revision of the “Treatment
Guideline for Dementia 2010” was decided. Around this time, preparation of the English version of the “Clinical Practice
Guideline for Chronic Headache 2013” was in progress, aiming to be published in 2015. Furthermore, the XXIII World
Congress of Neurology was scheduled to be held in Kyoto in September 2017. These events prompted a plan to publish theEnglish version of the revised treatment guideline for dementia.
In August 2017, the “Clinical Practice Guideline for Dementia 2017” in Japanese language was published. However, theEnglish version was not ready in time for the XXIII World Congress of Neurology. Nevertheless, discussions were continued
toward publication of the English version as originally planned.
After the publication of the “Clinical Practice Guideline for Dementia 2017” (Japanese version), some questions andopinions were received. The Committee addressed these issues and made some revisions, and at the same time simplified thecontents to some extent to prepare the text for the English version of the Guideline.
The policies of developing clinical practice guidelines are gradually evolving, and the current guideline is expected to berevised in the future. For the development of future guideline, some issues in the “Clinical Practice Guideline for Dementia
2017” have to be addressed. These will be discussed in the next revision. With anticipation to develop further improved andmore refined clinical practice guideline for dementia in the future, we embarked on preparing the English version of “Clinical
Practice Guideline for Dementia 2017”.
Kenji Nakajima
Chairman
Dementia Clinical Practice Guideline Development Committee
Japanese Society of Neurology

ii

Clinical Practice Guideline for Dementia 2017

Preface:
Clinical Practice Guideline for Dementia 2017, Japanese version
July 2017

The first “Treatment Guideline for Dementia” was published in 2002. Then in 2010, six academic societies; namely, theJapanese Society of Neurology, Japanese Society of Neurological Therapeutics, Japanese Society of Psychiatry and Neurology,
Japan Society for Dementia Research, Japan Geriatrics Society and Japanese Psychogeriatric Society, jointly developed the“Treatment Guideline for Dementia 2010” using the Clinical Question (CQ) format. Thereafter, with the addition of some
new knowledge, the “Treatment Guideline for Dementia 2010, Compact Edition” was published in 2012. Subsequent to thispublication, revision of the guideline was discussed at the Japanese Society of Neurology Guideline Executive Committee,
and revision of the guideline was decided in 2014.

[Target Readers of this Guideline]
Along with the 2002 and 2010 guidelines, the current guideline was prepared assuming that the readers are general
doctors in principle. However, the preparation work was done with the intention that this guideline will also be read bypeople other than doctors.

[Flow of Guideline Revision]
In 2014, after revision of the guideline was decided, chairman of the committee was elected and the office of guideline
preparation was placed in the chairman’s affiliated facility. In the same manner as the previous guideline, the revision task
was to be undertaken jointly by the six dementia-related societies mentioned above. Another five societies were invited toparticipate or collaborate. Committee members, research collaborators, and evaluation/coordination committee members
were elected from the six societies. The method for the revision work was discussed and decided at the committee, and it was
decided that each committee member would provide feedback to his/her academic society as the work progressed. Moreover,although the previous guidelines were called “treatment guidelines”, the contents also included diagnosis. Like the previous
guidelines, the revised guideline is not limited to treatment but covers the entire clinical practice from diagnosis to treatment
of dementia. Therefore, the revised guideline was developed as a “clinical practice guideline”
The Japanese Society of Neurology Guideline Executive Committee considered that although the current revision was inprinciple to be implemented according to the Minds Handbook for Clinical Practice Guideline Development 2014, thesystem was still not fully developed in Japan. As a policy to respond appropriately to the actual situation, it was decided thatthe specific methods for guideline development should be decided through discussions at the Dementia Clinical Practice
Guideline Development Committee.
Based on the above guideline development policy, the guideline: (1) used the CQ format; (2) confirmed the sources offunding for guideline preparation and managed the conflict of interest (COI) of committee members; (3) conducted literaturesearch using a uniform method; (4) discussed and decided evidence level and strength of recommendation based on the
GRADE system recommended by Minds 2014; (5) listened to opinions from patient groups; (6) for CQs in which“recommendation” statement was difficult to compose because the strength of recommendation could not be decided, an“Answer” statement was prepared; (7) the draft guideline was reviewed by the evaluation/coordination committee andexternal committees, and (8) the draft guideline was opened to the public, and comments were invited. Thereafter, the“Clinical Practice Guideline for Dementia” was finalized.

[Funding Sources and Conflict of Interest (COI)]
Funds necessary for preparation of this guideline were borne by the Japanese Society of Neurology. The funds provided
payment of expenses such as meeting room charges for committee meetings and transportation expenses for attending thecommittee, but did not provide remuneration for committee members and research collaborators for drafting manuscripts
and participation in meetings.
This guideline was prepared based on appropriate COI management according to the “Regulations related to preparationof Japanese Society of Neurology clinical practice guideline”, “Guide to preparation of Japanese Society of Neurology
clinical practice guideline” and “Rules for establishment and operation of Japanese Society of Neurology conflict of interest
committee”.

Prefaceiii

Every year, the chairman, vice chairman, committee members, research collaborators, and evaluation/coordinationcommittee members declared COI to the Chairman of Board of Directors of the Japanese Society of Neurology. Declaration
was based on the following criteria: board member renumeration, etc. (1 million yen or more); stocks, etc. (1 million yen or
more, or 5% or more of the total stocks); patent royalty (1 million yen or more); lecture fees, etc. (500,000 yen or more);manuscript fee, etc. (500,000 yen or more); contract research fee, joint research fees, etc. (2 million yen or more, 1 million
yen or more for the 2015 declaration); scholarship (incentive) donation, etc. (2 million yen or more, 1 million yen or more
for the 2015 declaration); endowed chair; provision of travel and gifts (50,000 yen or more).
Enterprises that declared COI are as follows:
Ajinomoto Co., Inc.; Astellas Pharma Inc.; AstraZeneca Co., Ltd.; Igaku-Shoin, Ltd.; Iset Co.; Eisai Co., Ltd.; MSD
K.K.; Otsuka Pharmaceutical Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Kyowa Hakko Kirin Co., Ltd.; GlaxoSmithKline
K.K.; Kowa Pharmaceutical Co., Ltd.; Social and Medical Corporation Kowakai Sapporo Shirakabadai Hospital; Medical
Corporation Seijinkai; Daiichi Sankyo Co., Ltd.; Sumitomo Dainippon Pharma Co., Ltd.; Takeda Pharmaceutical Co.,
Ltd.; Chugai Pharmaceutical Co., Ltd.; Nippon Boehringer Ingelheim Co., Ltd.; Nippon Medi-Physics Co., Ltd.; Novartis
Pharma K.K.; Bayer Yakuhin Ltd.; Pfizer Japan, Inc.; Mochida Pharmaceutical Co., Ltd.; Morimoto Pharma Co., Ltd.;
Janssen Pharmaceutical K.K.

[Process of Guideline Revision, Determination of Level of Evidence and Recommended Grade]
The first committee meeting was held in September 2014, and guideline development work began. First, we invited an
instructor from Minds to confirm the Minds policy for guideline development. We also invited external committee members
to participate, and decided the committee composition, guideline development policy, schedule, and items, and also decided
work sharing. The scope was discussed. The scope of this guideline was decided to cover from diagnosis to treatment andlong-term care for dementia. CQs would be prepared taking into consideration that the guideline is a reference material for
doctors to decide the best methods of clinical care. Comments would be written as general items according to the scope. CQs
were to be formulated with reference to PICO (P: patients, problem, population; I: interventions; C: comparisons, controls,comparators; O: outcomes).
Thereafter, the Guideline Executive Committee decided that this guideline is expected to be written concisely with
contents that support routine clinical care. To address this point, it was necessary to consider the user-friendliness ofguidelines; i.e., users can easily access the content they want to read from the table of contents. Initially, the plan was to limit
CQs to important clinical issues, while general clinical and epidemiological features are described under the preface of eachsection. However, the general features also would have to be presented in a way such that readers can easily find what theywant to read. Eventually, the plan was changed: all the contents are presented based on CQs. This format is similar to thatused in the previous version. For this reason, items concerning specific clinical issues are mixed with items describing generalclinical and epidemiological features, all under CQs (without the initially planned preface). Despite the adoption of thisformat in the present guideline, which is also partially due to consideration of continuity with the previous version, continuous
efforts have to be made to find the optimal format for use in the next revision.
We determined key words (KW) for the CQs and requested Professor Shinichi Abe at the Academic Information Center,
the Jikei University School of Medicine to perform search of literature. Since literature search for the previous guideline wasconducted until 2008, the search period for this guideline was in principle from 2009. Therefore, literature search from 2009
until April 2015 was conducted during May to July 2015. From the reference list obtained from the search, the referenceswere evaluated using evaluation sheets, not only by subcommittee members and research collaborators, but also bycollaborators recommended by each committee member. The level of evidence for each outcome and the body of evidence
were evaluated. For CQs that did not have sufficient references from this search process, the key words were changed asnecessary, and literature search was repeated. Furthermore, additional manual search was conducted when it was deemednecessary by the committee.
Regarding systematic reviews, the system for conducting quantitative systematic reviews including meta-analysis is not yet
adequately established. Therefore, following the policy of the Japanese Society of Neurology Guideline Executive Committee,
quantitative systematic review was a non-binding target, and would be conducted if feasible based on the judgment of eachcommittee member, while the main work was to conduct systematic literature search followed by qualitative systematic
review, as was done in previous guideline development. All the collaborators of this work will be acknowledged with gratitude
at the end of this message.
The level of evidence was evaluated not for individual reference, but by each outcome for studies grouped by study design,
such as randomized controlled trial and observational study. The body of evidence was evaluated for risk of bias, indirectness,iv

Clinical Practice Guideline for Dementia 2017

inconsistency, imprecision, and publication bias. In the next revision, the methods of conducting systematic review including
quantitative systematic review will be thoroughly examined before the work begins. Next, the responsible area for eachcommittee member and research coordinator was decided. Texts for CQs, recommendation statements, and comments andevidence were drafted, and the draft was discussed and decided by all members of the committee.
Table 1. Recommendation grade and level of confidence.
Recommendation grade:
1 (Strong): Recommend to “perform” or “not to perform”
2 (Weak): Propose to “perform” or “not to perform”
Strength of body of evidence:
A: Strong
B: Moderate
C: Weak
D: Very weak
The manuscript thus prepared was reviewed by the evaluation/coordination committee. In addition, external committee
members and persons related to patient organizations were invited to review the manuscript, and this guideline development
committee also participated to listen to their opinions.
Public comments were invited during August 1–21, 2016. The comments received were reviewed and corrections were
made. There were opinions pointing out the need for including more recent references, especially reports from Japan, after
April 2015, which exceeded the period of literature search set for this guideline. This was discussed at the guideline
development committee and additional manual search as needed was adopted. Since the public comments also included arequest to conduct another round of public comment invitation, public comments were again invited during November
16–30, 2016.

[Contents and Items in this Guideline]
This guideline also places importance on continuity, and the contents almost conform to the previous “Treatment
Guideline for Dementia 2010”. The guideline covers general items including definition, epidemiology, symptoms, assessment
scales, diagnosis, examinations, non-pharmacological treatments and pharmacotherapy, interventions for delirium andcoexisting diseases, risk factors, prevention, mild cognitive impairment, severity and interventions by severity, long-termcare, social resources, community liaison, ethics, and legal issues. In addition, for diseases of dementia by etiology, which aredealt with in the section of “Specific Diseases”, Alzheimer’s disease dementia, Lewy body disease, frontotemporal lobar
degeneration (FTLD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain dementia,
senile dementia of the neurofibrillary tangle type, vascular dementia, prion disease, and medical diseases are included.
For PSP, CBD, and Huntington’s disease, although management of motor symptoms is important, including these
discussions will further expand the volume of the guideline. Therefore, it was decided to limit discussions to cognitive
impairment only, which is in line with the previous guideline. Incidentally, a guideline for these diseases has been planned,
which includes motor symptoms and all other disorders except cognitive impairment. The guideline was in the process ofdevelopment as of November 2016.
Although molecular pathological classification shows that FTLD includes PSP and CBD, clinical differentiation of these
diseases is possible based on clinical symptoms and other tests. Furthermore, since FTLD, PSP, and CBD are specified
separately as designated intractable disease in Japan, these three diseases are handled as related diseases and described inseparate chapters in this clinical practice guideline. For differential use of terms between FTLD and frontotemporal dementia(FTD), and between CBD and corticobasal syndrome (CBS), please refer to the descriptions in the corresponding chapters.
On the other hand, since a separate guideline for prion disease has been developed (Clinical Practice Guideline for Prion
Disease 2014), prion disease is described briefly in this guideline while citing the Clinical Practice Guideline for Prion
Disease 2014.
In an evaluation questionnaire after publication of the previous guideline, there was opinion that medical diseases causedby vitamin deficiency should also be included. In this guideline, therefore, vitamin deficiency, hypothyroidism, neurosyphilis,
hepatic encephalopathy, and idiopathic normal pressure hydrocephalus (iNPH) are described. In the next revision, while
reviewing the target diseases to be included in the guideline, it seems necessary to discuss whether the above diseases/items
should be included.

Prefacev

[Names of therapeutic drugs and terms]
In principle, the terms used in the previous “Treatment Guideline for Dementia 2010” are adopted in this guideline.
<Names of therapeutic drugs>
Drug that are approved for dementia treatment in Japan and those that are used clinically even though they are notcovered by health insurance for dementia treatment in Japan are written in katakana. Drugs that are used only overseas but
not used in Japan are written in English.
<“Cognitive impairment” and “behavioral and psychological symptoms of dementia (BPSD)”>“Core symptom” of dementia is described as “cognitive impairment”. The term “peripheral symptoms” is not used, and is
replaced by “behavioral and psychological symptoms of dementia (BPSD)”. A combination of cognitive impairment an
BPSD is described as “dementia symptoms”.
<Description of severity>
Regarding the severity of dementia, the terms “severe” and “high level” are used almost synonymously for the advanced
stage. “Severe” was used in the Treatment Guideline for Dementia 2002 and 2010. Following these previous guidelines,“severe” is used in this guideline.
<Classification related to time of onset: “juvenile dementia”>
Depending on the time of onset, terms such as “juvenile dementia”, “pre-senile dementia”, “senile dementia”, “early-onset
dementia”, and “late-onset dementia” are used. There is opinion that use of the term “juvenile dementia” may not be desirable,
because the same term may denote different age groups [Japan Society for Dementia Research (Ed.): Textbook of Dementia,
2008]. However, the term “early-onset dementia” is used in administrative documents such as “Measures for early-onset
dementia” (2009) (Ministry of Health, Labor and Welfare), as well as the Orange Plan and the New Orange Plan. In
response to these developments, a patient aged under 65 years with dementia is referred to as “early-onset dementia” in thisguideline (see “Chapter 5: Various Systems and Social Resources for Supporting Persons with Dementia and Their Families;
C. Early-onset Dementia”).
<“Alzheimer’s disease” and “Alzheimer’s disease dementia”
The term “Alzheimer’s disease” may refer to the pathological state of the disease or may be used to describe the clinicalsyndrome when dementia symptoms due to “Alzheimer’s disease” have become evident. According to the National Instituteon Aging and Alzheimer’s Association (2011), “Alzheimer’s disease” is defined as a term encompassing the underlying
pathophysiological processes, and “Alzheimer’s disease” is distinguished from “Alzheimer’s disease dementia” which describes
the state of dementia caused by “Alzheimer’s disease”. In Japan, “Alzheimer’s disease dementia” has been used from the past
as a term to describe the state of dementia considered to be caused by “Alzheimer’s disease”. Therefore, in this guideline, theterm “Alzheimer disease dementia” is used for dementia that is considered to have occurred based on the pathologicalbackground of “Alzheimer’s disease”. However, this guideline does not differentiate between “Alzheimer disease dementia”(diagnosed from clinical features) and “Alzheimer disease dementia caused by Alzheimer’s disease” (evidence that dementia
is caused by Alzheimer’s disease has been confirmed), because this differentiation has little utility in clinical practice.
<Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)>
In DSM-5 published by the American Psychiatric Association in 2013, the term “neurocognitive disorder” was introduced.
This term includes “delirium” and “major and mild neurocognitive disorder”. The Japanese translations for “major and mild
neurocognitive disorder” are “dementia (DSM-5)” and “mild cognitive impairment (DSM-5)”, respectively.
<“Mild cognitive impairment” and “MCI”>
In this guideline, “mild cognitive impairment” and “MCI” are described as ”mild cognitive impairment (MCI)”.
<Others>
Terms including “senile dementia of the neurofibrillary tangle type (SD-NFT)”, “tangle-predominant senile dementia/
NFT-predominant form of senile dementia”, “tangle only dementia”, and “primary age-related tauopathy (PART)” are useduniformly in the guideline.

vi

Clinical Practice Guideline for Dementia 2017

[Using this clinical practice guideline in clinical care for dementia]
This guideline provides reference materials to support the clinical practice and care for dementia with the purpose toimprove clinical practice for dementia, and does not intend to constrain clinical practice for dementia in the clinical setting.
With future developments and changes in medical care and research, as well as diversification of persons with dementia andthe environment surrounding these persons, guidelines are expected to change over time. This guideline does not restrict thedecision of clinicians over treatment, neither does it stipulate medical treatment in response to changes in the clinical setting.
Sometimes the recommendations in this guideline may not apply. There are cases where the physician in charge may perform
treatments that deviate from the descriptions in this guideline, and cases where the deviation may be appropriate. In actual
clinical practice, it is important to formulate an individualized treatment plan that responds to the dementia of each patient,
without being restricted by the contents of this guideline. In addition, the contents described in this guideline do not serveas grounds for medical lawsuits.

[Promotion of utilization of the guideline, future plans including the next revision, and evaluation]
In order to promote the utilization of this guideline, the guideline is scheduled to be introduced and publicized by postingon the websites of the academic societies that participated in guideline development, presented at scientific conferences andother meetings of the academic societies, and published in scientific journals.
For the convenience of readers, a compact edition has been published both for the Treatment Guideline for Dementia
2002 and 2010 editions. For this guideline also, publication of a compact version will be considered. Furthermore, theJapanese Society of Neurology has published the English version of other clinical practice guideline, and we hope that thepossibility of publishing the English version of the Clinical Practice Guideline for Dementia will be discussed at the guideline
development committee.
In the case that addition or correction is necessary due to new knowledge obtained after publication of this guideline,
additional or revised CQ will be prepared as a supplement and posted on the society website. In addition, the JapaneseSociety of Neurology has a policy of revising clinical practice guidelines every five years. This guideline development
committee will also consider the next revision and composition of the next guideline development committee, and the results
will be submitted to the Japanese Society of Neurology Guideline Executive Committee for deliberation.
The previous two guidelines for the treatment of dementia were evaluated by an evaluation committee set up at theJapanese Society of Neurology. It is anticipated that the current Clinical Practice Guideline for Dementia 2017 will also be
evaluated by an evaluation committee.

[Acknowledgment to committee members and research collaborators]
Revision and development of the present guideline were undertaken with the collaboration of six dementia-related
associations. I would like to express my gratitude to all members of the committee and the research collaborators for their
participation in the committee and for their great efforts despite their busy schedules. This guideline was developed with thesupport of many colleagues such as evaluation/coordinating committee members, external committee members, andcollaborators. I would like to thank them all for their collaboration. I would also like to thank Ms. Noriko Ono and Ms.
Yoriko Matsushita from the Tokyo Branch of the Alzheimer’s Association Japan for their opinions in preparing the guideline.
Furthermore, I would like to express my sincere appreciation to those who have provided many valuable comments in theinvitation of public comments. I would also like to thank staff members of Minds for their advice.
Kenji Nakajima
Chairman
Dementia Clinical Practice Guideline Development Committee
Japanese Society of Neurology

Prefacevii

LIST OF AUTHORS
Editing Supervisors:
Japanese Society of Neurology
Japanese Society of Neurological Therapeutics, Japanese Society of Psychiatry and Neurology, Japan Society for Dementia
Research, Japan Geriatrics Society, Japanese Psychogeriatric Society

Editors:
Dementia Clinical Practice Guideline Development Committee
Participating societies: Japanese Society of Neurology, Japanese Society of Neurological Therapeutics, Japanese Society ofPsychiatry and Neurology, Japan Society for Dementia Research, Japan Geriatrics Society, Japanese Psychogeriatric Society

Chairman
Kenji Nakajima: Matsue Medical Center

Vice-chairman
Hidekazu Tomimoto: Department of Neurology, Mie University

Committee members
Ikuko Aeba: Department of Neurology, Higashinagoya National Hospital
Masahiro Akishita: Geriatric Medicine, University of Tokyo Hospital
Shuichi Awata: Tokyo Metropolitan Institute of Gerontology
Setsu Iijima: National Rehabilitation Center for Persons with Disabilities
Takeshi Ikeuchi: Department of Molecular Genetics, Brain Research Institute, Niigata University
Manabu Ikeda: Department of Psychiatry, Osaka University Graduate School of Medicine
Masafumi Ihara: Division of Cerebrovascular Medicine and Neurology, National Cerebral and Cardiovascular Center
Hiroaki Kazui: Department of Psychiatry, Osaka University Graduate School of Medicine
Nobuo Sanjo: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Mikio Shoji: Department of Neurology, Hirosaki University Graduate school of Medicine
Kyoko Suzuki: Department of Clinical Neuroscience, Yamagata University Graduate School of Medical Science
Makio Takahashi: Department of Neurology, Osaka Red Cross Hospital
Akira Tamaoka: Graduate School of Comprehensive Human Sciences, University of Tsukuba
Seishi Terada: Department of Neuropsychiatry, Okayama University
Aki Nakanishi: Department of Neurology, Osaka City Kosaiin Hospital
Haruo Hanyu: Geriatric Medicine, Tokyo Medical University
Hideo Hara: Division of Neurology, Saga University
Katsuyoshi Mizukami: Faculty of Health and Sport Sciences, University of Tsukuba
Yukihiko Washimi: Department of Brain Function Examination, National Center for Geriatrics and Gerontology
Hirohisa Watanabe: Brain and Mind Research Center, Nagoya University
Kenji Wada: Division of Neurology, Tottori University

Research Collaborators
Haruhiko Akiyama: Dementia Research Project, Tokyo Metropolitan Institute of Medical Science
Tadashi Adachi: Division of Neurology, Tottori University
Atsushi Iwata: Department of Neurology, University of Tokyo
Tomomi Ogihara: Department of Psychiatry, Shinshu University
Naoto Kamimura: Department of Neuropsychiatry, Kochi University
Takayoshi Shimohata: Department of Neurology, Brain Research Institute, Niigata University
Kazuko Hasegawa: Department of Neurology, Sagamihara National Hospital
Osamo Yokoto: Kinoko Espoir Hospitalviii

Clinical Practice Guideline for Dementia 2017

Evaluation/Coordination Committee Members
Takashi Asada: Center for Brain Integration Research, Tokyo Medical and Dental University
Naoji Amano: Okaya City Hospital
Hiroyuki Arai: Institute of Development, Aging and Cancer, Tohoko University
Fukashi Udaka: Sumitomo Hospital
Kochi Okamoto: Geriatrics Research InstituteShun Shimohama: Department of Neurology, Sapporo Medical University
Masatoshi Takeda: Aino University
Akira Honma: Otafuku Monowasure Clinic
Masahito Yamada: Department of Neurology and Neurobiology of Aging, Kanazawa University(Late)Dr. Hideo Mori: Department of Neurology, Juntendo University Koshigaya Hospital

External Committee Member
Masayo Kojima: Department of Medical Education, Nagoya City University

Collaborators
Yusuke Yakushiji: Division of Neurology, Saga University
Makoto Eriguchi: Division of Neurology, Saga University
Masafumi Kosugi: Division of Neurology, Saga University
Jun Tanaka: Division of Neurology, Saga University
Kohie Suzuyama: Department of Neurology, Saga University
Yasuo Harigaya: Japanese Red Cross Maebashi Hospital
Etsuro Matsubara: Department of Neurology, Oita University
Noriyuki Kimura: Department of Neurology, Oita University
Takeshi Kawarabayashi: Department of Neurology, Hirosaki University
Masaki Ikeda: Department of Neurology, Guma University
Kokoro Ozaki: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Maya Higuma: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Yoko Ito: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Fumiko Furukawa: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Takefumi Sato: Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Ryo Tagawa: Tagawa Kusunoki Clinic
Yumi Kameyama: Geriatric Medicine, University of Tokyo HospitalMichihito Masuda: Department of Neurology, Nagoya University
Kazunori Imai: Department of Neurology, Nagoya University

Prefaceix

Table of Contents
Publication of the English Version of “Clinical Practice Guideline for Dementia 2017”
Preface: Clinical Practice Guideline for Dementia 2017, Japanese version

Chapter 1

Overview of Dementia: Epidemiology, Definitions, Terms

CQ 1-1
CQ 1-2
CQ 1-3
CQ 1-4
CQ 1-5
CQ 1-6
CQ 1-7
CQ 1-8What are the diagnostic criteria for dementia?...........................................................................................  2
What other terms are related to dementia?.................................................................................................  3
What are the causes of dementia and how are they classified?....................................................................  5
What pathological conditions should be differentiated from dementia?.....................................................  6
What is the prevalence of dementia in Japan?............................................................................................  7
Are there changes in prevalence depending on subtype of dementia?.........................................................  8
Is the disease duration of dementia getting longer?....................................................................................  9
What is the pathological background of dementia?.................................................................................... 10

Chapter 2

Syndrome, Rating Scales, Tests, Diagnosis

CQ 2-1
CQ 2-2
CQ 2-3
CQ 2-4

What kinds of cognitive function impairment are found in dementia? ..................................................... 15
What are the behavioral and psychological symptoms of dementia (BPSD)? ............................................ 17
What are the useful scales for assessing cognitive impairment in dementia? ............................................. 18
What are the useful rating scales for behavioral and psychological symptoms of dementia (BPSD),
activities of daily living (ADL), and global severity?.................................................................................. 19
How is quality of life (QOL) evaluated in persons with dementia? ........................................................... 21
How is primary progressive aphasia (PPA) classified and evaluated?.......................................................... 22
How is dementia diagnosed and differentiated?......................................................................................... 24
How are imaging examinations carried out in dementia?.......................................................................... 25
What are the useful blood and cerebrospinal fluid tests for the diagnosis of dementia?............................. 27
Which physical and neurological findings require attention when diagnosing dementia?.......................... 29
What are the drugs that affect the diagnosis of dementia?......................................................................... 30
Are there useful genetic tests for the diagnosis of dementia?...................................................................... 32

CQ 2-5
CQ 2-6
CQ 2-7
CQ 2-8
CQ 2-9
CQ 2-10
CQ 2-11
CQ 2-12Chapter 3 Treatment
A | Overview of Treatment
CQ 3A-1
CQ 3A-2
CQ 3A-3
CQ 3A-4
CQ 3A-5
CQ 3A-6
CQ 3A-7-1
CQ 3A-7-2

How should interventions and support be given following a diagnosis of dementia?................................. 34
How should pharmacotherapy, non-pharmacologic interventions and care be provided during treatment
of dementia? .............................................................................................................................................. 35
What are the principles and precautions of pharmacotherapy in older people with dementia?................... 37
What are the adverse events of psychotropic drugs [such as falls, declined activity of daily living (ADL),
cognitive impairment, and aspiration pneumonia]?.................................................................................... 38
What are the treatment procedures when using pharmacotherapy for dementia?...................................... 39
What are the adverse events due to cholinesterase inhibitors and NMDA receptor antagonists, and whatshould be done in case of these events?..................................................................................................... 40
What are the non-pharmacological therapies for dementia?...................................................................... 42
What are the symptoms that respond to non-pharmacological therapies for dementia?............................. 43

B | Treatment for behavioral and psychological symptoms of dementia (BPSD)
CQ 3B-1
CQ 3B-2
CQ 3B-3
CQ 3B-4
CQ 3B-5x

What are the effective non-pharmacological therapies and pharmacotherapy for anxiety?........................ 44
What are the effective non-pharmacological therapies and pharmacotherapy for agitation?..................... 46
What are the effective non-pharmacological therapies and pharmacotherapy for hallucinations anddelusions?................................................................................................................................................... 48
What are the effective non-pharmacological therapies and pharmacotherapy for depression?.................... 50
What are the effective non-pharmacological therapies and pharmacotherapy for wandering?.................... 52

Clinical Practice Guideline for Dementia 2017

CQ 3B-6
CQ 3B-7

What are the effective non-pharmacological therapies and pharmacotherapy for sleep disturbance(excluding REM sleep behavior disorder)? ................................................................................................ 54
What are the effective non-pharmacological therapies and pharmacotherapy for apathy?.......................... 56

C | Interventions for Coexisting Diseases
CQ 3C-1
CQ 3C-2
CQ 3C-3
CQ 3C-4
CQ 3C-5
CQ 3C-6
CQ 3C-7
CQ 3C-8
CQ 3C-9
CQ 3C-10
CQ 3C-11
CQ 3C-12
CQ 3C-13

How is delirium treated?............................................................................................................................ 58
How epilepsy including seizures should be treated in patients with dementia?.......................................... 59
What are the interventions for dysphagia (including prevention of aspiration pneumonia)?...................... 61
What are the interventions for eating disorder and undernutrition?........................................................... 63
What are the interventions for sarcopenia and frailty?.............................................................................. 64
What are the interventions and preventive measures for falls and fractures?.............................................. 65
What are the interventions for pressure ulcers?.......................................................................................... 67
What are the approaches to treat acute physical illness?............................................................................. 68
How should decisions be made regarding invasive examinations and treatments including dialysis anddental treatment?....................................................................................................................................... 69
What are the interventions for edema?....................................................................................................... 71
What are the interventions for urinary disorder?....................................................................................... 72
What are the interventions for constipation?.............................................................................................. 74
How should diabetes, hypertension and other lifestyle-related diseases be managed?................................ 75

Chapter 4 Clinical Course and Treatment
A | Risk Factors and Protective Factors of Dementia
CQ 4A-1
CQ 4A-2
CQ 4A-3
CQ 4A-4
CQ 4A-5
CQ 4A-6
CQ 4A-7
CQ 4A-8
CQ 4A-9
CQ 4A-10
CQ 4A-11
CQ 4A-12

What are the risk factors and protective factors of dementia?..................................................................... 78
Are hypertension control and antihypertensive drugs effective in dementia prevention? .......................... 80
Is diabetes control effective in dementia prevention? ................................................................................. 82
Is treatment for dyslipidemia effective for dementia prevention? ............................................................... 83
Does metabolic syndrome worsen dementia? ............................................................................................ 85
Does smoking worsen dementia? .............................................................................................................. 86
Is exercise effective in preventing dementia? .............................................................................................. 87
Are leisure activities, social participation, mental activities, cognitive training, and artistic activities suchas music effective in preventing dementia and cognitive decline in older people?....................................... 88
Are there dietary factors associated with dementia? ................................................................................ 90
Is moderate drinking effective in preventing cognitive decline and dementia? .......................................... 91
Does sleep apnea syndrome worsen cognitive function? ............................................................................ 92
Are depression and bipolar disorder risk factors for dementia? .................................................................. 93

B | Mild Cognitive Impairment
CQ 4B-1
CQ 4B-2
CQ 4B-3
CQ 4B-4
CQ 4B-5
CQ 4B-6
CQ 4B-7

What are the prevalence and incidence of mild cognitive impairment (MCI)? ......................................... 94
What is the conversion rate from mild cognitive impairment (MCI) to dementia, and the reversion ratefrom MCI to cognitive normal? ................................................................................................................ 95
What are the useful biomarkers for predicting conversion of mild cognitive impairment (MCI) to
dementia?................................................................................................................................................... 96
What rating scales are recommended when mild cognitive impairment (MCI) is suspected? ................... 98
How is mild cognitive impairment (MCI) diagnosed? .............................................................................. 99
Are there methods to prevent progression from mild cognitive impairment (MCI) to dementia?..............101
What kinds of guidance and support are available for people with mild cognitive impairment (MCI)?.....103

C | Disease Severity and Interventions According to Severity
CQ 4C-1
CQ 4C-2
CQ 4C-3What kind of guidance and support can be given to persons with mild to moderate dementia?................104
What kind of guidance and support can be given to caregivers of persons with mild to moderatedementia? ..................................................................................................................................................106
What kind of guidance and support can be given to persons with severe dementia?..................................107xi

CQ 4C-4
CQ 4C-5

What kind of guidance and support can be given to caregivers of persons with severe dementia?..............108
How should end-of-life care be given to persons with dementia?...............................................................109

Chapter 5 Various Systems and Social Resources for Supporting Persons with Dementia
and Their Families
A | Various Systems and Social Resources for Supporting Medical and Long-term Care for Persons
with Dementia
CQ 5A-1
CQ 5A-2
CQ 5A-3
CQ 5A-4
CQ 5A-5

What are the functions and roles of the medical center for dementia?.......................................................112
What are the roles of certified dementia support doctors? ......................................................................... 114
What are the roles of long-term care insurance system for persons with dementia and theircaregivers?.................................................................................................................................................. 115
What are the functions and roles of Community General Support Center?............................................... 117
What are the functions and roles of the initial-phase intensive support team for dementia?...................... 118

B | Advocacy for People with Dementia
CQ 5B-1
CQ 5B-2
CQ 5B-3

Is it possible to evaluate the abilities of judgment and decision-making in persons with dementia?........... 119
How can the adult guardianship system be used to protect the rights of people with dementia?................121
What role does the Prevention of Elder Abuse Act play in preventing abuse to persons
with dementia? ..........................................................................................................................................123

C | Early-onset Dementia
CQ 5C-1
CQ 5C-2
CQ 5C-3
CQ 5C-4

What is early-onset dementia?....................................................................................................................125
What are the support systems to help persons with early-onset dementia with their economic
challenges?.................................................................................................................................................127
What are the systems that can be used to support the living of persons with early-onset dementia? .........129
What kind of consultation support is available for persons with early-onset dementia?.............................131

D | Road Traffic Act
CQ 5D-1

What should be done if one finds that a person diagnosed with dementia holds a driver license and is
still driving?...............................................................................................................................................132

Chapter 6

Alzheimer’s Disease Dementia

CQ 6-1
CQ 6-2
CQ 6-3
CQ 6-4
CQ 6-5
CQ 6-6
CQ 6-7
CQ 6-8
CQ 6-9
CQ 6-10What are the features and key points of diagnosis for neuropsychiatric symptoms in Alzheimer’s
disease dementia?.......................................................................................................................................137
What are the diagnostic criteria for Alzheimer’s disease dementia?............................................................139
What are the characteristic image findings of Alzheimer’s disease dementia?............................................140
Is APOE genetic testing useful for the diagnosis of Alzheimer’s disease dementia?....................................142
What are the useful biomarkers for the diagnosis of Alzheimer’s disease dementia? ..................................143
Is amyloid PET examination useful for the diagnosis of Alzheimer’s disease dementia? ............................ 145
What are the pharmacotherapy and treatment algorithms for Alzheimer’s disease dementia? ...................147
What are the effects of non-pharmacological therapies for Alzheimer’s disease dementia?......................... 151
What are the key points in care for Alzheimer’s disease dementia?............................................................ 153
What kind of social support is available for Alzheimer’s disease dementia?................................................154

Chapter 7

Dementia with Lewy bodies

CQ 7-1

What are the diagnostic criteria and key points for early diagnosis of dementia with Lewy bodies(DLB)?.......................................................................................................................................................156
What are the clinical and pathological differences between dementia with Lewy bodies (DLB) andParkinson’s disease with dementia (PDD)?................................................................................................. 157
What are the characteristic laboratory and imaging biomarker of dementia with Lewy bodies(DLB)? ...................................................................................................................................................... 159
What are the clinical course and prognosis of dementia with Lewy bodies (DLB)?................................... 161

CQ 7-2
CQ 7-3
CQ 7-4xii

Clinical Practice Guideline for Dementia 2017

CQ 7-5
CQ 7-6

CQ 7-9
CQ 7-10What is the treatment strategy planned for dementia with Lewy bodies (DLB)?.......................................162
Are there any drugs for the treatment of cognitive impairment in dementia with Lewy bodies(DLB)?.......................................................................................................................................................163
Are there any treatments for behavioral and psychological symptoms of dementia (BPSD) and REM
sleep behavior disorder (RBD) in dementia with Lewy bodies (DLB)?......................................................165
Are there any treatments for autonomic symptoms (such as orthostatic hypotension, constipation,
sweating, urination disorder) in dementia with Lewy bodies (DLB)?.........................................................167
What are the suitable treatments for parkinsonism in dementia with Lewy bodies (DLB)?.......................168
What are the non-pharmacological interventions for dementia with Lewy bodies (DLB)?........................169

Chapter 8

Frontotemporal Lobar Degeneration

CQ 8-1

What are the diagnostic key points and diagnostic criteria for frontotemporal lobar degeneration(FTLD)?.................................................................................................................................................... 174
What are the characteristics of image findings of frontotemporal lobar degeneration (FTLD)?.................176
Are there effective drugs for frontotemporal lobar degeneration (FTLD)?.................................................178
Are there effective non-pharmacological therapies for frontotemporal lobar degeneration (FTLD)?..........180
What kind of instructions should be given to families and caregivers of frontotemporal lobar
degeneration (FTLD) patients?..................................................................................................................183

CQ 7-7
CQ 7-8

CQ 8-2
CQ 8-3
CQ 8-4
CQ 8-5Chapter 9

Progressive Supranuclear Palsy (PSP)CQ 9-1
CQ 9-2

What are the features of dementia symptoms in progressive supranuclear palsy (PSP)?.............................187
Are there useful therapies for cognitive impairment in progressive supranuclear palsy (PSP)? ...................188

Chapter 10

Corticobasal Degeneration

CQ 10-1

What are the features of cognitive impairment in corticobasal degeneration (CBD), and what are
the test methods? ...................................................................................................................................... 191
Are there effective pharmacological and non-pharmacological therapies for cognitive impairment
in corticobasal degeneration (CBD)? .........................................................................................................192

CQ 10-2

Chapter 11

Argyrophilic Grain Dementia

CQ 11-1
CQ 11-2
CQ 11-3What is the frequency of argyrophilic grain disease (AGD)?......................................................................194
How is a clinical diagnosis made for argyrophilic grain dementia?............................................................195
What kinds of treatments are available for argyrophilic grain dementia? ..................................................196

Chapter 12 Senile Dementia of the Neurofibrillary Tangle TypeCQ 12-1

What kind of disease is senile dementia of the neurofibrillary tangle type (SD-NFT)?.............................198

Chapter 13

Huntington Disease

CQ 13-1

What are the features and diagnosis of cognitive symptoms in Huntington disease?.................................202

Chapter 14

Vascular Dementia

CQ 14-1
CQ 14-2
CQ 14-3
CQ 14-4
CQ 14-5
CQ 14-6
CQ 14-7
CQ 14-8
CQ 14-9
CQ 14-10

What are the diagnostic criteria for vascular dementia (VaD)?.................................................................. 204
How are the types of vascular dementia (VaD) classified?..........................................................................205
What are the imaging features of vascular dementia (VaD)? .................................................................... 206
What is the condition when vascular dementia (VaD) coexists with Alzheimer’s disease dementia?......... 208
What are the clinical course and prognosis of vascular dementia (VaD)?.................................................. 209
What are the systemic complications and associated symptoms of vascular dementia (VaD)? ..................210
What are the risk factors for vascular dementia (VaD) and how are they controlled?................................. 211
What is antithrombotic therapy for vascular dementia (VaD)?..................................................................213
Are there effective drugs for cognitive impairment in vascular dementia (VaD)? ...................................... 215
What is the clinical position of cerebral amyloid angiopathy (CAA)?........................................................ 217

xiii

Chapter 15 Prion Disease
CQ 15-1
CQ 15-2
CQ 15-3
CQ 15-4
CQ 15-5

What are the clinical features of sporadic Creutzfeldt-Jakob disease (CJD)?............................................. 220
What are the electroencephalographic, cerebrospinal fluid, and MRI findings of sporadic
Creutzfeldt-Jakob disease (CJD)? ..............................................................................................................221
What are the types and features of genetic prion disease in Japan?........................................................... 222
What are the types and features of acquired (infectious) prion disease in Japan?.......................................223
What are the infection control measures and effective sterilization methods for prion disease? ................224

Chapter 16

Medical Diseases and Others

CQ 16-1
CQ 16-2
CQ 16-3
CQ 16-4
CQ 16-5

What are the features of cognitive impairment due to vitamin deficiency?............................................... 226
What are the features of cognitive impairment due to hypothyroidism?................................................... 228
What are the features of cognitive decline due to neurosyphilis?...............................................................229
What are the features of cognitive impairment caused by hepatic encephalopathy (HE)?..........................230
What are the features, diagnosis, and treatment strategies for dementia symptoms of idiopathic normalpressure hydrocephalus (iNPH)? ...............................................................................................................231

xiv

Clinical Practice Guideline for Dementia 2017

Chapter 1
Overview of Dementia: Epidemiology,
Definitions, Terms

CQ 1-1

What are the diagnostic criteria for dementia?
AnswerRepresentative diagnostic criteria for dementia include the International Statistical Classification of Diseases andRelated Health Problems, Tenth Revision (ICD-10) published by the World Health Organization, the diagnostic criteria
proposed by the National Institute on Aging–Alzheimer’s Association Workgroup (NIA-AA), and Diagnosis andStatistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association.

Comments and evidence
In ICD-10 (1993), dementia is described as “a syndrome due to disease of the brain, usually of a chronic or progressive
nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation,
comprehension, calculation, learning capacity, language, and judgement”. Detailed diagnostic criteria are provided in
ICD-10 1).
In the diagnostic criteria of dementia proposed by the NIA-AA (2011), impaired ability to acquire or remember new
information, impaired executive function, impaired visuospatial abilities, and impaired language functions are treatedequally, and the diagnostic criteria include behavioral impairment and subtypes of dementia other than Alzheimer’s disease
dementia 2).
DSM-5 (2013) introduced a new term, “neurocognitive disorders”, and replaces the term “dementia” with “major
neurocognitive disorder”. DSM-5 details six cognitive domains that may be affected in neurocognitive disorders. A diagnosis
of major neurocognitive disorder (dementia) requires evidence of significant decline in one or more of the following cognitive
domains: complex attention, executive function, learning and memory, language, perceptual-motor function, and social
cognition, and that the cognitive deficits interfere with independence in activities of daily living 3). DSM-5 provides new
information sources for these criteria.

▪ References
1) World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th Revision. Geneva: World HealthOrganization; 1993.
2) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
3) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American
Psychiatric Association; 2013.

▪ Search formula
PubMed search: July 3, 2015 (Friday), August 8, 2015 (Friday)#1 ((“Dementia/diagnosis” [Majr] OR “Dementia/classification” [Majr] OR dementia [TI]) AND (definition* [TIAB] OR criteria [TIAB] OR
concept* [TIAB])) OR ((“Cognition Disorders/diagnosis” [Majr] OR “Cognition Disorders/classification” [Majr] OR cognition disorder* [TI] OR“cognitive dysfunction” [TI]) AND (definition* [TIAB] OR criteria [TIAB] OR concept* [TIAB]))
Ichushi search: July 3, 2015 (Friday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive disorder/MTH OR Cognitive disorder /TI) AND ((((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionucleotide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Definition/TI
OR Criteria/TI)) OR (Term/TI OR Synonym/TI OR Synonym/TI OR Synonym/TI OR Disease name/TI OR Name/TI OR History/TI OR
Origin/TI))

2

Clinical Practice Guideline for Dementia 2017

CQ 1-2

What other terms are related to dementia?
Answer
The DSM-5 introduces the new terms of major neurocognitive disorder (replacing dementia) and mild neurocognitive
disorder (replacing mild cognitive impairment or MCI). Other terms include subjective cognitive impairment (SCI) andsubjective cognitive decline (SCD).

Comments and evidence
The National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroup classifies Alzheimer’s disease into threedisease stages based on the pathophysiological process of Alzheimer’s disease: preclinical Alzheimer’s disease 1), mild cognitive
impairment (MCI) due to Alzheimer’s disease 2), and dementia due to Alzheimer’s disease (Alzheimer’s disease dementia) 3).
In addition, the preclinical stage is divided into stage 1 (asymptomatic amyloidosis), stage 2 (amyloidosis + neurodegeneration),and stage 3 (amyloidosis + neurodegeneration + subtle cognitive decline).
In DSM-5 (2013), the new term “neurocognitive disorders” was introduced. Neurocognitive disorders are classified intodelirium, major neurocognitive disorder, and mild neurocognitive disorder. DSM-5 details the diagnostic criteria for thesethree types 4).
Vascular cognitive impairment (VCI) is a concept that comprehensively encompasses a range of cognitive deficits frommild cognitive impairment caused by cerebrovascular disorder to vascular dementia (VaD) 5). Vascular cognitive disorder(VCD) has been proposed as a diagnostic category that includes VCI, post-stroke dementia, genetic VaD [cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral autosomal recessive
arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), Binswanger disease, and Alzheimer’s disease
with VaD 6). (See CQ14-1).
Multiple definitions have been proposed for mild cognitive impairment, and the concept has undergone changes. Apartfrom the diagnostic criteria proposed by Peterson et al. 7) in 2004, diagnostic criteria have been provided in DSM-5, NIA-AA
and ICD-10 8), all of which differ to some extent (see CQ4B-5). In addition to mild cognitive impairment, other conditions
such as age-associated memory impairment (AAMI), aging-associated cognitive decline (AACD), mild cognitive disorder(MCD), mild neurocognitive decline (MNCD), and cognitive impairment no dementia (CIND) have been included in theconcept of prodromal stage of dementia9).

▪ References
1) Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 280-292.
2) Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the
National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3):270-279.
3) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
4) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American
Psychiatric Association; 2013.
5) Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive
impairment harmonization standards. Stroke. 2006; 37(9): 2220-2241.
6) Roman GC, Sachdev P, Royall DR, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment andvascular dementia. J Neurol Sci. 2004; 226(1-2): 81-87.
7) Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004; 256(3): 183-194.
8) World Health Organization. International Statistical Classification of Diseases and Related Health problems. 10th Revision. Geneva: World HealthOrganization; 1993.
9) “Treatment Guideline for Dementia” Preparation Joint Committee (Ed.) Japanese Society of Neurology (Supervision). Treatment Guideline for
Dementia 2010. Tokyo: Igaku Shoin; 2010. (In Japanese)

Chapter 1

3▪ Search formula
PubMed search: July 3, 2015 (Friday), August 8, 2015 (Friday)#1 ((“Dementia/diagnosis” [Majr] OR “Dementia/classification” [Majr] OR dementia [TI]) AND (definition* [TIAB] OR criteria [TIAB] OR
concept* [TIAB])) OR ((“Cognition Disorders/diagnosis” [Majr] OR “Cognition Disorders/classification” [Majr] OR cognition disorder* [TI] OR“cognitive dysfunction” [TI]) AND (definition* [TIAB] OR criteria [TIAB] OR concept* [TIAB]))
Ichushi search: July 3, 2015 (Friday)#1 (Dementia/MTH OR Dementia/TI OR Cognition disorder/MTH OR Cognition disorder /TI) AND ((((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionucleotide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Definition/TI
OR Criteria/TI)) OR (Term/TI OR Synonym/TI OR Synonym/TI OR Synonym/TI OR Disease name/TI OR Name/TI OR History/TI OR
Origin/TI))

4

Clinical Practice Guideline for Dementia 2017

CQ 1-3What are the causes of dementia and how are they classified?
AnswerDementia is caused by a variety of diseases and conditions. In DSM-5, the etiological subtypes of major neurocognitive
disorder (dementia) comprise Alzheimer’s disease, frontotemporal lobar degeneration, Lewy body disease, vascular disease,
traumatic brain injury, substance/drug use, HIV infection, prion disease, Parkinson’s disease, Huntington’s disease, othermedical conditions, multiple etiologies, and unspecified.

Comments and evidence
Many diseases and conditions may cause dementia or dementia-like symptoms 1).
ICD-10 classifies dementia into Alzheimer’s disease dementia, vascular dementia, dementia in other diseases classified
elsewhere, and unspecified dementia 2).
In the neurocognitive disorder category of DSM-5, the etiological subtypes of major neurocognitive disorder (dementia)
and minor neurocognitive disorder (mild cognitive impairment) are listed as follows: Alzheimer’s disease, frontotemporallobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance/drug use, HIV infection, priondisease, Parkinson’s disease, Huntington’s disease, other medical conditions, multiple etiologies, and unspecified 3).
Among these causative diseases and conditions, some neurosurgical diseases such as normal pressure hydrocephalus andchronic subdural hematoma, as well as some medical diseases such as hypothyroidism and vitamin B12 deficiency are being
treated under the concept of treatable dementia, and early diagnosis and appropriate treatments and interventions aredesirable.

▪ References
1) “Treatment Guideline for Dementia” Preparation Joint Committee (Ed.) Japanese Society of Neurology (Supervision). Treatment Guideline for
Dementia 2010. Tokyo: Igaku Shoin; 2010: 4-7. (In Japanese)
2) World Health Organization. International Statistical Classification of Diseases and Related Health problems. 10th Revision. Geneva: World HealthOrganization; 1993.
3) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American
Psychiatric Association; 2013.

▪ Search formula
PubMed search: July 3, 2015 (Friday)#1 (“Dementia/etiology” [Majr] OR (dementia [TI] AND etiology) OR “Cognition Disorders/etiology” [Majr] OR ((cognition disorder* [TI] OR“cognitive dysfunction” [TI]) AND etiology)) AND (“Risk Factors” [Majr] OR risk factor* [TI])
Ichushi search: July 3, 2015 (Friday)#1 (Dementia/MTH OR Dementia /TI OR Cognitive impairment/MTH OR Cognitive impairment /TI) AND ((SH = Etiology) OR Etiology/TI
or Cause/TI) AND ((Risk factor/TH OR Risk factor /TI OR Risk/TI) AND (PT = Review)) OR ((SH = Etiology) AND (Etiology /TI OR Cause/
TI))

Chapter 1

5

CQ 1-4

What pathological conditions should be differentiated from dementia?
AnswerPathological conditions that should be differentiated from dementia, especially Alzheimer’s disease dementia, include
normal cognitive decline accompanying aging (physiological amnesia), delirium, depression, other learning disabilities,
and mental retardation.

Comments and evidence
DSM-5 lists pathological conditions that should be differentiated from dementia as follows: normal cognitive decline
accompanying aging, delirium, depression, other learning disabilities, and mental retardation 1). Important points fordifferentiation of Alzheimer’s disease dementia from the above disorders are summarized below.

1. Physiological amnesia accompanying aging
In general, physiological amnesia is differentiated from dementia by partial forgetfulness of past experience, with no or
slow progression, preserved self-recognition of the disability, preserved orientation to time, and little disturbance in activities
of daily living.

2. Delirium
Delirium is an acute psychiatric symptom accompanied by impaired consciousness, causing difficulties to focus andmaintain attention. Common triggering factors include physical illnesses, environmental changes, and effects of drug. The
symptoms fluctuate, which differ from symptom persistence in dementia, but delirium and dementia are often foundconcomitantly.

3. Depression
Pseudodementia due to depression or a depressive state may cause psychomotor retardation and difficulties in concentration,
as well as memory decline and impaired judgement. Patients complain of reduced memorizing ability, which may be mistaken
as dementia. Unlike Alzheimer’s disease dementia, memory and executive dysfunctions usually do not persist in
pseudodementia, and patients often over-estimate their functional impairment (while dementia patients underestimate theirfunctional impairment, reflecting decreased awareness of disease). Response to antidepressants is another point ofdifferentiation.

▪ Reference1) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American
Psychiatric Association; 2013.

▪ Search formula
PubMed search: July 3, 2015 (Friday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis OR diagnostic)) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition
disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis OR diagnostic))) AND (“Diagnosis, Differential” [Majr] OR “Diagnostic Errors”[Mesh] OR “differential diagnosis” [TI] OR diagnostic error* [TI] OR misdiagnosis [TI])
Ichushi search: July 3, 2015 (Friday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive disorder/MTH OR Cognitive disorder /TI) AND ((((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionucleotide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND differential
diagnosis/MTH OR differentiation/TI OR misdiagnosis/MTH OR misdiagnosis/TI OR distinction/TI)

6

Clinical Practice Guideline for Dementia 2017

CQ 1-5

What is the prevalence of dementia in Japan?
AnswerIn the first half of the 2010s, the prevalence of dementia in older people aged 65 years and above in Japan was estimatedto be approximately 15%.
A

Comments and evidence
During the period from the 1980s to the 2000s, the prevalence of dementia in older people aged 65 years and above inJapan was reported to be 3.8-11%, and the prevalence of dementia has shown a tendency of increase 1). A survey on theprevalence of dementia in 8 municipalities nationwide estimated that there were 4.26 million older people with dementia in
2012, and the prevalence was reported to be about 15% 2, 3). Based on a longitudinal survey conducted in Hisayama Town,
Fukuoka Prefecture, the future prevalence of dementia was estimated and reported. Assuming that the prevalence of
dementia in each age group remains constant after 2012, the number of people with dementia in 2025 is estimated to be 6.75
million [95% confidence interval (CI); 5.41 million to 8.44 million]. When assuming that the frequency of diabetes increases
by 20% in the future, the number of people with dementia in 2025 is estimated to be 7.3 million (95% CI: 5.7 million to
9.36 million) 4).
The number of people with dementia in the world is estimated to be 46.8 million in 2015, and predicted to increase at apace of doubling every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. Furthermore, the increase in lowto middle-income countries is predicted to be markedly higher compared to high-income countries 5). On the other hand, a
study in the UK has reported decrease in prevalence of dementia 6), while studies in the Netherlands, Germany, Sweden and
US have reported decreases in incidence of dementia 7-10).

▪ References
1) Dodge HH, Buracchio TJ, Fisher GG, et al. Trends in the prevalence of dementia in Japan. Int J Alzheimers Dis. 2012; 2012: 956354.
2) Ikejima C, Hisanaga A, Meguro K, et al. Multicentre population-based dementia prevalence survey in Japan: a preliminary report. Psychogeriatrics.
2012; 12(2): 120-123.
3) Ministry of Health, Welfare and Labour Grant-in-aid for Dementia Control Integrated Research Project. Prevalence of dementia in urban areas andmeasures for impaired daily living functions in dementia. General Study Report for 2011-2012; 2013. (In Japanese)4) Ministry of Health, Welfare and Labour Grant-in-aid for Dementia Control Integrated Research Project. Study of prediction of future elderly
population with dementia in Japan. General and Partial Study report for 2014. Study Group for Prediction of Future Elderly Population with
Dementia In Japan; 2015. (In Japanese)5) Alzheimer’s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia: an analysis of prevalence, incidence, cost andtrends. London: Alzheimer’s Disease International; 2015.
6) Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from threegeographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013; 382(9902): 1405-1412.
7) Qiu C, von Strauss E, Backman L, et al. Twenty-year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden.
Neurology. 2013; 80(20): 1888-1894.
8) Schrijvers EM, Verhaaren BF, Koudstaal PJ, et al. Is dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam
Study. Neurology. 2012; 78(19): 1456-1463.
9) Doblhammer G, Fink A, Fritze T. Short-term trends in dementia prevalence in Germany between the years 2007 and 2009. Alzheimers Dement.
2015; 11(3): 291-299.
10) Satizabal CL, Beiser A, Chene G, et al. Temporal trends in dementia incidence in the Framingham Study. 2014 Jul 17; Copenhagen: AAIC; 2014.

▪ Search formula
Search formula: search period
PubMed search: May 28, 2015 (Thursday), October 19, 2015 (Thursday)#1 (“Dementia/epidemiology” [Majr] OR dementia [TI]) AND (“Morbidity” [Mesh] OR morbidity [TI] OR incidence [TI] OR prevalence [TI])
Ichushi search: May 28, 2015 (Thursday)#1 (Dementia/TH OR Dementia/TI) AND (Japan/TH OR Japan/TI OR This country/TI) AND (Incidence/TH OR Prevalence/TI OR Incidence/
TI OR Prevalence/TI)

Chapter 1

7

CQ 1-6

Are there changes in prevalence depending on subtype of dementia?
AnswerDementia shows a tendency of increase in Japan, and Alzheimer’s disease dementia is increasing compared to vasculardementia.
B

Comments and evidence
According to a nationwide survey conducted in the first half of the 2010s, the frequency of Alzheimer’s disease dementia
was the highest at 67.6%, followed by vascular dementia at 19.5%, and dementia with Lewy bodies /dementia with Parkinson’s
disease at 4.3% 1). In the 1980s, vascular dementia was more prevalent than Alzheimer’s disease dementia in Japan, but
Alzheimer’s disease dementia has shown a trend of increase since the latter half of the 1990s, especially in older people aged
80 years and above 2-5)

▪ References
1) Ministry of Health, Welfare and Labour Grant-in-aid for Dementia Control Integrated Research Project. Prevalence of dementia in urban areas andmeasures for impaired daily living functions in dementia. General Study Report for 2011-2012; 2013. (In Japanese)
2) Dodge HH, Buracchio TJ, Fisher GG, et al. Trends in the prevalence of dementia in Japan. Int J Alzheimers Dis. 2012; 2012: 956354.
3) Wakutani Y, Kusumi M, Wada K, et al. Longitudinal changes in the prevalence of dementia in a Japanese rural area. Psychogeriatrics. 2007; 7(4):150-154.
4) Sekita A, Ninomiya T, Tanizaki Y, et al. Trends in prevalence of Alzheimer’s disease and vascular dementia in a Japanese community: the Hisayama
Study. Acta Psychiatr Scand. 2010; 122(4): 319-325.
5) Suzuki M, Fukuda T, Narusei Y, et al. Prevalence over time of dementia viewed from a survey on senile dementia in Toyama Prefecture. Japanese
Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2003; 14(12): 1509-1518. (In Japanese)▪ Search formula
PubMed search: May 28, 2015 (Thursday)#1 (“Dementia/epidemiology” [Majr] OR dementia [TI]) AND (“Morbidity” [Mesh] OR morbidity [TI] OR incidence [TI] OR prevalence [TI])
AND (subtype [TI] OR subtypes [TI] OR “sub type” [TI] OR “sub types” [TI])
Ichushi search: May 28, 2015 (Thursday)#1 (Dementia/TH OR Dementia/TI) AND (Incidence/TH OR Incidence/TI OR Prevalence/TI OR Frequency/TI) AND Disease type/AL

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Clinical Practice Guideline for Dementia 2017

CQ 1-7Is the disease duration of dementia getting longer?
AnswerStudies have reported a possibility that the survival period of people with dementia may be prolonged. However,there is no report showing that the death rate of people with dementia is clearly lower compared to the general population.
C

Comments and evidence
In the United States, the hazard ratio (HR) for death in people with dementia aged 70 years and above compared to those
without dementia was 2.53 in 1993 and 3.11 in 2002, with no significant change during the 9-year period (p = 0.09) 1). In a
study conducted in Stockholm, Sweden, the mortality rate of people with dementia decreased by 29% over the 14-year
period from 1988 to 2002, but the HR compared to non-dementia subjects was 2.42 in 1988 and 2.47 in 2002, with nosignificant change during the 14 years 2). In these reports, while the incidence of dementia has declined, prevalence has notchanged, suggesting that the duration of dementia may be prolonged 1, 2). In a study using medical insurance claim data in
Germany, the death rate of people with dementia increased by 1% in men (p = 0.75) and 11% in women (P < 0.001) over a
3-year period from 2004 to 2007 3).
When the mean loss of life expectancy (%) (survival period from dementia onset to the mean age of death divided by themean life expectancy of the general population at the age of dementia onset) was analyzed by period, many reports show thatloss of life expectancy in people with dementia decreases after mid-1990s when compared to that from the 1980s to early
1990s 4).

▪ References
1) Langa KM, Larson EB, Karlawish JH, et al. Trends in the prevalence and mortality of cognitive impairment in the United States: is there evidenceof a compression of cognitive morbidity? Alzheimers Dement. 2008; 4(2): 134-144.
2) Qiu C, von Strauss E, Backman L, et al. Twenty-year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden.
Neurology. 2013; 80(20): 1888-1894.
3) Doblhammer G, Fink A, Fritze T. Short-term trends in dementia prevalence in Germany between the years 2007 and 2009. Alzheimers Dement.
2015; 11(3): 291-299.
4) Brodaty H, Seeher K, Gibson L. Dementia time to death: a systematic literature review on survival time and years of life lost in people withdementia. Int Psychogeriatr. 2012; 24(7): 1034-1045.

▪ Search formula
PubMed search: October 19, 2015 (Thursday)#1 (“Dementia/mortality” [Majr] OR “Cognition Disorders/mortality” [Majr] OR “Dementia/epidemiology” [Majr] OR “Cognition Disorders/
epidemiology” [Majr]) AND ((“Mortality” [Mesh] OR mortality [TIAB] OR survival [TIAB]) AND (“Morbidity” [Mesh] OR “Life Expectancy”[Mesh] OR “morbidity” [TI] OR “incidence” [TI] OR “prevalence” [TI] OR “disease duration” [TI])) OR (“dementia” [TI] AND (“morbidity”[TI] OR “incidence” [TI] OR “prevalence” [TI]))
Ichushi search: October 19, 2015 (Thursday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive Disorders/MTH OR Cognitive Disorders/TI) AND (Disease duration/TI OR Incidence/TH
OR Prevalence/TI OR Frequency/TI OR Survival period/TH OR Mortality/TH OR Survival period/TI OR Mortality/TI OR Survival rate/TI)

Chapter 1

9CQ 1-8What is the pathological background of dementia?
AnswerVarious underlying pathologies are associated with dementia, such as degenerative disease, cerebrovascular disorder,
infection, inflammation, and tumor, and the clinical picture is strongly influenced by the lesion distribution. The frequency
of degenerative diseases is high, and in the majority of these cases, abnormal protein accumulation is the core feature of
the pathology.

Comments and evidence

Alzheimer’s disease is characterized by the formation of large numbers of senile plaques [amyloid β (Aβ) plaque formation]and neurofibrillary tangles (fibrous aggregates of tau protein). Both senile plaques and neurofibrillary tangles also appear inolder people without dementia, but they are particularly abundant in Alzheimer’s disease. It remains unclear how theformation of senile plaques and neurofibrillary tangles leads to neuronal degeneration and loss. The main lesion of dementia
with Lewy bodies is abnormal accumulation of α-synuclein in neurons. In Parkinson’s disease, Lewy lesions are confined tothe brain stem, whereas in dementia with Lewy bodies, Lewy lesions spread to the cerebrum. Alzheimer’s lesions are observedin many patients with dementia with Lewy bodies 1).
Fronto-temporal lobar degeneration (FTLD) is broadly divided into a disease group showing tau accumulation and agroup showing TDP-43 accumulation, while there are rare cases of fused in sarcoma (FUS) protein accumulation 2). Although
there is not always a good correlation between clinical features and pathological diagnosis, many cases of semantic dementia
and cases with coexisting motor neuron disease are associated with TDP-43 accumulation. In Japan, familial FTLD is oftencaused by tau gene mutations.
Argyrophilic grain dementia showing granular accumulation of tau inside neurites, and primary age-related tauopathy(PART) showing abundant neurofibrillary tangles (similar to Alzheimer’s disease) localized to the hippocampal limbic
system but no significant Aβ accumulation are increasingly common in older people aged 80-90 years and above 3).
Hippocampal sclerosis is a general term for disease conditions showing severe neuronal loss and gliosis in hippocampal CA1
and subiculum, with diverse underlying diseases.
Vascular dementia is frequently caused by ischemic brain lesions, and the culprit vascular lesions are broadly classified into
those caused by macrovascular atherosclerosis and those caused by microvascular lesions. Microvascular lesions cause
multiple lacunar infarcts and white matter lesions, and are strongly associated with dementia 4). Amyloid angiopathy also
causes dementia, and in this case is often accompanied by Alzheimer’s lesions. The coexistence of Alzheimer’s lesion andvascular lesion is not simply comorbidity, but is thought to influence each other in pathological mechanisms (see CQ14-4).

▪ References
1) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.
2) Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an
update. Acta Neuropathol. 2010; 119(1): 1-4.
3) Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta
Neuropathol. 2014; 128(6): 755-766.
4) Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015; 11(3): 157-165.

▪ Search formula
PubMed search: July 24, 2015 (Friday)#1 ((“Dementia/pathology” [Majr] OR (dementia [TI] AND (pathology* [TI] OR neuropathology*[TI]))) AND (“Brain/pathology” [Majr] OR“Parkinson Disease/pathology” [Majr] OR “Inclusion Bodies/metabolism” [Mesh]) AND (neuropathologic [TI] OR neuropathological [TI] OR
pathologic [TI])) OR ((“Frontotemporal Lobar Degeneration/pathology” [Mesh] OR “Lewy Body Disease/pathology” [Mesh] OR “Alzheimer
Disease/pathology” [Majr] OR (Alzheimer* [TI] AND (pathology* OR neuropathology*))) AND (“Brain/pathology” [Mesh] OR “Parkinson
Disease/pathology” [Mesh] OR “primary age-related tauopathy” [TIAB] OR PART [TI]) AND (“pathological feature” [TIAB] OR “pathologicalprocess” [TIAB] OR “pathologic process” [TIAB] OR “neuropathological criteria” [TIAB] OR neuropathological stage* [TIAB] OR pathogenic
mechanism* [TIAB])) OR ((“Frontotemporal Lobar Degeneration/classification” [Majr] OR “Lewy Body Disease/physiopathology” [Majr] OR(“Tauopathies/pathology” [Majr] AND “Aging/pathology” [Majr]) OR (“Athletic Injuries/pathology” [Majr] AND Cognition [Mesh])) AND

10

Clinical Practice Guideline for Dementia 2017

(“Brain/pathology” [Majr] OR “Inclusion Bodies/metabolism” [Mesh]) AND (neuropathology* [TI] OR pathology* [TI] OR “pathologic
assessment” [TIAB]))
Ichushi search: July 24, 2015 (Friday)#1(Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Fronto-temporal lobar degeneration/TI OR Lewy body/TI) AND (Brain/TH OR
Brain/TI OR Parkinson disease/TH OR Parkinson/TI) AND (((SH = Pathology) OR Pathology/TH) AND Pathology /TI AND (Background/TI
OR Dementia/TI OR Alzheimer/TI OR Fronto-temporal lobe/TI OR Lewy body/TI))

Chapter 1

11

Chapter 2
Syndrome, Rating Scales, Tests, Diagnosis

Objective
To understand the symptoms and rating scales of dementia, to conduct the necessary tests, and to diagnose dementia
accurately.

Symptoms
The dementia syndrome comprises impairment of cognitive functions including memory, language, and visuospatial
cognition, together with associated behavioral and psychological symptoms of dementia (BPSD). Multiple cognitive
functions are impaired, reflecting the sites of functional decline in various disorders. The basis of BPSD is cognitive
impairment, and arise as a result of influences by physical factors, environmental factors, and psychological factors. Various
rating scales have been devised to prevent overlooking symptoms and to monitor changes over time.

History taking
Taking history from the patient, family members, and caregivers is important. By taking history from the patient,cognitive functions such as memory, language, and thinking; the degree of disease awareness; and psychological symptoms
can be estimated. Ask family members about specific symptoms and their changes over time. Ask about the patient’s life
history including handedness, educational history, and occupation, which will be useful to estimate the patient’s capabilities
before disease onset and to explore the mechanisms of BPSD.

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Clinical Practice Guideline for Dementia 2017

CQ 2-1

What kinds of cognitive function impairment are found in dementia?
AnswerMultiple cognitive functions are impaired in dementia, reflecting the sites of functional decline in various disorders.
The main cognitive function impairments include general attention impairment, amnesia, aphasia, visuospatial
impairment, apraxia, and executive function impairment.

Comments and evidence
As a part of the neurological examination, neuropsychological evaluations for the cognitive functions shown below can beused to capture the characteristic cognitive impairment of each disease 1).

1. General attention impairment
General attention is a function that forms the basis of perceiving and selecting stimulation in the surrounding and acting
appropriately in response to the stimulation. In dementia, the retention, selectivity, and allocation of attention are often
impaired from a relatively early stage, regardless of the etiological subtype, subsequently affecting various individual cognitive
functions. If general attention is impaired, the amount of information that can be processed at one time is reduced, making
it difficult to understand, memorize, and react to relatively complex matters.

2. Executive function impairment
Executive function refers to the functions of planning and executing a task with a purpose, and carrying on with the task
while continuously feeding back the result. Impairment of executive function is a typical symptom of frontotemporal lobar
degeneration (FTLD), but may also be present in other types of dementia. Executive function is related to all the complex
actions, and its impairment may become noticeable when work and housework are not carried out in a usual manner.

3. Memory impairment
Memory is a function by which new experience is preserved, and that experience is reproduced in consciousness or action 2).
Memory includes the process of memorizing the experience, retaining (storing) it for a certain period, and then retrieving(recalling) the experience. Memory is classified according to the contents to be memorized and the period of retention as
follows.
a. Classification by content
Declarative memory refers to the memory that can be consciously recalled and expressed verbally. Non-declarative
memory is the memory that cannot be expressed explicitly; an example is procedural memory. Declarative memory is
subdivided into episodic memory and semantic memory.
Episodic memory is the memory of events including the context of when and where, and impairment of episodic memory
is called amnesia. Amnesia is observed in many types of dementia, and is a particularly common manifestation in the earlystage of Alzheimer’s disease. Episodic memory deficit is further divided into retrograde amnesia which is failure to recall
events before the onset of disease, and anterograde amnesia which is failure to recall events after the onset of disease.
Semantic memory is equivalent to knowledge including meaning of objects and names. In semantic dementia, the patient
initially cannot recall the names of objects, gradually cannot understand when being told the names of objects, and eventuallycannot understand even though when being shown the actual objects.
Non-declarative memory includes procedural memory of skills such as riding a bicycle. Since non-declarative memory ispreserved even in an amnestic patient, it may be useful for maintaining activities of daily living.
b. Classification by length of retention
Based on the length of time a stimulus is retained, memory can be divided into immediate (short-term) memory, recent
memory, and remote memory. Immediate memory is a function related to general attention, while recent and remote memory
are episodic memory. Immediate memory is a function that stores a stimulus for a few seconds and reproduces it immediately,

Chapter 215and can be tested, for example, by forward digit span. To assess the presence or absence of amnesia, it is necessary to test theepisodic memory by asking the patient to memorize a stimulus and then to recall after other tasks have been completed.
c. Other types of memory
Working memory is a function that uses immediate memory to hold information and utilizes it to perform cognitive task.
The task of sequentially subtracting 7 from 100 corresponds to this memory. Prospective memory is the function ofremembering a planned action and executing it at an appropriate time and situation.

4. Aphasia
Aphasia refers to the state of impairment at the language level while basic functions such as articulation and hearing arepreserved. Primary progressive aphasia is a subtype in which aphasia presents as the first symptom, and remains a foreground
symptom as dementia advances (see CQ2-6). Aphasia coexists commonly with dementia.

5. Visuospatial impairment
Visuospatial impairment is commonly found in Alzheimer’s disease and dementia with Lewy bodies (DLB), which aremainly related to posterior cerebral functions. Constructional apraxia can be detected by the inability to copy drawings andimitate hand postures. In dementia with Lewy bodies, illusion and vivid visual hallucination are found. Posterior cortical
atrophy (PCA) is an atypical dementia with visuospatial impairment as the dominant symptom, and is commonly caused by
Alzheimer’s disease.

6. Apraxia
Apraxia refers to the failure to perform habitual movements or using tools, which cannot be explained by impaired motor
ability or object recognition. Limb-kinetic apraxia mainly refers to a state of clumsy upper limb movement, and may be seenin corticobasal degeneration. Ideomotor apraxia (inability of gestures and habitual movements), ideational apraxia (inabilityof using tools), and dressing apraxia (inability of getting dressed) may occur in various subtypes of dementia. However,apraxia is often complicated by visuospatial impairment and extrapyramidal symptoms, manifesting complicated clinicalpresentations.

7. Social cognition impairment
Impairment of social cognition is the failure to recognize emotions and situations, and to act accordingly.

▪ References
1) Sachdev PS, Blacker D, Blazer DG, et al. Classifying neurocognitive disorders: the DSM-5 approach. Nat Rev Neurol. 2014; 10(11): 634-642.
2) Yamadori A. Neuropsychology of Memory. Tokyo: Igaku Shoin; 2002. (In Japanese)

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Clinical Practice Guideline for Dementia 2017

CQ 2-2

What are the behavioral and psychological symptoms of dementia (BPSD)?
Answer
The basis of BPSD is cognitive impairment of dementia, and BPSD arise as a result of influences by physical factors,
environmental factors, and psychological factors 1,2). They consist of behavioral symptoms such as agitation, aggression,and disinhibition, and psychological symptoms including anxiety, depression, hallucination, and delusion.

Comments and evidence
Based on the classification of BPSD in Alzheimer’s disease reported by the European Alzheimer Disease Consortium 1, 2),
this section outlines the BPSD of Alzheimer’s disease and other subtypes of dementia.

1. Symptoms related to hyperactivity
These symptoms include agitation, irritability, disinhibition, and abnormal behaviors. When patients become aware of
their forgetfulness and start feeling anxious and frustrated, they get upset by even trivial matters leading to irritability. And,
when fueled by inappropriate responses from people around them, they may develop into aggression and agitation such as
using abusive language and violence. Behavioral symptoms include wandering and aggressive behaviors, which are related tovarious underlying cognitive impairments, and necessitate individual management.

2. Psychosis-like symptoms
These symptoms include hallucination, delusion, and nocturnal abnormal behaviors. Delusion is a false belief that cannot
be corrected, and is caused by psychological factors with amnesia and misperception in the background. Delusion of theftand persecutory delusion are well known in Alzheimer’s disease, while jealousy delusion and phantom boarder delusion are
well known in DLB. Visual hallucination and REM sleep behavior disorder are considered to be one of the core symptomsof DLB.

3. Symptoms related to affective symptoms
Anxiety and a depressive state are often observed in the early stage of Alzheimer’s disease. For DLB, more than one halfof the patients show a depressive state during the course of disease, and these symptoms are included as supportive featuresin the diagnostic criteria of DLB. In addition, a depressive state is the first symptom of DLB in a considerable number ofpatients.

4. Symptoms related to apathy
Apathy refers to reduced spontaneity and motivation. Apathetic symptoms may manifest in the affective domain such aslack of emotions, in the behavioral domain such as inactivity, and in the cognitive domain such as lack of interest toward thesurrounding. Unlike depression, apathy is characterized by a lack of feeling of sorrow and self-accusation. Apathy is seen ata high frequency in frontotemporal lobar degeneration, while it is the most common BPSD symptom in Alzheimer’s disease,and is also found in more than one-half the patients with DLB.

▪ References
1) Aalten P, Verthey FRJ, Boziki M, et al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: Part
I. Dement Geriatr Cogn Disord. 2007; 24(6): 457-463.
2) Aalten P, Verthey FRJ, Boziki M, et al. Consistency of neuropsychiatric syndromes across dementias: results from the European Alzheimer Disease
Consortium. Part II. Dement Geriatr Cogn Disord. 2008; 25(1): 1-8.

Chapter 2

17

CQ 2-3What are the useful scales for assessing cognitive impairment in dementia?
Answer
As a useful scale for evaluating cognitive impairment in dementia, the Mini Mental State Examination (MMSE) iswidely used internationally in clinical setting and in research. It is desirable to add necessary tests according to the subject
evaluated, the purpose and the environment, and interpret the results taking into account the background and conditionof each patient.
C

Comments and evidence
MMSE is widely used internationally in the clinical setting and in research as a screening for cognitive impairment. The
maximum MMSE score is 30 points; 29 points for tests including language function and 1 point for copying a drawing. In
general, a score of 23 points or below indicates a suspicion of dementia. The sensitivity is low in mild patients, in patientswith high premorbid ability, and in patients with visuospatial impairment as the main symptom 1). Even in mild dementia,
the score will be low when the patient has language impairment. In Japan, the Revised Hasegawa’s Dementia Scale (HDS-R)
is also commonly used and has a high correlation with MMSE. There are no tasks that can be performed nonverbally in
HDS-R. In general, a score of 20 or below indicates a suspicion of dementia.
For mild dementia and mild cognitive impairment (MCI), the Montreal Cognitive Assessment-Japanese version (MoCA-J)
and the Japanese version of Addenbrooke’s Cognitive Examination-Revised (ACE-R) are used (See CQ4B-4). Moreover, adding
neuropsychological tests such as trail making test and logical memory task to MMSE increases the rate of diagnosing mild
dementia 2). The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (Japanese version) (ADAS-Jcog) is an examination
centered on memory and visuospatial recognition, and is used to evaluate the changes of Alzheimer’s disease symptoms.
If more detailed examinations are required to assess various cognitive functions, select the appropriate tests. Severe Impairment
Battery (SIB) 3, 4) and Severe Cognitive Impairment Rating Scale (SCIRS) 5, 6) are assessments for patients with severe dementia.
It is essential to evaluate cognitive dysfunction not only based on the cutoff values of various tests alone, but also to
consider the patient’s premorbid ability as well as the physical and mental states at the time of testing. Estimating the
cognitive and behavioral changes from premorbid state is important.

▪ References
1) Velayudhan L, Ryu SH, Raczek M, et al. Review of brief cognitive tests for patients with suspected dementia. Int Psychogeriatric. 2014; 26(8): 12471262.
2) Wouters H, Appels B, van der Flier WM, et al. Improving the accuracy and precision of cognitive testing in mild dementia. J Int Neuropsychol Soc.
2012; 18(2): 314-322.
3) Saxton J, McGonigle-Gibson KL, Swihart A, et al. Assessment of the severely impaired patient: description and validation of a new neuropsychologicaltest battery. Psychol Assess. 1990; 2(3): 298-303.
4) Niina R, Honnma A, Sugai Y. Reliability, validity and clinical usefulness of the Japanese version of SIB and Japanese version of revised ADCS-ADL.
Japanese Journal of Geriatric Psychiatry. (Ronen Seishin Igakushi) 2005; 16(6): 683-691. (In Japanese)
5) Choe JY, Youn JC, Park JH, et al. Th­ e Severe Cognitive Impairment Rating Scale-an instrument for the assessment of cognition in moderate tosevere dementia patients. Dement Geriatr Cogn Disord. 2008; 25(4): 321-328.
6) Tanaka H, Uematsu M, Nagata Y, et al. Cognitive function test for severe dementia patients: Clinical usefulness of the Japanese version of Severe
Cognitive Impairment Rating Scale. Japanese Journal of Geriatric Psychiatry. (Ronen Seishin Igakushi) 2013; 24(10): 1037-1046. (In Japanese)▪ Search formula
PubMed search: July 15, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis OR diagnoses OR diagnostic)) OR “Cognition Disorders/diagnosis” [Majr]
OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (diagnosis OR diagnoses OR diagnostic))) AND (“Neuropsychological Tests”[Majr] OR neuropsychological test* [TI] OR “Psychiatric Status Rating Scales” [Majr] OR assessment scale* [TI])
Ichushi search: July 15, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function/TI) AND(Neuropsychological examination/TH OR Neuropsychological examination/TI OR Neuropsychological tests/TI OR Psychiatric rating scale /TH
OR rating scale/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 2-4

What are the useful rating scales for behavioral and psychological symptoms
of dementia (BPSD), activities of daily living (ADL), and global severity?
Answer
The Neuropsychiatric Inventory (NPI) is a rating scale for BPSD, and Physical Self-Maintenance Scale (PSMS) is a
rating scale for ADL . The Clinical Dementia Rating (CDR) is widely used to evaluate global severity, and the Japaneseversion is available.
C

Comments and evidence
BPSD, ADL, and global severity are evaluated based on the behaviors of a person with dementia in various situations asobserved by other persons. Since the methods of observing behavior may be affected by the observer’s skill and condition, an
appropriate rating method should be selected considering the patient’s environment including the caregivers.

1. Evaluation of BPSD
BPSD are evaluated based on a semi-structured interview with the caregiver who closely observes the behaviors of theperson with dementia. The NPI evaluates the presence or absence, frequency, and severity of 10 domains of psychiatric
symptoms (delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, dysphoria, apathy, disinhibition,
irritability, and aberrant motor behavior). Recently, a 12-domain version with the addition of two domains; nighttime
behavior disturbance and appetite/eating abnormalities, is commonly used. This tool is widely used internationally and isalso commercially available in Japan. A questionnaire version (NPI-Q) and a nursing home version (NPI-NH) are available.
The Behavioral Pathology in Alzheimer ’s Disease (Behave-AD) has 25 items and is scored on a 4-point severity scale. The
Cohen-Mansfield Agitation Inventory (CMAI) is a scale that systematically evaluates the frequency of 29 agitated behaviors
rated on a 7-point scale.

2. Evaluation of ADL
Patients with dementia have disability in daily living, and the core disability is deterioration of ADL. The Physical SelfMaintenance Scale (PSMS) consists of 6 basic ADL items (toilet, feeding, dressing, grooming, physical ambulation, andbathing), and Instrumental ADL Scale (IADL) consists of 8 ADL items using instruments (ability to use telephone, shopping,food preparation, housekeeping, laundry, mode of transportation, responsibility of own medications, and ability to handle
finance), both of which are rated by the caregiver. These scales are widely used internationally, and Japanese versions of bothscales are also available 1).

3. Evaluation of global severity
The Clinical Dementia Rating (CDR) is widely used internationally. It is an evaluation method based on a semistructured
interview with the patient’s caregiver regarding six domains of cognitive and functional performance: memory, orientation,
judgment and problem solving, community affairs, home and hobbies performance, and personal care. The patient’s
impairment of each item is scored, and the global score is classified into five stages: 0; normal, 0.5: very mild dementia, 1:
mild dementia, 2: moderate dementia, 3: severe dementia. Attention is required when there is insufficient information fromthe caregiver or when the rater’s training is insufficient, because inter-rater agreement may not be adequate. Based on CDR,a method that considers a simple cognitive function test for the patient, a method that uses the total score of the 6 items, anda revised shortened version have been proposed 2). Rating scales that were developed in Japan, including the Nishimura
Mental Scale as well as the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) thatexamines changes between two time points 3), are also used.

▪ References
1) Sikkes SA, de Lange-de Klerk ES, Pijnenburg YA, et al. A systematic review of instrumental activities of daily living scales in dementia: room for
improvement. J Neurol Neurosurg Psychiatry. 2009; 80(1): 7-12.
2) Duara R, Loewenstein DA, Greig-Custo MT, et al. Diagnosis and staging of mild cognitive impairment, using a modi­fication of the clinical

Chapter 219dementia rating scale: the mCDR. Int J Geriatr Psychiatry. 2010; 25(3): 282-289.
3) Nakamura Y, Usui M, Nishikawa T, et al. CIBIC Plus-J assessment using a videotaped method in Alzheimer’s disease patients. Dement Geriatr
Cogn Dis Extra. 2012; 2(1): 271-277.

▪ Search formula
PubMed search: July 15, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis OR diagnoses OR diagnostic)) OR “Cognition Disorders/diagnosis” [Majr]
OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (diagnosis OR diagnoses OR diagnostic))) AND (“Neuropsychological Tests”[Majr] OR neuropsychological test* [TI] OR “Psychiatric Status Rating Scales” [Majr] OR assessment scale*[TI])
Ichushi search: July 15, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function/TI) AND(Neuropsychological examination/TH OR Neuropsychological examination/TI OR Neuropsychological test/TI OR Neuropsychological rating
scale/TH OR Rating scale/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 2-5

How is quality of life (QOL) evaluated in persons with dementia?
AnswerThere are various viewpoints regarding the methods of QOL evaluation in people with dementia. Although there is no
standard method, an appropriate one can be selected and used through considering the severity and environment of theperson with dementia.
C

Comment and evidence
QOL is a concept that integrates physical and mental functions, ability of performing activities of daily living, and social
activities. The evaluation method varies depending on how the concept is perceived. QOL evaluation methods are broadly
divided into self-rating and rating by others (proxy-rating), and a combination of the two. Self-rating becomes more difficult
as dementia progresses, and proxy rating has limitations including observer bias 1).
SF-36 and EQ-5D are widely used internationally as self-rating methods for overall health-related QOL, but they are
difficult to score for persons with advanced dementia and therefore have low validity in persons with dementia 2). In Englishspeaking countries, there are more than 15 QOL rating methods specialized for dementia 3), but the definition and focus of
QOL differ depending on the rating method, and there is no standard.
Quality of Life in Alzheimer’s Disease (QoL-AD) 4), a simple rating method that combines self-rating and caregiver-rating,is suitable for Alzheimer’s disease dementia up to moderate severity, and is widely used in clinical research 5).

▪ References
1) Graske J, Meyer S, Wolf-Ostermann K. Quality of life ratings in dementia care-across-sectional study to identify factors associated with proxyratings. Health Qual Life Outcomes. 2014; 12: 177.
2) Smith S, Lamping D, Banerjee S, et al. Measurement of health-related quality of life for people with dementia: development of a new instrument(DEMQOL) and an evaluation of current methodology. Health Technol Assess. 2005; 9(10): 1-93.
3) Perales J, Cosco TD, Stephan BC, et al. Health-related quality of life in the Cambridge City over-75s Cohort (CC75C): development of a dementiaspeci­fic scale and descriptive analyses. BMC Geriatr. 2014; 14: 18.
4) Logston RG, Gibbons LE, McCurry SM, et al. Quality of life in Alzheimer’s disease: patient and caregiver reports. J Ment Health Aging. 1999; 5(1):21-32.
5) Matsui T, Nakaaki S, Murata Y, et al. Determinants of the quality of life in Alzheimer’s disease patients as assessed by the Japanese version of the
Quality of Life-Alzheimer’s disease scale. Dement Geriatr Cogn Disord. 2006; 21(3): 182-191.

▪ Search formula
PubMed search: July 15, 2015 (Wednesday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR cognition disorder* [TI] OR cognitive disorder* [TI]) AND(“Neuropsychological Tests” [Majr] OR neuropsychological test* [TI] OR “Psychiatric Status Rating Scales” [Majr] OR scale* [TI]) AND (“Qualityof Life” [Majr] OR “quality of life” [TI])
Ichushi search: July 15, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function/TI) AND(Neuropsychological examination/TH OR Neuropsychological examination/TI OR Neuropsychological test/TI OR Neuropsychological rating
scale/TH OR Rating scale/TI) AND (QOL/TH OR QOL/TI OR “Quality of Life”/TI)

Chapter 2

21

CQ 2-6

How is primary progressive aphasia (PPA) classified and evaluated?
AnswerPrimary progressive aphasia (PPA) can be divided into (1) non-fluent/agrammatic type, (2) semantic type, and (3)logopenic type. Clinical classification is based on assessment of language and semantic memory as well as lesion
distribution.
C

Comments and evidence
PPA refers to a group of degenerative dementia that manifests aphasia as the onset symptom, and aphasia remains theforeground symptom as disease progresses. PPA is divided into 3 types according to the characteristics of aphasia. The 3
types show characteristic distribution of site of atrophy on MRI and site of decreased blood flow/metabolism on SPECT/PET 1).
For clinical diagnosis, examine the patient for speech production features (motor speech, sound errors, and word-finding
pauses), single-word and syntax comprehension, functions of confrontation naming and repetition, and reading/writing. The
non-fluent/agrammatic type is characterized by inconsistent speech sound errors called apraxia of speech as well asagrammatism in speech/comprehension, but some patients manifest only one of these features. A variant of this type isprimary progressive apraxia of speech manifesting only apraxia of speech without aphasia, which has similar site of atrophy
as non-fluent/agrammatic type PPA with prominent apraxia of speech 2). In the semantic type, impaired single-wordcomprehension and confrontation naming are the core symptoms, which progress to impairment of semantic memory suchas object knowledge. Speech fluency and repetition are spared. As disease progresses, semantic memory is impaired, and thepatient becomes unable to understand even when being shown an object. The logopenic type manifests impaired single-word
retrieval in spontaneous speech and naming. While single word comprehension and repetition are spared, repetition ofsentences and phrases is impaired and phonetic errors are prominent.
The Western Aphasia Battery (WAB) and Standard Language Test of Aphasia (SLTA) are used for semi-quantitativeevaluation of language. However, it has been reported that using a picture description task can reveal the distinct speechcharacteristics 3). Using the current diagnostic criteria, approximately one-third of the cases cannot be classified into any of
the clinical types, while some cases are classified into two types. Reconsidering the classification may be required 4).
Since PPA is a clinical syndrome, it has heterogeneous neuropathologic causes. Regarding agreement of PPA classification
with pathological diagnosis, 77% of patients with non-fluent/agrammatic variant PPA had frontotemporal lobar degeneration(FTLD) (tau; 51%, TDP-43; 26%), and 21% of them had Alzheimer’s disease. Moreover, 88% of the patients with semantic
variant PPA had FTLD (tau; 15%, TDP-43; 73%), and 12% of them had Alzheimer’s disease. Finally, 56% of the patientswith logopenic variant PPA had Alzheimer’s disease and 36% of them had FTLD (tau; 11%, TDP-43; 24%) 5, 6). Roughly
speaking, the semantic variant is strongly related to FTLD-TDP, while about a half of the non-fluent/agrammatic variant isrelated to FTLD-tau and about a half of the logopenic variant is related to Alzheimer’s disease.

▪ References
1) Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classifi­c ation of primary progressive aphasia and its variants. Neurology. 2011; 76(11): 10061014.
2) Josephs KA, Du‑y JR, Strand EA, et al. Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA. Neurology.
2013; 81(4): 337-345.
3) Ash S, Evans E, O’Shea J, et al. Differentiating primary progressive aphasias in a brief sample of connected speech. Neurology. 2013; 81(4): 329-336.
4) Botha H, Du‑y JR, Whitwell JL, et al. Classi­fication and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech.
Cortex. 2015; 69: 220-236.
5) Harris JM, Gall C, Thompson JC, et al. Classi­fication and pathology in primary progressive aphasia. Neurology. 2013; 81(21): 1832-1839.
6) Harris JM, Jones M. Pathology in primary progressive aphasia syndromes. Curr Neurol Neurosci Rep. 2014; 14(8): 466.

22

Clinical Practice Guideline for Dementia 2017

▪ Search formula
PubMed search: July 15, 2015 (Wednesday)#1 (“Aphasia, Primary Progressive/classification” [Majr] OR (“primary progressive aphasia” [TI] AND classification) OR ((“Aphasia, Primary
Progressive/diagnosis” [Mesh] OR (“primary progressive aphasia” [TI] AND (diagnosis OR diagnoses OR diagnostic))) AND (“Neuropsychological
Tests” [Mesh] OR neuropsychological test* [TI]) AND assessment*)) OR ((“Aphasia, Primary Progressive/diagnosis” [Majr] OR (“primary
progressive aphasia” [TI] AND (diagnosis OR diagnoses OR diagnostic)) OR ((“Aphasia, Primary Progressive/diagnosis” [Mesh] OR (“primary
progressive aphasia” [TI] AND (diagnosis OR diagnoses OR diagnostic))) AND (“Neuropsychological Tests” [Mesh] OR neuropsychological test*[TI]))) AND (three variant* OR (variant* AND (criteria [TI]OR “Diagnosis, Differential” [Mesh] OR “differential diagnosis” [TI] OR classification[TI] OR classification [SH] OR assessment* [TI]))))
Ichushi search: July 15, 2015 (Wednesday)#1 (Aphasia-primary progressive/TH OR Primary progressive aphasia/TI) AND (Classification/TH OR Classification/AL OR Evaluation/AL OR
Criteria/AL OR Variation/TH OR Variation/AL OR Variant/AL)

Chapter 2

23

CQ 2-7

How is dementia diagnosed and differentiated?
AnswerFor clinical diagnosis of dementia, history taking as well as physical and neurological examinations are important. During
this step, efforts should be made to comprehensively understand whether dementia is present, and if so, the symptoms andseverity of dementia. Then conduct cognitive function tests, structural brain imaging (CT or MRI), functional brain imaging,as well as blood and cerebrospinal fluid tests to diagnose the type of dementia. In this process, efforts should be made not tooverlook treatable dementia, and to rule out delirium, depression, and drug-induced cognitive impairment.

Comments and evidence
Dementia can be summarized as “a state of continuous impairment of multiple acquired cognitive and mental functions,
not due to disturbance of consciousness, to the extent that daily living and social life are affected”. Diagnosis of dementia
requires two steps. First, determine whether the patient has dementia by comprehensively confirm whether the functions ofdaily living are disabled due to acquired and chronic cognitive impairment 1). In this process, perform history taking andcognitive function tests. Definitions of and diagnostic criteria for dementia are provided by the International Statistical
Classification of Diseases and Related Health Problems, Tenth Edition (ICD-10) 2), the Diagnosis and Statistical Manual for
Mental Disorders, Fifth Edition (DSM-5) 3), and the criteria of the National Institute on Aging–Alzheimer’s Association
workgroup (NIA-AA) 4). Even when the conditions of a case do not meet the criteria for dementia, it may be classified into
the category of mild cognitive impairment if there is cognitive impairment present in the background.
The next step is to determine the underlying disease of dementia. In this process, perform various examinations asnecessary, such as physical findings, neurological examinations, imaging examinations, and blood and cerebrospinal fluid
tests. In order not to overlook treatable dementia, it is desirable to perform structural imaging by head CT or MRI whendementia is diagnosed 5-7). Blood counts, hematology and blood biochemistry, as well as measurements of thyroid hormone,electrolytes, fasting blood glucose, vitamin B12, and folic acid are recommended. Cerebrospinal fluid test is recommended forpatients with atypical types and other conditions that are difficult to differentiate 5-7). In view of the diverse differential
diagnoses for juvenile dementia, consider referring the patient to a specialist 1).
Refer to the dementia diagnosis flowchart (2017) modified from the previous version published in Treatment Guideline
for Dementia 2010.

▪ References
1) Galvin JE, Sadowsky CH. Practical guidelines for the recognition and diagnosis of dementia. J Am Board Fam Med. 2012; 25(3): 367-382.
2) World Health Organization. International Statistical Classifi­c ation of Diseases and Related Health Problems. 10th Revision. Geneva: World HealthOrganization; 1993.
3) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Arlington, VA: American Psychiatric Association; 2013.
4) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
5) Noel-Storr AH, McCleery JM, Richard E, et al. Reporting standards for studies of diagnostic test accuracy in dementia: The STARDdem Initiative.
Neurology. 2014; 83(4): 364-373.
6) Sorbi S, Hort J, Erkinjuntti T, et al. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurol.
2012; 19(9): 1159-1179.
7) Arai H. Diagnosis of dementia. Japan Society of Dementia Research (Ed.) Textbook of Dementia. Tokyo: Chugai Igakusha; 2008: 158-163. (In Japanese)▪ Search formula
PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis[TI] OR diagnoses [TI] OR diagnostic [TI]))) AND(“Diagnosis, Di­fferential” [Majr] OR “di­fferential diagnosis” [TI] OR “Diagnostic Errors” [Majr] OR diagnostic error* [TI] OR misdiagnosis [TI])
Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Di­fferential
diagnosis/MTH or Differentiation/TI or Misdiagnosis/MTH or Misdiagnosis/TI)

24

Clinical Practice Guideline for Dementia 2017

CQ 2-8

How are imaging examinations carried out in dementia?

Structural imaging (CT or MRI) is used to exclude treatable dementia. On MRI, the brain atrophy pattern in brain
regions, and the presence and distribution of signal changes are useful for differential diagnosis of dementia. Functional
imaging techniques such as cerebral blood flow single-photon emission computerized tomography (SPECT), dopaminetransporter scintigraphy, and MIBG myocardial scintigraphy are also useful for differential diagnosis of dementia.
B

Comment and evidence
It is desirable to perform structural imaging test (CT or MRI) to exclude dementia treatable by neurosurgery, such as
chronic subdural hematoma, brain tumor, and normal pressure hydrocephalus 1). In addition, MRI is superior fordiscriminating brain atrophy patterns, which is useful for differential diagnosis 2). Evaluation of signal changes on MRI is
useful for differential diagnosis of cerebrovascular diseases, leukoencephalopathy, encephalitis, demyelinating diseases, andothers 2).
The basic MRI sequences are T1-weighted image, T2-weighted image, and FLAIR image. When a brain tumor, inflammatory
lesion, or infectious lesion is suspected, perform contrast enhanced imaging to look for contrast enhancement 3). Diffusionweighted images are superior for detecting acute cerebral vascular lesions and lesions with high signal intensity in the cerebral
cortex or striatum/thalamus in Creutzfeldt-Jakob disease. T2*-weighted imaging and susceptibility-weighted imaging (SWI)
are excellent for detecting micro-hemorrhages in amyloid angiopathy.
Cerebral blood flow SPECT is useful for differential diagnosis of dementia due to lesions with low blood flow. Cerebral
blood flow SPECT uses nuclides such as 123I-IMP and 99mTc-ECD. Cerebral blood flow SPECT images can be interpreted
visually or analyzed using statistical methods [such as 3D-stereotactic surface projection (3D-SSP) and easy Z-score imaging
system (eZIS)]. Alzheimer’s disease dementia is characterized by decreased blood flow in the posterior cingulate gyrus,
anterior wedge, and parietal association area 3). FDG-PET detects decreased glucose metabolism and is more sensitive thancerebral blood flow SPECT, but this examination is not covered by medical insurance in Japan 4). In dementia with Lewy
bodies, disturbance of cardiac sympathetic nerve causes a decrease in MIBG uptake on MIBG scintigraphy 5). Dopaminetransporter scintigraphy using 123I-FP-CIT is considered to reflect the density of dopamine transporter in the striatum. This
test is approved for health insurance coverage in Japan for differentiating between dementia with Lewy bodies and Alzheimer’s
disease dementia, and is increasingly being used clinically.
For molecular imaging, techniques for visualizing amyloid β (Aβ) and tau have been established 6). 11C-PIB, 18F-Florbetapir,
18
F-Flutemetamol, and 18F-Florbetaben have been developed as ligands targeting Aβ 7). Refer to CQ6-6 for the clinicalsignificance of amyloid PET testing. 11C-PBB3 and 18F-T807 have been developed as ligands for visualizing tau. These
techniques are mainly used for research purposes, and currently they are not covered by health insurance in Japan.

▪ References
1) Filippi M, Agosta F, Barkhof F, et al. EFNS task force: the use of neuroimaging in the diagnosis of dementia. Eur J Neurol. 2012; 19(12): e131-e140.
2) Harper L, Barkhof F, Scheltens P, et al. An algorithmic approach to structural imaging in dementia. J Neurol Neurosurg Psychiatry. 2014; 85(6):692-698.
3) Yeo JM, Lim X, Khan Z, et al. Systematic review of the diagnostic utility of SPECT imaging in dementia. Eur Arch Psychiatry Clin Neurosci. 2013;
263(7): 539-552.
4) Shivamurthy VK, Tahari AK, Marcus C, et al. Brain FDG PET and the diagnosis of dementia. AJR Am J Roentgenol. 2015; 204(1): W76-W85.
5) King AE, Mintz J, Royall DR. Meta-analysis of 123I-MIBG cardiac scintigraphy for the diagnosis of Lewy body-related disorders. Mov Disord.
2011; 26(7): 1218-1224.
6) Pearson SD, Ollendorf DA, Colby JA. Amyloid-β positron emission tomography in the diagnostic evaluation of Alzheimer disease: summary ofprimary fi­ ndings and conclusions. JAMA Intern Med. 2014; 174(1): 133-134.
7) Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive
impairment, and education. Amyloid Imaging Task Force of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging.
Alzheimers Dement. 2013; 9(4): e106-e109.

Chapter 225▪ Search formula
PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])))AND (“Diagnostic Imaging” [Majr] OR imaging [TI] OR neuroimaging [TI] OR MRI [TI] OR CT [TI] OR SPECT [TI] OR PET [TI ]ORMIBG [TI])
Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR Diagnosis/TI AND (Diagnostic imaging/
MTH or Imaging/TI or MRI/TI and CT/TI or SPECT/TI or PET/TI or MIBG/TI)

26

Clinical Practice Guideline for Dementia 2017

CQ 2-9What are the useful blood and cerebrospinal fluid tests for the diagnosis ofdementia?
AnswerBlood tests are done to identify dementia associated with medical diseases. No useful blood tests for identifying
degenerative dementia have been established. Cerebrospinal fluid examination is used to exclude infections, tumors, andinflammatory disorders in the central nervous system. Decreased amyloid β42 (Aβ42) and elevated phosphorylated tau in
cerebrospinal fluid have been reported in Alzheimer’s disease dementia.
B

Comment and evidence
Blood tests are recommended to diagnose dementia and detect cognitive decline associated with medical diseases. Bloodcounts, hematology and blood biochemistry, and measurements of thyroid hormone, electrolytes, fasting blood glucose,vitamin B12, and folic acid are recommended. Serological tests for syphilis and human immunodeficiency virus (HIV) are
performed when such diagnoses are suspected based on medical history 1).
Cerebrospinal fluid examination is performed in atypical cases and other cases in which dementia subtype is difficult todiagnose 2). General examination and cytology are used to exclude infections, tumors (malignant lymphoma and metastatic
tumors), and inflammatory diseases in the central nervous system.
Alzheimer’s disease dementia manifests decrease in amyloid β42 (Aβ42) peptide and increases in total tau andphosphorylated tau proteins. The decrease in Aβ42 in cerebrospinal fluid is thought to reflect the accumulation of Aβ in thebrain and correlates with the results of amyloid positron emission tomography (PET) 3). These biomarkers have been
incorporated into various diagnostic criteria for Alzheimer’s disease dementia [International Working Group (IWG)-2
criteria 4) and National Institute on Aging–Alzheimer’s Association workgroup (NIA-AA) diagnostic criteria 5)]. As a
supplementary diagnostic test for dementia, phosphorylated tau measurement is covered by health insurance in Japan.
However, Aβ42 measurement is not covered by insurance. Mild cognitive impairment that converts to Alzheimer’s disease
dementia has been reported to show decrease in Aβ42 and increases in total tau and phosphorylated tau 1, 2).
According to a meta-analysis, α-synuclein in cerebrospinal fluid is lower in dementia with Lewy bodies compared toAlzheimer’s disease dementia, but this biomarker has not been applied to clinical use 6). Biomarkers for frontotemporallobar degeneration are also in the stage of development and none have been applied to clinical use. Measurement of total
tau in cerebrospinal fluid as a supplementary diagnostic test for Creutzfeldt-Jakob disease is covered by health insurancein Japan.

▪ References
1) Ahmed RM, Paterson RW, Warren JD, et al. Biomarkers in dementia: clinical utility and new directions. J Neurol Neurosurg Psychiatry. 2014;85(12): 1426-1434.
2) Noel-Storr AH, Flicker L, Ritchie CW, et al. Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia.
Alzheimers Dement. 2013; 9(3): e96-e105.
3) van Harten AC, Kester MI, Visser PJ, et al. Tau and p-tau as CSF biomarkers in dementia: a meta-analysis. Clin Chem Lab Med. 2011; 49(3): 353366.
4) Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6): 614-629.
5) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
6) Lim X, Yeo JM, Green A, et al. The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies—a systematic
review and meta-analysis. Parkinsonism Relat Disord. 2013; 19(10): 851-858.

Chapter 227▪ Search formula
PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis[TI]OR diagnoses [TI] OR diagnostic [TI])))AND (“Biological Markers” [Majr] OR biological marker* [TI] OR biomarker* [TI] OR “Hematologic Tests” [Mesh] OR hematologic test* [TI]
OR blood test* [TI] OR “Cerebrospinal Fluid” [Mesh] OR “cerebrospinal fluid” [TI] OR “cerebrospinal fluid” [SH])Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Biological marker/
MTH OR Biological marker/TI OR Biomarker/TI OR Hematological test/TH OR Hematological test/TI OR Blood test/TI OR Cerebrospinal
fluid test/TH OR Cerebrospinal fluid test/TI)

28

Clinical Practice Guideline for Dementia 2017

CQ 2-10

Which physical and neurological findings require attention when diagnosing
dementia?
AnswerPhysical and neurological examinations are performed in the process of diagnosing dementia. Findings from physicalexamination may lead to a diagnosis of treatable dementia associated with medical disorders. Findings obtained fromneurological examinations are useful in the diagnosis of different types of degenerative dementia.

Comment and evidence
Physical and neurological examinations are performed as the first step in the diagnosis of dementia 1).
Physical examinations include (1) hair, skin; (2) palpebral conjunctiva, pupil; (3) oral mucosa, pharynx, tongue; (4) neck:lymph nodes, thyroid gland, auscultation of vascular murmur; (5) pulse and blood pressure; (6) chest; (7) abdomen; (8)extremities: skin, joints, check for edema 1). Cervical vascular murmur and pulse irregularity suggest the presence of
cerebrovascular lesions. Pay attention to the presence or absence of otolaryngologic disorders accompanied by hearing
impairment. Alopecia, thyroid swelling, and non-pitting edema in the lower extremities are found in hypothyroidism. Erythemanodosum, oral aphtha, and genital ulcer are findings of neuro-Behçet’s disease. Asterixis is observed in hepatic encephalopathy.
Neurological examinations include investigations of the (1) level of consciousness; (2) cognitive function tests; (3) cranial
nerves, (4) motor system of extremities; (5) deep tendon reflex and pathological reflex; (6) involuntary movement; (7) sensory
system; (8) posture/gait; and (9) autonomic nervous system 2, 3).
The presence or absence of impaired consciousness is required to differentiate dementia from delirium. The presence ofsemi-blindness (hemianopsia) may suggest cerebrovascular lesions in the brain. If observation of the fundus using an
ophthalmoscope reveals optic disc edema, the presence of intracranial lesion causing increased intracranial pressure should
be suspected. Finding of weakened light reflex but preserved convergence reflex (Argyll Robertson pupil) is a symptom ofsuspected neurosyphilis. Impairment of vertical eye movement is seen at high frequency in progressive supranuclear palsy.
Restricted eye movement and diplopia are observed in Wernicke encephalopathy. Limb-kinetic apraxia and ideomotor
apraxia are characteristics of corticobasal degeneration. Tongue atrophy and fasciculation are observed in dementia associatedwith motor neuron disorder. Chorea is observed in Huntington’s disease and dentatorubral-pallidoluysian atrophy (DRPLA).
Resting tremor is found in dementia with Lewy bodies and Parkinson’s disease. Myoclonus is manifested in CreutzfeldtJakob disease, corticobasal degeneration, Alzheimer’s disease dementia, and others. Frontal lobe signs such as grasp reflex
and suck reflex are observed in patients with frontotemporal lobar degeneration. Sensory disturbances in distal extremities
occur in patients with peripheral neuropathy due to vitamin B12 deficiency. Deep sensory impairment is observed in tabes
dorsalis due to neurosyphilis and subacute combined degeneration of the spinal cord. Shuffling gait and freezing gait arecharacteristics of dementia with Lewy bodies. Shuffling wide-based gait is seen in normal pressure hydrocephalus. Autonomic
dysfunction such as orthostatic hypotension, dysuria, and constipation are observed in dementia with Lewy bodies 4).

▪ References
1) Ames D, Burns A, O’Brien J (Eds.). Dementia, fourth edition. Boca Raton, Fl: CRC Press; 2010.
2) Mizuno M. Handbook of Neurosurgical: Differential Diagnosis and Treatment, 4th edition. Tokyo: Igaku Shoin; 2010. (In Japanese)3) Shibazaki H. For Persons Learning Neurological Diagnosis, 2nd edition. Tokyo: Igaku Shoin; 2013. (In Japanese)4) Idiaquez J, Roman GC. Autonomic dysfunction in neurodegenerative dementias. J Neurol Sci. 2011; 305(1-2): 22-27.

▪ Search formula

PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia[TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])))AND (“Physical Examination” [Mesh] OR physical examination* [TI] OR physical ­finding*[TI])
Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Physiological test/
MTH OR Physiological test/TI OR Physical findings/TI)

Chapter 2

29

CQ 2-11

What are the drugs that affect the diagnosis of dementia?
Recommendations
It is necessary to keep in mind the possibility that drug-induced effects may underlie the decline in cognitive function.
Therefore, confirm the medications taken by the patients. Drug-induced cognitive impairment is more likely to occur
when the patients are of advanced age, have hepatic or renal dysfunction, or are taking multi-drug combination. Apartfrom causing delirium, drugs may induce cognitive impairment with a latent or subacute course. Anticholinergics andbenzodiazepines are risk factors of cognitive impairment and dementia.
1B

Comment and evidenceDrug-induced cognitive impairment has the following characteristics 1-2): (1) decreased attention is prominent; (2) druginduced cognitive impairment changes over time; (3) patient may manifest symptoms resembling delirium; (4) cognitive
impairment improves by discontinuing drug use; and (5) cognitive function deteriorates by drug overdose. Drug-induced
cognitive impairment occurs more commonly in patients with advanced age, hepatic or renal dysfunction, or are taking
multi-drug combination.
Among patients who show cognitive impairment, 2-12% is estimated to be associated with drugs 1). It should also be kept
in mind that some drugs cause delirium. One report shows that delirium is related to drugs in 11-30% of hospitalized older
patients 1).
Some drug classes tend to induce cognitive impairment. Among psychotropic drugs, phenothiazine antipsychotics with
anticholinergic effects, benzodiazepines that are anxiolytics, and tricyclic antidepressants more readily induce cognitive
impairment. Anti-parkinsonian drugs, opioid analgesics, NSAIDs and corticosteroids are drugs with a potential to induce
cognitive impairment. Attention should also be paid to the following drugs: drugs for the cardiovascular system including
some anti-hypertensive drugs, anti-arrhythmic drugs, digitalis, and diuretics; antibacterial and antiviral drugs; antitumor
drugs; drugs for overactive bladder and drugs for asthma with anticholinergic effects; and drugs for the digestive system with
anti-histamine effect.
Anticholinergic drugs used in older persons have been reported to increase the risk of cognitive decline and developmentof dementia 3). Cognitive impairment caused by anti-cholinergic drugs includes reduced memory, impaired attention, anddelirium, and is particularly common in older persons 4).
Cognitive impairment caused by long-term use of benzodiazepines includes impaired spatial perception, impaired verbal
memory, and attention deficits. A meta-analysis reports that taking oral benzodiazepines is a risk of dementia 5).
The Beers criteria clearly define appropriate drug prescriptions, created for the purpose of correcting inappropriate multidrug combinations and avoiding overdosage in older patients 6). In addition, the “Guidelines for Medical Therapy and its
Safety in the Elderly 2015” was published by the Japan Geriatrics Society 7). Refer to this reference when prescribing for older
patients. In addition, it is possible to browse the package inserts of pharmaceuticals from the website of the Pharmaceuticals
and Medical Devices Agency (https://www.pmda.go.jp/) and search for adverse events of individual drugs 8).

▪ References
1) Moore AR, O’Keefe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999; 15(1); 15-28.
2) Shinohara M, Yamada M. Cognitive impairment caused by drugs. Brain Nerve. 2012; 64(12); 1405-1410.
3) Carriere I, Fourrier-Reglat A, Dartigues JF, et al. Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general
population; the 3-city study. Arch Intern Med. 2009; 169(14): 1317-1324.
4) Rudolph JL, Salow MJ, Angelini MC, et al. The anticholinergic risk scale and anticholinergic adverse eff­ects in older persons. Arch Intern Med.
2008; 168(5); 508-513.
5) Zhong G, Wang Y, Zhang Y, et al. Association between benzodiazepine use and dementia; A meta-analysis. PLoS One. 2015; 10(5): e0127836.
6) Campanelli CM. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc
2012; 60: 616-631.
7) Japan Geriatrics Society, Japan Agency for Medical Research and Development / Study Group on Safety of Medical Treatment in the Elderly (Ed.)
Guidelines for Medical Treatment and its Safety in the Elderly 2015. Tokyo; Medical Tribune; 2015. (In Japanese)8) Pharmaceuticals and Medical Devices Agency, Information in Package Insert of Pharmaceuticals.
http://www.info.pmda.go.jp/psearch/html/menu_tenpu_base.html (In Japanese)

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Clinical Practice Guideline for Dementia 2017

▪ Search formula
PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia[TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic[TI])))AND (“Physiological E­ffects of Drugs” [Mesh] OR “Pharmacologic Actions/adverse effects” [Mesh] OR (“Chemicals and Drugs Category” [Majr]
AND “adverse effects” [SH]))
Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR Diagnosis/TI) AND ((SH = Toxicity/side
effect, chemical induction, adverse effect)OR Substance-related impairment /TH OR physiological action of drug/MTH)

Chapter 2

31

CQ 2-12

Are there useful genetic tests for the diagnosis of dementia?
AnswerFor hereditary dementia with Mendelian mode of inheritance, the causative genes have been identified, and a definitive
diagnosis can be established by identifying the gene mutation. Genetic diagnosis in principle requires patient’s consent
and should not be coerced. Provide genetic counseling as necessary. APOE polymorphism is a genetic factor of Alzheimer’s
disease dementia. and the frequency of carrier of the APOE ε4 allele is significantly higher in individuals with Alzheimer’s
disease dementia. Use of APOE polymorphism as a supplementary diagnostic test for Alzheimer’s disease dementia is notrecommended.

Comment and evidence
The causative genes of familial dementia that show Mendelian inheritance pattern have been identified. A diagnosis is establishedwhen a pathological mutation in the causative gene is identified. Mutations in APP, PSEN1, and PSEN2 are known to cause
familial Alzheimer’s disease, and more than 100 cases have been reported in Japan 1). Familial Alzheimer’s disease associatedwith genetic mutations often develops in the 40s and 50s 1, 2). The genetic causes of familial Lewy body dementia include SNCA
missense mutation and duplication mutation. Several genes responsible for frontotemporal lobar degeneration (FTLD) have beenreported 3). In Japan, hereditary FTLD is associated frequently with MAPT mutations, and rarely with GRN mutations 1).
APOE is a susceptibility gene for Alzheimer’s disease dementia, and polymorphisms of this gene influence the susceptibilityof an individual to the disease 4). The frequency of ε4 allele of APOE is high in Alzheimer’s disease dementia. According toan analysis of a larger number of Japanese patients, APOE ε4 allele is positive in approximately one-half of the patients with
Alzheimer’s disease dementia. Testing the APOE polymorphism as a supplementary diagnostic test for Alzheimer’s disease
dementia is not recommended 5). Genome-wide association studies in a large-scale sample of Alzheimer’s disease dementia
identifies 19 significant susceptibility genes, but the odds ratios are not high 6).
Genetic diagnosis in principle requires patient’s consent and should not be coerced 7). Consideration should be given to thepatient’s psychological burden of being diagnosed with a hereditary disease through genetic diagnosis, and the impact on thepatient’s family. Consider to provide opportunities for genetic counseling as needed.

▪ References
1) Kasuga K, Kikuchi M, Tokutake T, et al. Systematic review and meta-analysis of Japanese familial Alzheimer’s disease and FTDP-17. J Hum Genet.
2015; 60(5): 281-283.
2) Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer’s disease. Lancet Neurol. 2013; 12(1): 92-104.
3) Pelicano Paulos J, Massano J. Clinical, genetic and neuropathological features of frontotemporal dementia: an update and guide. Acta Med Port.
2013; 26(4): 392-401.
4) Schellenberg GD, Montine TJ. ­The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol. 2012; 124(13): 305-323.
5) Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American Collegeof Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011; 13(6): 597-605.
6) Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease.
Nat Genet. 2013; 45(12): 1452-1458.
7) “Guidelines on Genetic Diagnosis of Neurological Diseases” Preparation Committee (Ed.). Japanese Society of Neurology (Supervision). Guidelines
on Genetic Diagnosis of Neurological Diseases 2009. Tokyo: Igaku Shoin; 2009. (In Japanese)▪ Search formula
PubMed search: July 1, 2015 (Wednesday)#1 (“Dementia/diagnosis” [Majr] OR (dementia [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Majr] OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI])))AND (“Genetic Testing” [Mesh] OR “Heterozygote Detection” [Mesh] OR “Genetic Predisposition to Disease” [Mesh] OR “Molecular Diagnostic
Techniques” [Mesh] OR “Mutation” [Majr] OR genetic test* OR genetic diagnosis* OR mutation [TI])
Ichushi search: July 1, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Genetic testing/
TH OR Genetic testing/TI OR Gene testing/TI OR Gene diagnosis/TI OR Gene analysis/TI OR Gene analysis/TI)

32

Clinical Practice Guideline for Dementia 2017

Chapter 3
TreatmentA | Overview of Treatment
CQ 3A-1

How should interventions and support be given following a diagnosis
of dementia?
AnswerTo improve the quality of life (QOL) of people with dementia and their families, it is necessary to provide postdiagnostic support from the early stage after dementia is diagnosed, which involves giving advice on ways to live withdementia, guidance to connect to social resources, and help with making future plans. Different countries adopt various
approaches of post-diagnostic support, including education on dementia and participation in peer support groups such as
dementia café, with some countries even considering to prepare written informed decision and future care plan according
to each person’s wishes. Careful discussions are required to find the approaches of post-diagnostic interventions andsupport which are appropriate to Japan.

Comment and evidence
Until now, medical care for dementia has focused on early diagnosis and treatment initiation. However, it has been
pointed out that these approaches alone are not sufficient to mitigate the psychological impact on the patients and theirfamilies or their fear of a future without hope. The current view is that to help persons affected by dementia prepare their
future with confidence, post-diagnostic support is necessary from the early stage following the diagnosis, by providing usefuladvice on living with dementia and information on social resources, and helping them plan the future. Such approaches havealready been started in some countries 1).
Regarding the future approaches of post-diagnostic intervention and support in Japan, careful discussions from various
perspectives are needed, taking into consideration the unique cultural characteristics and actual circumstances in Japan.

▪ References
1) Innes A, Szymczynska P, Stark C. Dementia diagnosis and post-diagnostic support in Scottish rural communities: experiences of people withdementia and their families. Dementia (London). 2014; 13(2): 233-247.

▪ Search formula
PubMed search: July 7, 2015 (Tuesday)#1 “Dementia/therapy” [Majr] OR “Cognition Disorders/therapy” [Majr] OR “Memory Disorders/therapy” [Majr] OR ((dementia [TI] OR
cognition disorder* [TI] OR cognitive disorder* [TI] OR memory disorder* [TI]) AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))
OR(“Dementia/diagnosis” [Mesh] OR (dementia [TI] AND post [TI] AND (diagnosis [TI] OR diagnostic [TI] OR diagnoses [TI]))) AND(“Social Support” [Majr] OR support* [TI]) OR ((“Dementia” [Mesh] OR dementia [TI]) AND post-diagnostic) OR post-diagnostic support*
Ichushi search: July 7, 2015 (Tuesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI OR Cognitive function impairment /TI
OR Memory disorder/MTH OR Memory disorder/TI) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment) OR Treatment/MTH OR Therapeutic use/MTH OR Treatment/TI OR Therapy/
TI)

34

Clinical Practice Guideline for Dementia 2017

CQ 3A-2

How should pharmacotherapy, non-pharmacologic interventions and care beprovided during treatment of dementia?
AnswerUse a combination of pharmacotherapy and non-pharmacologic interventions to treat dementia with the goal to
improve cognitive function and quality of life (QOL). For behavioral and psychological symptoms of dementia (BPSD),
in principle, non-pharmacologic interventions should take priority over pharmacotherapy. When using psychotropic
drugs, continuously monitor for adverse events and whether medication is necessary.

Comment and evidence
In the treatment of dementia, the target symptoms include cognitive impairment, which is called the core symptom, as
well as BPSD including delusion and irritability. Treat these symptoms by a combination of pharmacotherapy and nonpharmacologic interventions. When BPSD are observed, investigate whether there are physical diseases causing these
symptoms and whether care is appropriate; and for treatment, give priority to non-pharmacologic interventions overpharmacotherapy 1, 2).

1. Treatment for cognitive impairment
For Alzheimer’s disease dementia, cholinesterase inhibitors and NMDA receptor antagonist are recommended.
Cholinesterase inhibitors are recommended for dementia with Lewy bodies. After medication is started, evaluate cognitive
function regularly by psychological tests such as the Mini-Mental State Examination.

2. Treatment for BPSD
For BPSD, evaluate changes in physical conditions that may have caused the symptoms, and whether care and environment
are appropriate 1). For environmental modification, consider using long-term care insurance services such as day service.
Non-pharmacologic interventions mitigate BPSD 3). Care for patients with dementia, whether at home or in an institution,
should be based on person-centered care that respects the will and hope of individual patients 4). Giving guidance to caregivers
regarding appropriate care delays admission to institution 5). Occupational therapy using sensory stimulation is reported to
improve BPSD 6).
After starting psychotropic drugs, continuously evaluate efficacy and adverse effects. If the demerits outweigh the benefits,consider dose reduction or discontinuation of the drug, while paying attention to the possibility of relapse of psychiatric
symptoms following drug withdrawal 1).

▪ References
1) Kales HC, Gitlin LN, Lyketsos CG, et al. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from amultidisciplinary expert panel. J Am Geriatr Soc. 2014; 62(4): 762-769.
2) Gauthier S, Cummings J, Ballard C, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr. 2010; 22(3): 346-372.
3) Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;
169(9): 946-953.
4) Kitwood T (translated by Takahashi S). Person-centered Care for Dementia. Tokyo: Tsutsui Shobo; 2005: 5-37. (In Japanese)5) Olazaran J, Reisberg B, Clare L, et al. Nonpharmacological therapies in Alzheimer’s disease: a systematic review of e­fficacy. Dement Geriatr Cogn
Disord. 2010; 30(2): 161-178.
6) Kim SY, Yoo EY, Jung MY, et al. A systematic review of the effects of occupational therapy for persons with dementia: a meta-analysis of randomized
controlled trials. NeuroRehabilitation. 2012; 31(2): 107-115.

▪ Search formula
PubMed search: July 7, 2015 (Tuesday)#1 ((“Dementia/drug therapy” [Majr] OR (dementia [TI] AND (“drug therapy” [TI] OR chemotherapy [TI] OR pharmacotherapy [TI] OR“pharmacological therapy” [TI]))) OR (“Cognition Disorders/drug therapy” [Majr] OR ((cognition disorder* [TI] OR cognitive disorder* [TI])
AND (“drug therapy” [TI] OR chemotherapy [TI] OR pharmacotherapy [TI] OR “pharmacological therapy” [TI]))) OR (“Memory Disorders/drug therapy” [Majr] OR (memory disorder* [TI] AND (“drug therapy” [TI] OR chemotherapy [TI] OR pharmacotherapy [TI] OR

Chapter 335

“pharmacological therapy” [TI])))) OR ((“Dementia/rehabilitation” [Majr] OR (dementia [TI] AND rehabilitation [TI]))OR(“Cognition Disorders/rehabilitation” [Majr]OR((cognition disorder* [TI]OR cognitive disorder* [TI]) AND rehabilitation [TI])) OR (“Memory Disorders/rehabilitation”[Majr] OR (memory disorder* [TI] AND rehabilitation [TI]))) OR ((“Dementia/therapy” [Majr] AND “Rehabilitation” [Mesh]) OR (“Cognition
Disorders/therapy” [Majr] AND “Rehabilitation” [Mesh]) OR (“Memory Disorders/therapy” [Majr] AND “Rehabilitation” [Mesh])) OR((“Dementia/nursing” [Majr] OR (dementia [TI] AND nursing [TI])) OR (“Cognition Disorders/nursing” [Majr] OR ((cognition disorder* [TI]
OR cognitive disorder* [TI]) AND nursing [TI])) OR (“Memory Disorders/nursing” [Majr] OR (memory disorder* [TI] AND nursing [TI])) OR((“Dementia/diet therapy” [Majr] OR (dementia[TI] AND “diet therapy” [TI])) OR (“Cognition Disorders/diet therapy” [Majr] OR ((cognition
disorder* [TI] OR cognitive disorder* [TI]) AND “diet therapy” [TI])) OR (“Memory Disorders/diet therapy” [Majr] OR (memory disorder* [TI]
AND “diet therapy”[TI]))) OR (( “Dementia/surgery” [Majr] OR (dementia[TI] AND (surg* [TI] OR operation* [TI]))) OR (“Cognition Disorders/surgery” [Majr] OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (surg*[TI] OR operation* [TI]))) OR (“Memory Disorders/surgery” [Majr] OR (memory disorder* [TI] AND (surg* [TI] OR operation* [TI])))) OR ((“Dementia/radiotherapy” [Majr] OR (dementia [TI]
AND radiotherapy [TI])) OR (“Cognition Disorders/radiotherapy” [Majr] OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND
radiotherapy [TI])) OR (“Memory Disorders/radiotherapy” [Majr] OR (memory disorder* [TI] AND radiotherapy [TI]))) OR (((“Dementia/
therapy” [Majr] AND “Psychotherapy” [Mesh]) OR (dementia [TI] AND psychotherapy [TI])) OR (“Cognition Disorders/therapy” [Majr] AND“Psychotherapy” [Mesh]) OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND psychotherapy [TI]) OR (“Memory Disorders/therapy”[Majr] AND “Psychotherapy” [Mesh]) OR (memory disorder* [TI] AND psychotherapy [TI])) OR (((“Dementia/therapy” [Majr] AND “Social
Support” [Mesh]) OR (dementia [TI] AND social support* [TI])) OR (“Cognition Disorders/therapy” [Majr] AND “Social Support” [Mesh]) OR((cognition disorder* [TI] OR cognitive disorder* [TI]) AND social support* [TI]) OR (“Memory Disorders/therapy” [Majr] AND “Social
Support” [Mesh]) OR (memory disorder* [TI] AND social support* [TI])) OR ((“Dementia/therapy” [Majr] AND “Patient Care” [Mesh]) OR(dementia [TI] AND “patient care” [TI])) OR (“Cognition Disorders/therapy” [Majr] AND “Patient Care” [Mesh]) OR ((cognition disorder* [TI]
OR cognitive disorder* [TI]) AND “patient care” [TI]) OR (“Memory Disorders/therapy” [Majr] AND “Patient Care” [Mesh]) OR (memory
disorder* [TI] AND “patient care” [TI]) OR ((“Dementia/therapy”[Majr] AND “Quality of Life” [Mesh]) OR (dementia [TI] AND quality of life*[TI])) OR (“Cognition Disorders/therapy” [Majr] AND “Quality of Life” [Mesh]) OR ((cognition disorder* [TI] OR cognitive disorder* [TI])
AND quality of life* [TI]) OR (“Memory Disorders/therapy” [Majr] AND “Quality of Life” [Mesh]) OR (memory disorder* [TI] AND quality oflife* [TI]) OR ((“Dementia/therapy” [Majr] AND “Informed Consent” [Mesh]) OR (dementia [TI] AND “informed consent” [TI]) OR (“Cognition
Disorders/therapy” [Majr] AND “Informed Consent” [Mesh]) OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND “informed
consent” [TI]) OR (“Memory Disorders/therapy” [Majr] AND “Informed Consent” [Mesh]) OR (memory disorder* [TI] AND “informed consent”[TI]) OR ((“nonpharmacological therapy” OR “non pharmacological therapy”) AND (“Dementia/therapy” [Majr] OR dementia [TI] OR“Cognition Disorders/therapy” [Majr] OR cognition disorder* [TI] OR cognitive disorder* [TI] OR “Memory Disorders/therapy” [Majr] OR
memory disorder* [TI]))
Ichushi search: July 7, 2015 (Tuesday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI OR Cognitive function impairment/TI
OR Memory disorder/MTH OR Memory Disorder/TI) AND ((SH = Pharmacotherapy, Rehabilitation, Nursing, Surgical therapy, Transplantation,
Dietary therapy, Psychiatric therapy, Radiotherapy) OR Pharmacotherapy/MTH OR Pharmacological action/MTH OR Pharmacotherapy/TI OR
Pharmacotherapy/TI OR Medication/TI OR Rehabilitation/MTH OR Rehabilitation/TI OR Nursing/MTH OR Nursing/TI OR Surgery/MTH
OR Surgical operation/TI OR Surgery/TI OR Transplantation/TI OR Dietary therapy/MTH OR Dietary therapy/TI OR Therapeutic diet/TI OR
Psychiatric therapy/TH OR Psychiatric therapy/TI OR Radiotherapy/MTH OR Radiological treatment/TI OR Radiotherapy/TI OR Social
support/MTH OR Social support/TI OR Patient management/MTH OR Patient management/TI OR Patient care/TI OR Informed consent/TH
OR “Informed Consent”/TI OR QOL/TH OR QOL/TI OR “Quality of Life”/TI)

36

Clinical Practice Guideline for Dementia 2017

CQ 3A-3

What are the principles and precautions of pharmacotherapy in older people
with dementia?
AnswerOlder people with dementia tend to develop adverse events during pharmacotherapy. (1) Consider starting with a low
dose, such as one-half to one-quarter of the dose used in young adults, depending on the type of drug to be prescribed.
(2) Evaluate drug efficacy after a short period of treatment. (3) Simplify the method of drug taking. (4) Avoid taking
multiple drugs as far as possible, while paying attention to adverse events specific to older people. Periodically evaluate thetype of drug, the dosage, and the necessity of long-term prescription. (5) Confirm adherence to drug-taking with family
members, caregivers, pharmacists, and others.

Comments and evidence
Many older people are affected by multiple diseases and the symptoms tend to be atypical. In addition, they show large
individual differences in symptoms and response to drugs. For these reasons, they tend to use multiple drugs in combination
for prolonged periods. The frequencies of adverse events are also high in older people; 15% of those aged 75 years or above
have adverse events 1).
In view of the physiological deterioration of liver and renal functions in older people, consider starting with a low dose,such as one-half to one-quarter of the dose used in young adults, depending on the type of drug used.
Evaluate efficacy after a short period of treatment.
Simplify the method of drug taking.
Avoid using multiple drugs.
Confirm adherence to drug-taking with both the patient and also the caregiver.

▪ References
1) Toba K, Akishita M, Mizuno Y, et al. Adverse drug reaction in the elderly. Japanese Journal of Geriatrics (Nippon Ronen Igakkai Zasshi) 1999;
36(3): 181-185. (In Japanese)▪ Search formula
PubMed search: July 7, 2015 (Tuesday)#1 (“Dementia/drug therapy” [Majr] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Majr]
OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug therapy”[Majr] OR(memory disorder* [TI] AND (“drug therapy” OR chemotherapy))) AND “Aged, 80 and over” [Mesh]
Ichushi search: July 6, 2015 (Monday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI OR Cognitive function impairment/TI
OR Memory disorder/MTH OR Memory disorder/TI) AND (CK = Elderly (80~)) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/MTH
OR Pharmacological effect/MTH OR Drug treatment/TI OR Pharmacotherapy /TI OR Therapeutic drug/TI)

Chapter 3

37

CQ 3A-4

What are the adverse events of psychotropic drugs [such as falls, declined activityof daily living (ADL), cognitive impairment, and aspiration pneumonia]?
AnswerAdverse events of antipsychotic drugs include over-sedation, hypotension, falls, dysphagia, constipation, and neuroleptic
malignant syndrome. Antipsychotic drugs are also associated with increased risk of death. Pay special attention to impaired
glucose tolerance when using olanzapine and quetiapine. Selective serotonin reuptake inhibitor (SSRI) and serotoninnorepinephrine reuptake inhibitor (SNRI) may cause nausea, loose stools, and serotonin syndrome. Benzodiazepine
anxiolytics and hypnotic drugs may cause falls, aspiration, somnolence, and respiratory depression.
A

Comments and evidence
Older people with dementia are prescribed drugs under the situations of impaired walking function and judgement ability
together with increased susceptibility to developing adverse events. Adverse events of antipsychotics include over-sedation,
falls, fracture, dysphagia, constipation, urinary tract infection, cerebrovascular disease, cardiovascular event, venous
thrombosis, edema, gait disturbance, neuroleptic malignant syndrome, and increased risk of death 1).
Olanzapine and quetiapine are contraindicated in patients with diabetes and those with a history of diabetes. Risperidone
and aripiprazole should be administered with caution in patients with diabetes or a history of diabetes, and patients with risk
factors of diabetes including a family history of diabetes, hyperglycemia, and obesity. For olanzapine, quetiapine, andaripiprazole, warning has been issued regarding the need to monitor blood glucose and explain to patients what to do whenadverse effects occur.
The antidepressant SSRI and SNRI may cause gastrointestinal symptoms such as nausea and loose stools, and serotonin
syndrome (including tremor, sweating, tachycardia, anxiety, and agitation). Among anxiolytics and hypnotic drugs,
benzodiazepines is the main drug class that may cause weakness, falls, aspiration, dysphagia, somnolence, and respiratory
depression, etc.

▪ Reference
1) Huybrechts KF, Gerhard T, Crystal S, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs:
population based cohort study. BMJ. 2012; 344: e977.

▪ Search formula
PubMed search: July 7, 2015 (Tuesday)#1 (“Dementia/drug therapy” [Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy”[Mesh] OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug
therapy” [Mesh] OR (memory disorder* [TI] AND (“drug therapy” OR chemotherapy))) AND (“Psychotropic Drugs/adverse effects” [Mesh] OR((psychotropic drug* [TI] OR psychotropic agent* [TI]) AND (side effect* [TI] OR adverse effect* [TI] OR adverse reaction* [TI])) OR“Psychopharmacology/adverse effects” [Mesh] OR (psychopharmacology [TI] AND (side effect* [TI] OR adverse effect* [TI] OR adverse reaction*[TI])) OR ((antipsychotic agent* [TI] OR antipsychotic drug* [TI]) AND (side effects* [TI] OR adverse effect* [TI] OR adverse reaction* [TI])))
Ichushi search: July 6, 2015 (Monday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI OR Cognitive function impairment/TI
OR Memory disorder/MTH OR Memory disorder/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy /MTH OR Pharmacological action/
MTH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI) AND (Antipsychotic drug/TH OR Antipsychotic drug/TI OR
Psychopharmacology/TH OR Psychopharmacology/TI OR Antipsychotic drug/TI)AND ((SH = Toxicity·Adverse effect, Chemical induction,
Adverse effect) OR Toxicity/TI OR Side effect/TI OR Adverse/TI)

38

Clinical Practice Guideline for Dementia 2017

CQ 3A-5

What are the treatment procedures when using pharmacotherapy for dementia?
Answer
Before starting pharmacotherapy for dementia patients, consider carefully whether such therapy is necessary. Ifpharmacotherapy is required, confirm adherence to drug taking and the indications of the drug, give sufficient explanations
to patients and caregivers, and then start treatment.
B

Comments and evidence
Since older people already have other physical illnesses, they may be using a combination of multiple drugs. Before
starting pharmacotherapy for dementia, consider carefully the necessity of the therapy, and initiate treatment if the treatment
is judged to be necessary.
Before initiating pharmacotherapy, explain the general benefits and risks of pharmacotherapy using language that is easy
to understand even for the patient with dementia, and give due consideration also to respect the will of the patient. Despite
these explanations, if the patient’s intention cannot be confirmed, or if the patient lacks the ability to make a judgment,
explain to family members or other proxies and obtain consent.
People with dementia have difficulties managing medication from a relatively early stage of the disease due to cognitive
impairment. Accidents such as unintentional overdose may occur due to the inability to manage medication. Whenprescribing medications for patients with dementia, it is necessary to simplify the method of drug taking such as minimizing
the number of drug-taking, to facilitate visual medication management by dispensing drugs together in one package or using
a pill box, and to modify the environment so that it can be shared between the patient and caregiver. Depending on theseverity of dementia, the caregiver may need to fully manage the medication. It is desirable to start pharmacotherapy after
making the above preparations and confirming that the environment allows maintenance of good adherence.
Behavioral and psychological symptoms of dementia (BPSD) can appear at any stage of dementia. Parallel topharmacotherapy for cognitive impairment, start treatment (non-pharmacological interventions or pharmacotherapy) for
BPSD any time when the need arises. Also provide concomitant treatments for neurological symptoms associated with theprimary disease, coexisting conditions specific to older people (including delirium, dysphagia, falls/fractures, pneumonia,
urinary disorder, and constipation), and physical complications (including hypertension, diabetes, and dyslipidemia).
Regardless of the drugs used, pay close attention to adverse events. When adverse events are observed, consider changing
or discontinuing the drug promptly.

▪ Further reading
1) Toba K. Dementia (second volume): Pharmacotherapy for dementia: compliance and adherence to drug taking. Japanese Journal of Clinical
Medicine (Nihon Rinsho) 2011; 69: 22-25 (In Japanese)
2) Japan Geriatrics Society, Japan Agency for Medical Research and Development / Study Group on Safety of Medical Treatment in the Elderly (Ed.)
Guidelines for Medical Treatment and its Safety in the Elderly 2015. Tokyo; Medical Tribune; 2015. (In Japanese)▪ Search formula
PubMed search: July 4, 2015 (Saturday), July 18, 2015 (Saturday)#1 “Dementia/drug therapy” [Majr] OR (dementia[TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Majr]
OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND(“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug therapy”[Majr] OR (memory disorder* [TI] AND (“drug therapy” OR chemotherapy))
Ichushi search: July 4, 2015 (Saturday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI OR Cognitive function impairment/TI
OR Memory disorder/TI OR Memory disorder/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/MTH OR Pharmacological action/
MTH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)

Chapter 3

39

CQ 3A-6

What are the adverse events due to cholinesterase inhibitors and NMDA
receptor antagonists, and what should be done in case of these events?
Recommendation
The common adverse events of cholinesterase inhibitors are gastrointestinal symptoms including nausea/vomiting anddiarrhea.
The common side effects of NMDA receptor antagonists include somnolence, dizziness, constipation, and headache.
In principle, these adverse events are managed by dose reduction or discontinuation of the responsible drug.

1B

Comments and evidence
Regarding serious adverse events of medications used to treat Alzheimer’s disease dementia, cholinesterase inhibitors havebeen reported to cause adverse effects of the cardiovascular system such as syncope, bradycardia, and QT prolongation 1). The
NMDA receptor antagonist memantine has been reported to cause serious adverse events including syncope and psychiatric
symptoms 2).
Cholinesterase inhibitors are associated with high frequencies of adverse events of the gastrointestinal system such as
diarrhea, nausea/vomiting, and headache 3). Gastrointestinal symptoms are more likely to appear when administration is
initiated or when the dose is increased, and the incidence increases as the dose becomes higher. The rates of syncope 1, 4),
fracture 1, 4), accidental injury 4), bradycardia 1), pacemaker implantation 1) have been shown to be higher under administrationof cholinesterase inhibitors compared to controls 3). Rivastigmine patch is a transdermal formulation that achieves relatively
stable blood level. While the frequency of gastrointestinal symptoms associated with the patch formulation is lower than thatof the oral formulation 5), skin reaction may occur at the site of application.
Although dizziness, somnolence, headache, and constipation have been reported to be relatively frequent adverse effectsof memantine 2), one meta-analysis finds no significant difference compared with placebo 6).
Since the frequencies of occurrence of common adverse events differ depending on the disease, attention is required.
There is little evidence on how to manage adverse effects. Domperidone may be effective for gastrointestinal symptoms 7).
A moisturizer may be used to prevent inflammation at the site of application of the rivastigmine patch. If inflammation
persists, consider using topical steroids 8).
In all cases, including those mentioned above, if adverse events are serious, consider reducing the dose or discontinuing
the causative drug.
There is little evidence on the treatment of acute intoxication due to overdose or mistaken administration. Since acuteintoxication may sometimes lead to death, caution is required.

▪ References
1) Howes LG. Cardiovascular e­ffects of drugs used to treat Alzheimer’s disease. Drug Saf. 2014; 37(6): 391-395.
2) Honma A, Ozawa M, Shiosakai K, et al. Safety and efficacy of memantine hydrochloride in patients with Alzheimer’s disease: Interim results ofspecified drug use survey on long-term use of memantine hydrochloride. Journal of Geriatrics(Nippon Ronen Igakkai Zasshi) 2014; 25(4): 419-433.
(In Japanese)3) Ihl R, Frolich L, Winblad B, et al. WFSBP Task Force on Treatment Guidelines for Alzheimer’s Disease and other Dementias. World Federation ofSocieties of Biological Psychiatry (WFSBP) guidelines for the biological treatment of Alzheimer’s disease and other dementias. World J Biol
Psychiatry. 2011; 12(1): 2-32.
4) Kim DH, Brown RT, Ding EL, Kiel DP, Berry SD. Dementia medications and risk of falls, syncope, and related adverse events: meta-analysis ofrandomized controlled trials. J Am Geriatr Soc. 2011; 59(6): 1019-1031.
5) Birks JS, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2015; (4): CD001191.
6) Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS One. 2015; 10(4):e0123289.
7) Kano O, Urita Y, Ito H, et al. Domperidone e­ffective in preventing rivastigmine-related gastrointestinal disturbances in patients with Alzheimer’s
disease. Neuropsychiatr Dis Treat. 2013; 9: 1411-1415.
8) Tahira T. Pharmacotherapy‒core symptom. Tahira T: ABC of New Diagnosis and Treatment 22; Neurology 3; Alzheimer’s Disease Dementia 2nd
Edition. 138-145, Osaka: Saishin Igakusha; 2014. (In Japanese)

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Clinical Practice Guideline for Dementia 2017

▪ Search formula
PubMed search: July 4, 2015 (Saturday)#1 (“Dementia/drug therapy” [Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy”[Mesh] OR ((cognition disorder* [TI] OR cognitive disorder* [TI]) AND (“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug
therapy” [Mesh] OR (memory disorder* [TI] AND (“drug therapy” OR chemotherapy))) AND (“Cholinesterase Inhibitors/adverse effects” [Mesh]
OR (cholinesterase inhibitor* [TI]) OR “Memantine/adverse effects” [Mesh] OR (memantine [TI] OR NMDA receptor antagonist* [TI] OR
N-Methyl-D-Aspartate receptor antagonist* [TI]))
Ichushi search: July 4, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI OR
Cognitive impairment/TH OR Memory disorder/TI) AND (((“Cholinesterase Inhibitors”/TH OR “Cholinesterase Inhibitor”/TI OR cholinesterase
inhibitor/TI OR cholinesterase inhibitor/TI)AND((SH = Toxicity/side effect, chemical induction, adverse effect) OR adverse reaction/TI OR
adverse effect/TI OR toxicity/TI)) OR ((Memantine/TH OR Memantine/TI OR memantine/TI OR NMDA receptor antagonist/TI OR NMDA
receptor antagonist/TI) AND ((SH = side effect, chemical induction, adverse effect) OR adverse reaction/TI OR adverse effect/TI OR toxicity/TI)))

Chapter 3

41

CQ 3A-7-1

What are the non-pharmacological therapies for dementia?
AnswerNon-pharmacological interventions for persons with dementia include cognitive function training, cognitive
stimulation, exercise therapy, reminiscence, music therapy, and activities of daily living (ADL) training.
C

Comment and evidence
Among the treatments for dementia, all the therapies other than pharmacotherapy are grouped together as nonpharmacological therapies. Non-pharmacological therapies aim to improve not only cognitive impairment but also behavioral
and psychological symptoms of dementia (BPSD) as well as functions of daily living. Non-pharmacological therapies fordementia are broadly divided into interventions for patients with dementia and interventions for the caregivers. In practice,
however, the two kinds of interventions are conducted in combination.
It should be noted that non-pharmacological therapies are intended not only for mitigating psychiatric symptoms andbehavioral disorders but also for other benefits. For example, methods such as music therapy and reminiscence therapy arehighly significant as means to engage dementia patients in active communication and involve them in daily living. Therefore,
the validity and importance of these therapies cannot be judged solely based on whether mental symptoms are improved. In
the clinical setting, it is necessary to consider intervention methods also for the purpose of maintaining the patients’ qualityof life (QOL) and their motivation in daily living.
Caregivers also should receive care. Appropriate interventions for caregivers are effective to preventive burnout. Structured
psychological education for caregivers (a combination of learning knowledge, communication skills, behavior management,
cognitive behavioral therapy, etc.) has been shown to reduce caregiver burnout and depression 1).

▪ Reference
1) Jensen M, Agbata IN, Canavan M, et al. E­ffectiveness of educational interventions for informal caregivers of individuals with dementia residing in
the community: systematic review and meta-analysis of randomised controlled trials. Int J Geriatr Psychiatry. 2015; 30 (2):130-143.

▪ Further reading
1) Olazaran J, Reisberg B, Clare L, et al. Nonpharmacological therapies in Alzheimer’s disease: a systematic review of efficacy. Dement Geriatr Cogn
Disord. 2010; 30(2): 161-178.
2) Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;
169(9): 946-953.

▪ Search formula
PubMed search: July 4, 2015 (Saturday), August 3, 2015 (Sunday)#1 (“Dementia/therapy” [Majr] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition Disorders/therapy” [Majr] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic[TI] OR treatment [TI])) OR “Memory Disorders/therapy”[Majr] OR (memory disorder* [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) NOT (“Dementia/drug therapy” [Mesh] OR(dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Mesh] OR (“cognition disorder*” [TI] AND(“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug therapy” [Mesh] OR (memory disorder* [TI] AND (“drug therapy” ORchemotherapy))) OR (“Dementia/therapy” [Mesh] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition
Disorders/therapy” [Mesh] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Memory Disorders/therapy” [Mesh] OR (memory disorder* [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) AND (neuropsychiatric symptom* OR
behavioral symptom* OR behavioural symptom* OR psychological symptom*) OR “neuropsychiatric symptoms of dementia” OR “behavioral andpsychological symptoms of dementia”
Ichushi search: July 4, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI OR
Memory disorder/TI OR Memory disorder/TI ) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment)OR Treatment/TH OR Treatment/TI OR Therapy/TI) NOT ((SH = Pharmacotherapy)
OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)

42

Clinical Practice Guideline for Dementia 2017

CQ 3A-7-2

What are the symptoms that respond to non-pharmacological therapies fordementia?
Recommendation
Non-pharmacological therapies and exercise therapy that exert effects on cognitive function, such as cognitive
stimulation, are effective in improving cognitive impairment in dementia. Exercise therapy may be effective in improving
activities of daily living (ADL), and music therapy may be effective to treat behavioral and psychological symptoms ofdementia (BPSD).
2C

Comments and evidence
Non-pharmacological therapies that are effective for cognitive impairment in Alzheimer’s disease dementia include
cognitive stimulation 1, 2). A meta-analysis shows that interventions using cognitive stimulation improves the Mini Mental
State Examination score by 1.74 points (95% confidence interval 1.13 to 2.36) and ADAS-cog by 2.27 points (95%
confidence interval 0.99 to 3.55) compared to the no intervention group, and the effect remains evident during the follow-up
period of 1 to 3 months 3). Multi-component interventions have also been shown to improve ADL, quality of life (QOL), as
well as behavior and mood 1). When cognitive stimulation is used, participants’ self-evaluation for QOL and well-being
improves 1). However, little evidence is available for other non-pharmacological interventions including transcutaneouselectrical stimulation therapies (transcranial, peripheral), exercise therapy, music therapy, reminiscence therapy, ADL
training, massage, recreational therapy, light therapy, multisensory stimulation therapy, supportive psychotherapy, validation
therapy, acupuncture, transcranial magnetic stimulation, and muscle relaxation. Future reports with high-quality evidence
are awaited. In the actual clinical setting, it is important to select an intervention method that matches the individuality ofthe patient.
Providing multi-component interventions including psychological education for caregivers delays institutionalization ofhome-care patients, reduces BPSD, and improves caregiver outcomes.

▪ References
1) Olazaran J, Reisberg B, Clare L, et al. Nonpharmacological therapies in Alzheimer’s disease: a systematic review of e­fficacy. Dement Geriatr Cogn
Disord. 2010; 30(2): 161-178.
2) Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;
169(9): 946-953.
3) Woods B, Aguirre E, Spector AE, et al. Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database Syst
Rev. 2012; 2: CD005562.

▪ Search formula
PubMed search: July 4, 2015 (Saturday), August 3, 2015 (Sunday)#1 (“Dementia/therapy” [Majr] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition Disorders/therapy” [Majr] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Memory Disorders/therapy”[Majr] OR (memory disorder* [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) NOT (“Dementia/drug therapy” [Mesh] OR(dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Mesh] OR (“cognition disorder*” [TI] AND(“drug therapy” OR chemotherapy)) OR “Memory Disorders/drug therapy” [Mesh] OR (memory disorder* [TI] AND (“drug therapy” ORchemotherapy))) OR (“Dementia/therapy” [Mesh] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition
Disorders/therapy” [Mesh] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Memory Disorders/therapy” [Mesh] OR (memory disorder* [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) AND (neuropsychiatric symptom* OR
behavioral symptom* OR behavioural symptom* OR psychological symptom*) OR “neuropsychiatric symptoms of dementia” OR “behavioral andpsychological symptoms of dementia”
Ichushi search: July 4, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI OR
Memory disorder/TI OR Memory disorder/TI ) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment) OR Treatment/TH OR Treatment /TI OR Therapy/TI) NOT ((SH =Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)

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43

B | Treatment for behavioral and psychological symptoms
of dementia (BPSD)
CQ 3B-1

What are the effective non-pharmacological therapies and pharmacotherapy
for anxiety?
Recommendation
Anxiety is an important symptom that can cause or induce other behavioral and psychological symptoms of dementia(BPSD). The fundamental approach is to interact with the patient by speaking in a reassuring tone with a caring attitude.
As non-pharmacological therapies for anxiety, music therapy and cognitive behavioral therapy may be effective, and theyshould be considered. If these treatments are not adequately effective, consider prescribing risperidone, olanzapine orquetiapine.
2C

Comments and evidence
Anxiety is an important symptom that can cause or induce other BPSD. First, the fundamental approach is to interact
with the patient in a reassuring voice and attitude. Music therapy has been confirmed to be effective as a non-pharmacologicaltherapy for anxiety 1). Music therapy is desirably provided directly by music therapists, and is especially recommended forpeople with moderate to severe dementia. Cognitive behavioral therapy has been shown to be effective for persons with mild
to moderate dementia 2).
If the above interventions do not provide adequate effect, consider pharmacotherapy.
A double-blind RCT comparing risperidone with haloperidol confirms the superiority of risperidone for anxiety symptoms 3).
Olanzapine has also been shown to be a safe and effective drug compared with placebo as control in a double-blind RCT for thetreatment of anxiety in patients with Alzheimer’s disease dementia 4). In an open-label study comparing quetiapine and haloperidol,
quetiapine improves anxiety and is well tolerated whereas haloperidol is not effective 5). Since these atypical antipsychotics are used
off-label, it is necessary to give adequate explanations to the patients and families, and to pay attention to adverse events while using
the drugs. In addition, even if a drug is effective, it should not be used casually; keep in mind to reduce the risk of adverse effects
by adjusting the dose or withdrawing the drug when symptoms have improved.
Benzodiazepines have been used to mitigate mild anxiety symptoms, but there is no clear evidence. When using this drug,
pay attention to adverse events such as sedation, disorientation, delirium, confusion, disinhibition, ataxia, falls, fracture, anddrug dependence at usual doses.

▪ References
References 3-5 on pharmacotherapy are the same as the references in the previous version of the guideline.
1) Raglio A, Bellelli G, Mazzola P, et al. Music, music therapy and dementia: a review of literature and the recommendations of the Italian Psychogeriatric
Association. Maturitas. 2012; 72(4): 305-310.
2) Stanley MA, Calleo J, Bush AL, et al. ­The Peaceful Mind Program: a pilot test of a CBT-based intervention for anxious patients with dementia. Am
J Geriatr Psychiatry. 2013; 21(7): 696-708.
3) Suh GH, Greenspan AJ, Choi SK. Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia.
Int J Geriatr Psychiatry. 2006; 21(7): 654-660.
4) Mintzer J, Faison W, Street JS, et al. Olanzapine in the treatment of anxiety symptoms due to Alzheimer’s disease: a post hoc analysis. Int J Geriatr
Psychiatry. 2001; 16(Suppl 1): S71-S77.
5) Savaskan E, Schnitzler C, Schroder C, et al. Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer’s disease
haloperidol vs. quetiapine. Int J Neuropsychopharmacol. 2006; 9(5): 507-516.

▪ Search formulaNon-pharmacological therapy
PubMed search: October 2, 2015 (Friday)

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Clinical Practice Guideline for Dementia 2017

#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [Mesh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indifference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR“Delusions” [Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR
dysphoria [TI] OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual
Behavior” [Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI] OR “inappropriate sexual behavior” [TI] OR restlessness[TI] OR(“Motor Activity” [Mesh]AND aberrant [TI]) OR “aberrant motor behaviour” [TI] OR “aberrant motor behavior” [TI] OR “Sleep
Disorders” [Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR“Apathy” [Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indifference OR aggression OR agitation OR
irritability OR delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour”
OR “inappropriate sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR“sleep disturbance” OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Alzheimer/TI OR frontotemporal lobar degeneration/TI OR “frontotemporal lobar
degeneration”/TI) AND ((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Non-pharmacotherapy/
TI OR Non-pharmacological treatment/TI OR validation therapy/TH OR validation therapy/TI OR “validation therapy”/TI OR Reality
orientation/TH OR “Reality orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH
OR Music therapy/TI OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR
Aromatherapy/TI OR “aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise
therapy/TH OR Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR
Physical exercise/TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive
training/TI OR “cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR“stimulation therapy”/TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver/TH OR
Caregiver/TI) AND (Education/TI OR Intervention/TI)) OR (caregiver/TI) AND (“psycho-education”/TI OR intervention/TI)) OR Nursing careservice/TH OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia
day service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND (Anxiety/TH OR Anxiety/TI OR Indifference/TI
OR Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual
perversion/TH OR ((Deviation OR Abnormality) AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleeping disturbance/
TI OR Dyssomnia/TI OR Insomnia/TI OR Sleepiness/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 (Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug th­erapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”))
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/
TI OR Therapeutic drug/TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Anxiety/TH OR Anxiety/TI OR Indifference/TI)

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CQ 3B-2

What are the effective non-pharmacological therapies and pharmacotherapy
for agitation?
Recommendation
Treat agitation based on person-centered care; consider the reasons and causes for the symptoms and try to resolve
them. It is also effective for the caregivers to learn appropriate conversation skills with persons with dementia and topractice the skills. Other non-pharmacological interventions such as group activities, music therapy, tactile care, andmassage have been shown to be effective. For pharmacotherapy, atypical antipsychotics such as risperidone and aripiprazole
have been shown to be effective. Consider also to use Yokukansan (liver-inhibiting powder), tiapride, carbamazepine,
sertraline, escitalopram, and trazodone.
2C

Comments and evidence
In a systematic review that examines the effectiveness of 33 non-pharmacological interventions for agitation, educating
caregivers about personal-centered care and training them to acquire appropriate communication skills with persons withdementia improve agitation 1). Other non-pharmacological therapies including group activities, music therapy conducted byexperts based on a program, tactile care, and massage have been shown to be effective.
If non-pharmacological therapies do not provide adequate effect, consider pharmacotherapy. Note that all the drugs
described below are used off-label, and should be used with caution after explaining adequately to the patients and families
and paying attention to adverse events during use. In addition, even when a drug is effective, it should not be used casually,and efforts should be made to decrease the risk of adverse effects by reducing the dose or withdrawing the drug when
symptoms have improved.
In a systematic review that summarizes 18 studies on atypical antipsychotics compared with placebo for agitation andaggression in Alzheimer’s disease dementia, low-dose risperidone is most promising and aripiprazole can be expected to be
as effective as risperidone, while the effect of olanzapine is variable, and quetiapine is not effective 2).
A systematic review on antidepressants finds little research and insufficient evidence, but the effectiveness of sertraline,
escitalopram, and trazodone has been reported 3). Carbamazepine can also be expected to be effective 2). A multicenter study inJapan has reported the effectiveness of Yokukansan 4). Tiapride is also reported to be effective for agitation and aggression 5). Useof tiapride may be considered because it is covered by health insurance in Japan for aggressive behavior and hyperphrenia
associated with the sequelae of cerebral infarction.

▪ References
1) Livingston G, Kelly L, Lewis-Holmes E, et al. Non-pharmacological interventions for agitation in dementia: systematic review of randomised
controlled trials. Br J Psychiatry. 2014; 205(6): 436-442.
2) Ballard C, Corbett A. Agitation and aggression in people with Alzheimer’s disease. Curr Opin Psychiatry. 2013; 26(3): 252-259.
3) Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011; (2): CD008191.
4) Mizukami K, Asada T, Kinoshita T, et al. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatmentof the behavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol. 2009; 12(2): 191-199.
5) Allain H, Dautzenberg PH, Maurer K, et al. Double blind study of tiapride versus haloperidol and placebo in agitation and aggressiveness in elderly
patients with cognitive impairment. Psychopharmacology (Berl). 2000; 148(4): 361-366.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR

46

Clinical Practice Guideline for Dementia 2017

“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [Mesh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indifference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR“Delusions” [Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR
dysphoria [TI] OR “Wandering Behavior” [Mesh] OR wandering [TI]OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual
Behavior” [Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI] OR “inappropriate sexual behavior” [TI] OR restlessness[TI] OR(“Motor Activity” [Mesh]AND aberrant [TI]) OR “aberrant motor behaviour” [TI] OR “aberrant motor behavior” [TI] OR “Sleep
Disorders” [Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR“Apathy” [Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indi­fference OR aggression OR agitation OR
irritability OR delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour”
OR “inappropriate sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR“sleep disturbance” OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR frontotemporal lobar degeneration/TI OR “frontotemporal lobar degeneration”/TI)
AND((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR 非Pharmacotherapy/TI OR Nonpharmacological treatment/TI OR validation therapy/TH OR validation therapy/TI OR “validation therapy”/TI OR Reality Orientation/TH OR“Reality Orientation”/TI OR reminiscence/TH OR reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH OR Music therapy/TI
OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR Aromatherapy/TI OR“aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise therapy/TH OR
Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR Physical exercise/
TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive training/TI OR“cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR “stimulation
therapy”/TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR Caregiver/TI)
AND (Education/TI OR Intervention/TI)) OR (caregiver/TI) AND (“psycho-education”/TI OR intervention/TI)) OR Nursing care service/TH
OR Nursing care service/TI OR “dementia care service”/TI OR day care/TH OR day care/TI OR “adult day service”/TI OR “dementia day
service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND(Anxiety/TH OR Anxiety/TI OR Indifference/TI OR
Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness)OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR ((Deviation OR Abnormality)AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleeping disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Sleepiness/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug ­therapy” [Mesh]) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR (dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”)
Ichushi search: June 22, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/
TI OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Aggression/TH OR Aggression/TI OR Psychomotor
agitation/TH OR Irritable mood/ TH)

Chapter 347

CQ 3B-3

What are the effective non-pharmacological therapies and pharmacotherapy
for hallucinations and delusions?
Recommendation
For persons with dementia who manifest hallucinations and delusions, the first step is to reduce their anxiety throughan approach of acceptance. In addition, when a specific person is the object of delusion, consider keeping a temporal andphysical distance from that person. Also consider the possibility that the drugs being taken may cause hallucinations anddelusions, and investigate this possibility. In patients with Alzheimer ’s disease dementia, if symptoms do not improve byanti-dementia drugs and the above methods, consider using atypical antipsychotics such as risperidone, olanzapine,quetiapine, and aripiprazole. Yokukansan may also be considered.
2C

Comment and evidence
For hallucinations and delusions, it is important to listen to the patients’ complaint first, and then give them a sense of
security in a receptive and sympathetic manner without denial or affirmation. It is also important to give them a role andsomething to live for.
When a specific person in the family is the subject of delusion, it is useful to utilize care services to keep a time andphysical distance between the patient and that person. If such intervention does not solve the problem, pharmacotherapy has
to be considered. For delusions in Alzheimer ’s disease dementia, try to administer anti-dementia drug. If the symptoms do
not improve, consider using antipsychotic drugs. However, since these drugs are used off-label, it is necessary to explain
carefully to the patients and families and pay attention to adverse events during use. In addition, even if a drug is effective,
it should not be taken casually. Bear in mind the need to reduce the risk of adverse effects by adjusting the dose or withdrawing
the drug when symptoms have improved.
Regarding the use of antipsychotic drugs in persons with dementia, effectiveness has been reported in a few studies withsmall numbers of cases, but no large-scale randomized controlled trial (RCT) has been reported 1-3). When using antipsychotic
drugs, atypical antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) are recommended.
For drugs other than antipsychotics, Yokukansan has been reported to be effective in a small number of cases 2).
Regarding pharmacotherapy for visual hallucinations in Parkinson’s disease with dementia (PDD) and dementia with
Lewy bodies (DLB), see CQ7-6.

▪ References
1) Cipriani G, Danti S, Vedovello M, et al. Understanding delusion in dementia: a review. Geriatr Gerontol Int. 2014; 14(1): 32-39.
2) Mizukami K. Pharmacotherapy for BPSD. Jpn J Gen Hosp Psychiatry. 2011; 23(1); 19-26. (In Japanese with English abstract)3) Shinagawa S, Nakajima S, Plitman E, et al. Psychosis in frontotemporal dementia. J Alzheimers Dis. 2014; 42(2); 485-499.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [Mesh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indiff­erence* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR“Delusions” [Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR

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Clinical Practice Guideline for Dementia 2017

dysphoria [TI] OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual
Behavior” [Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI] OR “inappropriate sexual behavior” [TI] OR restlessness[TI] OR(“Motor Activity” [Mesh] AND aberrant [TI]) OR “aberrant motor behaviour” [TI] OR “aberrant motor behavior” [TI] OR “Sleep
Disorders” [Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR“Apathy” [Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indi­fference OR aggression OR agitation OR
irritability OR delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour”
OR “inappropriate sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR“sleep disturbance” OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Alzheimer/TI OR frontotemporal lobar degeneration/TI OR “frontotemporal lobar
degeneration”/TI) AND ((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Pharmacotherapy/TI
OR Non-pharmacological treatment/TI OR Validation therapy/TH OR Validation therapy/TI OR “validation therapy”/TI OR Reality Orientation/
TH OR “Reality Orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH OR Music
therapy/TI OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR Aromatherapy/
TI OR “aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise therapy/TH
OR Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR Physicalexercise/TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive training/TI
OR “cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR “stimulation
therapy”/ TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR Caregiver/TI)
AND (Education/TI OR Intervention/TI)) OR (caregiver/TI AND (“psycho-education”/TI OR intervention/TI)) OR Nursing care service/TH
OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia day
service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND(Anxiety/TH OR Anxiety/TI OR Indifference/TI OR
Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR ((Deviation OR Abnormality) AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Sleepiness/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 (Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug th­erapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh]OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”)) AND (“Delusions” [Mesh] OR delusion* OR “Hallucinations” [Mesh] OR hallucination*)
Ichushi: June 22, (Monday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy)OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI
OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Hallucination/TH OR Hallucination/TI OR Delusion/TH
OR Delusion/TI)

Chapter 349

CQ 3B-4

What are the effective non-pharmacological therapies and pharmacotherapy
for depression?
Recommendation
For depressive symptoms, consider the situation of the person with dementia and communicate with a receptive attitude.
Regarding non-pharmacological interventions, utilization of social support, reminiscence therapy, and music therapy are
effective. In Japan, utilization of long-term care services is a realistic measure. If no improvement is observed after theabove interventions have been given for a certain period of time, consider using antidepressants such as selective serotonin
reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI).
2C

Comments and evidence
A systematic review clarifies that social support, classified as a non-pharmacological intervention, may improve depressive
symptoms in people with dementia 1).
Two randomized controlled trials (RCTs) have demonstrated the effectiveness of music therapy. Both individual therapy 2)
provided by music therapists and group music activity program 3) are effective, and both singing and music appreciation are also
effective. A meta-analysis also shows that reminiscence therapy has a moderate improvement effect in reducing depressive
symptoms in older people with dementia 4). For exercise therapy, a meta-analysis concludes with moderate confidence that there
is no effect on depression 5).
Regarding antidepressants, a systematic review of 10 RCTs and 3 meta-analyses finds that the effect of antidepressants fordepression in dementia is inconclusive 6). In addition, a meta-analysis of 6 RCTs on SSRI also does not support the effectivenessof SSRI for depression in dementia 7). Furthermore, mirtazapine is not effective 8). The observation periods in most of theabove studies on non-pharmacological interventions are 5-12 weeks. Therefore, if symptoms do not improve after 12 weeks
of non-pharmacological intervention, consider starting antidepressants. When selecting drug options, start with SSRI andSNRI that have few adverse effects.

▪ References
1) Leung P, Orrell M, Orgeta V. Social support group interventions in people with dementia and mild cognitive impairment: a systematic review of theliterature. Int J Geriatr Psychiatry. 2015; 30(1): 1-9.
2) Raglio A, Oasi O, Gianotti M, et al. Eff­ects of music therapy on psychological symptoms and heart rate variability in patients with dementia. A pilot
study. Curr Aging Sci. 2010; 3(3): 242-246.
3) Sarkamo T, Tervaniemi M, Laitinen S, et al. Cognitive, emotional, and social benefits of regular musical activities in early dementia: randomized
controlled study. Gerontologist. 2014; 54(4): 634-650.
4) Huang HC, Chen YT, Chen PY, et al. Reminiscence therapy improves cognitive functions and reduces depressive symptoms in elderly people withdementia: A meta-analysis of randomized controlled trial. J Am Med Dir Assoc. 2015; 16(12): 1087-1094.
5) Forbes D, Forbes SC, Blake CM, et al. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2015; 4: CD006489.
6) Leong C. Antidepressants for depression in patients with dementia: a review of the literature. Consult Pharm. 2014; 29(4): 254-263.
7) Sepehry AA, Lee PE, Hsiung GY, et al. Eff­ect of selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid depression: a metaanalysis of depression and cognitive outcomes. Drugs Aging. 2012; 29(10): 793-806.
8) Banerjee S, Hellier J, Romeo R, et al. Study of the use of antidepressants for depression in dementia: the HTA-SADD trial- a multicentre, randomised,double-blind, placebo-controlled trial of the clinical eff­ectiveness and cost-effectiveness of sertraline and mirtazapine. Health Technol Assess. 2013;17(7): 1-166.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration”[TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR

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Clinical Practice Guideline for Dementia 2017

“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [sh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indi­fference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation[TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR “Delusions”[Mesh] OR delusion*[TI] OR “Hallucinations” [Mesh] OR hallucination*[TI] OR “Depression” [Mesh] OR depression [TI] OR dysphoria [TI]
OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual Behavior”[Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI]OR “inappropriate sexual behavior” [TI] OR restlessness [TI] OR(“Motor Activity” [Mesh]AND aberrant [TI]) OR “aberrant motor behaviour”[TI] OR “aberrant motor behavior” [TI] OR “Sleep Disorders”[Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI]OR “daytime sleepiness” [TI] OR “Apathy” [Mesh]
OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indiff­erence OR aggression OR agitation OR irritability OR delusion*
OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour” OR “inappropriate sexual
behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR “sleep disturbance” OR“daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Alzheimer/TI OR Frontotemporal lobar degeneration/TI OR “frontotemporal lobar
degeneration”/TI) AND ((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Non-pharmacotherapy/
TI OR Non-pharmacological treatment/TI OR Validation therapy/TH OR Validation therapy/TI OR “validation therapy”/TI OR Reality
Orientation/TH OR “Reality Orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH
OR Music therapy/TI OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR
Aromatherapy/TI OR “aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise
therapy/TH OR Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR
Physical exercise/TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive
training/TI OR “cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR“stimulation therapy”/ TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR
Caregiver/TI) AND (Education/TI OR Intervention/TI)) OR (caregiver/TI AND (“psycho-education”/TI OR intervention/TI)) OR Nursing careservice/TH OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia
day service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND(Anxiety/TH OR Anxiety/TI OR Indifference/TI
OR Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR ((Deviation OR Abnormality) AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Sleepiness/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 (Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug ­t herapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”)) AND (“Depression” [Mesh] OR depression OR dysphoria)
Ichushi search: June 22, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/
TI OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Depression/TH or Depression/TI)

Chapter 3

51

CQ 3B-5

What are the effective non-pharmacological therapies and pharmacotherapy
for wandering?
Recommendation
Consider the reason or cause of wandering from the viewpoint of the patient with dementia and take preventive
measures. For a person with dementia who wanders frequently, make a plan to facilitate finding of the missing person.
Regarding pharmacotherapy, risperidone may be considered, but the scientific evidence is insufficient. Tiapride may also
be considered, because this drug is covered by health insurance in Japan for wandering associated with the sequelae of
cerebral infarction. However, if the above interventions and treatments do not solve the issue, consider using nursing careservices such as institutional care service.
2C

Comments and evidence
To address wandering in patients with dementia, non-pharmacological interventions are the first choice, and when they
are not effective, pharmacotherapy is selected. Many of the drugs used for these behavioral symptoms are used off-label.
Therefore, it is necessary to use with caution, giving sufficient explanations to the patients and families and paying attention
to adverse events during use. In addition, even if the drug is effective, it should not be used casually. Keep in mind to decrease
the risk of adverse effects by reducing the dose or withdrawing the drug when symptoms have improved.

Wandering
Various actions of a person with dementia can be recognized by others as signs of wandering. First, consider the nature,reason and cause of the actions from the viewpoint of the person with dementia, and take preventive measures. While
wandering, the persons with dementia are often tense and confused. It is important to listen to them and make them feelreassured. For persons with dementia who frequently wander, it is important to take precautions even while they are calm.
For example, dress them in easily recognizable clothes, write contact information on the clothes and shoes they wear, and use
devices such as global positioning systems (GPS). Moreover, it is useful to obtain support from neighbors and to register inprograms for wandering persons in municipalities that have such mechanisms. Although there is no study that evaluates theeffectiveness of pharmacotherapy focusing on wandering in dementia patients, a randomized controlled trial (RCT) thatcompares the effects of risperidone on behavioral and psychological symptoms of dementia (BPSD) reports significant
improvement for wandering 1). Therefore, use of risperidone may be considered. Tiapride may also be used, as its indication
for wandering associated with the sequelae of cerebral infarction is covered by health insurance in Japan. In the case of
wandering associated with agitation, drugs for agitation may be considered (see CQ3B-2). In addition, improvement of sleep/
wake pattern has been reported to reduce wandering 2). Therefore, if the patient also has sleep disturbance, consider treatment
for sleep disturbance (see CQ3B-6). If there is no improvement despite various treatments and interventions, consider
utilizing institutional care services.

▪ References
1) Rabinowitz J, Katz IR, De Deyn PP, et al. Behavioral and psychological symptoms in patients with dementia as a target for pharmacotherapy withrisperidone. J Clin Psychiatry. 2004; 65(10): 1329-1334.
2) Meguro K, Meguro M, Tanaka Y, et al. Risperidone is eff­ective for wandering and disturbed sleep/wake patterns in Alzheimer’s disease. J Geriatr
Psychiatry Neurol. 2004; 17(2): 61-67.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR

52

Clinical Practice Guideline for Dementia 2017

“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [sh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indi­fference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR“Delusions” [Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR
dysphoria [TI] OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual
Behavior” [Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI]OR “inappropriate sexual behavior” [TI] OR restlessness[TI] OR (“Motor Activity” [Mesh] AND aberrant[TI]) OR “aberrant motor behaviour” [TI] OR “aberrant motor behavior” [TI] OR “Sleep
Disorders” [Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance”[TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR“Apathy” [Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indiff­erence OR aggression OR agitation OR
irritability OR delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour”
OR “inappropriate sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR“sleep disturbance” OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Alzheimer/TI OR frontotemporal lobar degeneration/TI OR “frontotemporal lobar
degeneration”/TI) AND ((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Non-pharmacologicaltreatment/TI OR Validation therapy/TH OR Validation therapy/TI OR “validation therapy”/TI OR Reality Orientation/TH OR “Reality
Orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH OR Music therapy/TI OR“music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR Aromatherapy/TI OR“aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise therapy/TH OR
Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR Physical exercise/
TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive training/TI OR“cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR “stimulation
therapy”/ TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR Caregiver/TI)
AND (Education/TI OR Intervention/TI)) OR (caregiver/TI AND (“psycho-education”/TI OR intervention/TI)) OR Nursing care service/TH
OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia day
service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND (Anxiety/TH OR Anxiety/TI OR Indifference/TI OR
Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR ((Deviation OR Abnormality) AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Sleepiness/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 ((Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug therapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR“Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine,
Kampo”[Mesh]OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR“alzheimer’s disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine
OR “selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”))) AND (“Wandering Behavior” [Mesh]OR wandering [TI] OR wandering OR “Inhibition(Psychology)” [Mesh] OR disinhibition* [TI] OR disinhibition* OR (“Sexual Behavior” [Mesh] AND inappropriate) OR “inappropriate sexual
behaviour” OR “inappropriate sexual behavior” OR (“Psychomotor Agitation” [Mesh] AND restlessness) OR restlessness OR (“Motor Activity”[Mesh] AND aberrant)OR “aberrant motor behaviour” OR “aberrant motor behavior”)
Ichushi search: June 22, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI)AND((SH = Pharmacotherapy)OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI
OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual
perversion/TH OR ((Deviation OR Abnormality) AND Sexual behavior/TH))

Chapter 3

53

CQ 3B-6

What are the effective non-pharmacological therapies and pharmacotherapy
for sleep disturbance (excluding REM sleep behavior disorder)?
Recommendation
First, assess sleep disturbance accurately and conduct differential diagnosis. If there are physical symptoms (such as
pain, urinary frequency, and itchiness), psychological or social stress, stimulant-containing products, and drugs that may
contribute to sleep disturbance, mitigate those factors. In addition, encourage the patient to do sunbathing and physicalactivities during the day, and to attempt to improve the sleep environment. If possible, consider bright light therapy. For
pharmacotherapy, use of trazodone or risperidone may be considered. However, benzodiazepines as sleep inducing agentsare not recommended because of the risk of adverse events such as sedation and falls.
2C

Comment and evidence
In Alzheimer’s disease dementia and dementia with Lewy bodies, complex sleep disturbances such as insomnia,
hypersomnia, and sleep/wake rhythm disturbances may occur 1). In addition, the patients tend to have various conditions
such as sleep apnea syndrome, restless legs syndrome (RLS), periodic limb movement disorder, nocturnal leg cramp, andREM sleep behavior disorder. Therefore, it is important to assess sleep disturbance accurately and conduct differential
diagnosis. Furthermore, sleep disturbance may become chronic due to diverse underlying factors including physicalsymptoms (such as pain, urinary frequency, and itchiness), exacerbation of psychiatric symptoms, increased psychologicaland social stress, and influence by stimulant-containing products (such as alcohol, caffeine, and nicotine) and drugs.
Therefore, removal of these factors is also important.
In a systematic review of 38 pharmacological or non-pharmacological intervention studies targeting sleep disturbances inpatients with mild to moderate Alzheimer’s disease dementia, bright light therapy gives the best results and is effective in
reducing nocturnal awakening and prolonging nighttime sleep 2). In addition, multi-faceted interventions including daytime
sunlight exposure, physical activity, exercise, restriction of daytime napping, structured bedtime routines (performing
certain actions in a predetermined order before going to bed), improvement of sleep environment such as reducing noise andlight at night are also effective in improving sleep disturbance. The use of pharmacotherapy is limited when consideringsafety. In particular, although sedative-hypnotic medications represented by benzodiazepines are widely used clinically, there
are few data supporting their use. Conversely, they may cause sedation, daytime somnolence, falls, confusion, and amnesia,
and should therefore be used with caution. Two randomized controlled trials (RCTs) have shown the effectiveness ofrisperidone, and this drug may be considered.
It has been reported that trazodone given to patients with Alzheimer’s disease dementia at a dose of 50 mg per day for 2
weeks prolongs total sleeping time and improves sleep efficiency. Use of this drug may be considered 3).
Regardless of which drugs are being used, even if they prove to be effective, they should not be used casually. Always
remember to reduce the risk of adverse effects by reducing the dose or withdrawing the drug when symptoms have improved.

▪ References
1) Mishima K (Ed.) Clinical Guidelines for Proper Use and Cessation of Hypnotics. Tokyo: Jibo; 2014. (In Japanese)
2) Salami O, Lyketsos C, Rao V. Treatment of sleep disturbance in Alzheimer’s dementia. Int J Geriatr Psychiatry. 2011; 26(8): 771-782.
3) McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer’s disease. Cochrane Database Syst Rev. 2014; (3):CD009178.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia[ TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR

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Clinical Practice Guideline for Dementia 2017

“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [sh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indi­fference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh]OR irritability [TI] OR “Delusions”[Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR dysphoria [TI]
OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual Behavior”[Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI] OR “inappropriate sexual behavior” [TI] OR restlessness [TI]
OR(“Motor Activity” [Mesh] AND aberrant[TI]) OR “aberrant motor behaviour”[TI] OR “aberrant motor behavior” [TI] OR “Sleep Disorders”[Mesh] OR “nighttime insomnia” [TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR “Apathy”[Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indiff­erence OR aggression OR agitation OR irritability OR
delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour” OR “inappropriate
sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR “sleep disturbance”
OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Frontotemporal lobar degeneration/TI OR “frontotemporal lobar degeneration”/TI)
AND((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Non-pharmacotherapy/TI OR Nonpharmacological treatment/TI OR Validation therapy/TH OR Validation therapy/TI OR “validation therapy”/TI OR Reality Orientation/TH OR“Reality Orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH OR Music therapy/
TI OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR Aromatherapy/TI OR“aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise therapy/TH OR
Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR Physical exercise/
TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive training/TI OR“cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR “stimulation
therapy”/ TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR Caregiver/TI)
AND (Education/TI OR Intervention/TI)) OR(caregiver/TI AND (“psycho-education”/TI OR intervention/TI)) OR Nursing care service/TH
OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia day
service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND (Anxiety/TH OR Anxiety/TI OR Indifference/TI OR
Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR((Deviation OR Abnormality) AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Somnolence/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 (Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug th­erapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR“Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine,
Kampo” [Mesh] OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease”
OR “alzheimer’s disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR
benzodiazepine OR “selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “moodstabilizer” OR anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR“orexin receptor antagonist” OR “melatonin receptor agonist”)) AND (“Sleep Disorders” [Mesh] OR “nighttime insomnia” OR “sleep disturbance”
OR “daytime napping” OR “daytime sleepiness”)
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI
OR Therapeutic drug/TI OR Kampo medicine/TH OR Antipsychotics/TH)) AND (Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/
TI OR Dyssomnia/TI OR Insomnia/TI OR Somnolence/TI)

Chapter 3

55

CQ 3B-7

What are the effective non-pharmacological therapies and pharmacotherapy
for apathy?
Recommendation
As a non-pharmacological intervention for apathy, therapeutic activities customized for individual patients withdementia are suggested to be effectiveness. In Japan, incorporating this approach as a program in dementia care service
seems to be a realistic measure. For pharmacotherapy, cholinesterase inhibitor is the first choice if indicated for the disease.
Memantine may be considered, but antidepressants and antiepileptic drugs have not been reported to be effective.

2C

Comments and evidence
Apathy is a state of reduced spontaneity, initiative, interest, concern, motivation, and emotion. Because these are notpositive symptoms such as delusion and irritability, they tend to be misunderstood as posing less burden on nursing care.
However, since patients may gradually stop executing actions that should be taken in daily life, or do not respond tocommunication from other persons, apathy is a symptom that requires treatment.
To verify the effects of non-pharmacological interventions for apathy, a systematic review of 56 studies suggests thattherapeutic activities, particularly those planned to match the level and interest of the individual, can be expected to bebeneficial 1). Specifically, these activities involve participant-led interactive discussions, and activities such as solving puzzles,
making salad, sorting beads, woodwork, and catching ball are conducted while an occupational therapist provides guidance
to the family caregivers. In Japan, receiving this treatment as a program in dementia care service seems to be a realistic
measure.
A systematic review that summarizes the effects of pharmacotherapy confirms the benefit of cholinesterase inhibitors forapathy, and recommends these drugs as first-line drug for patients with dementia if there is no contraindication 2). Memantine
may also be effective.

▪ References
1) Brodaty H, Burns K. Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry. 2012; 20(7): 549-564.
2) Berman K, Brodaty H, Withall A, et al. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 2012; 20(2): 104-122.

▪ Search formulaNon-pharmacological therapies
PubMed search: October 2, 2015 (Friday)#1 (“Dementia/therapy” [Majr] OR dementia [TI] OR “Alzheimer disease” [TI] OR “Alzheimer’s disease” [TI] OR “vascular dementia” [TI] OR“Lewy Body” [TI] OR “frontotemporal dementia” [TI] OR “frontotemporal lobar degeneration” [TI]) AND (“nonpharmacological therapy” OR“non pharmacological therapy” OR “nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “nonpharmacological treatment” OR “nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR
non pharmacological intervention* OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacologicalmanagement” OR “non pharmacological management” OR “nonpharmacologic management” OR “non pharmacologic management” OR“validation therapy” OR “reality orientation” OR “reminiscence therapy” OR “music therapy” OR “light therapy” OR “tactile therapy” OR“aromatherapy” OR “occupational therapy” OR “exercise therapy” OR “exercise training” OR “exercise program” OR “physical exercise” OR“cognitive training” OR “rehabilitation” OR “stimulation therapy” OR “psychological therapy” OR (caregiver* AND (“psycho-education” OR
intervention)) OR “dementia care service” OR “adult day service” OR “dementia day service” OR “Rehabilitation” [Mesh] OR “Phototherapy”[Mesh] OR “Exercise” [Mesh] OR “rehabilitation” [sh] OR “Psychotherapy” [Mesh] OR (“Caregivers” [Mesh] AND (“psycho-education” OR
intervention)) OR “Touch” [Mesh] OR “Day Care” [Mesh]) AND (“Anxiety” [Mesh] OR anxiety [TI] OR indi­fference* [TI] OR “Aggression”[Mesh] OR aggression [TI] OR “Psychomotor Agitation” [Mesh] OR agitation [TI] OR “Irritable Mood” [Mesh] OR irritability [TI] OR“Delusions” [Mesh] OR delusion* [TI] OR “Hallucinations” [Mesh] OR hallucination* [TI] OR “Depression” [Mesh] OR depression [TI] OR
dysphoria [TI] OR “Wandering Behavior” [Mesh] OR wandering [TI] OR “Inhibition (Psychology)” [Mesh] OR disinhibition* [TI] OR (“Sexual
Behavior” [Mesh] AND inappropriate [TI]) OR “inappropriate sexual behaviour” [TI] OR “inappropriate sexual behavior” [TI] OR restlessness[TI] OR (“Motor Activity” [Mesh] AND aberrant [TI])OR “aberrant motor behaviour” [TI] OR “aberrant motor behavior” [TI] OR “Sleep
Disorders” [Mesh] OR “nighttime insomnia”[TI] OR “sleep disturbance” [TI] OR “daytime napping” [TI] OR “daytime sleepiness” [TI] OR“Apathy” [Mesh] OR apathy [TI] OR “Delirium” [Mesh] OR delirium [TI] OR ((anxiety OR indiff­erence OR aggression OR agitation OR

56

Clinical Practice Guideline for Dementia 2017

irritability OR delusion* OR hallucination* OR depression OR dysphoria OR wandering OR disinhibition* OR “inappropriate sexual behaviour”
OR “inappropriate sexual behavior” OR restlessness OR “aberrant motor behaviour” OR “aberrant motor behavior” OR “nighttime insomnia” OR“sleep disturbance” OR “daytime napping” OR “daytime sleepiness” OR apathy OR delirium) AND (in process [SB] OR publisher [SB])))
Ichushi search: October 2, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer/TI OR Alzheimer/TI OR Frontotemporal lobar degeneration/TI OR “frontotemporal lobar
degeneration”/TI) AND ((SH = Surgical therapy, transplantation, dietary therapy, radiotherapy, nursing, rehabilitation) OR Non-pharmacotherapy/
TI OR Non-pharmacological treatment/TI OR Validation therapy/TH OR Validation therapy/TI OR “validation therapy”/TI OR Reality
Orientation/TH OR “Reality Orientation”/TI OR Reminiscence/TH OR Reminiscence/TI OR “reminiscence therapy”/TI OR Music therapy/TH
OR Music therapy/TI OR “music therapy”/TI OR Light therapy/TH OR Light therapy/TI OR “light therapy”/TI OR Aromatherapy/TH OR
Aromatherapy/TI OR “aromatherapy”/TI OR Occupational therapy/TH OR Occupational therapy/ TI OR “occupational therapy”/TI OR Exercise
therapy/TH OR Exercise therapy/TI OR “exercise therapy”/TI OR Exercise training/TH OR Exercise training/TI OR “exercise training”/TI OR
Physical exercise/TH OR Physical exercise/TI OR “physical exercise”/TI OR “exercise program”/TI OR Cognitive training/TH OR Cognitive
training/TI OR “cognitive training”/TI OR Rehabilitation/TH OR Rehabilitation/TI OR “rehabilitation”/TI OR Stimulation therapy/TI OR“stimulation therapy”/TI OR Psychological therapy/TH OR Psychological therapy/TI OR “psychological therapy”/TI OR ((Caregiver /TH OR
Caregiver/TI) AND (Education/TI OR Intervention/TI)) OR (caregiver/TI AND (“psycho-education”/TI OR intervention/TI)) OR Nursing careservice/TH OR Nursing care service/TI OR “dementia care service”/TI OR Day care/TH OR Day care/TI OR “adult day service”/TI OR “dementia
day service”/TI OR Therapeutic touch/TH OR “tactile therapy”/TI OR Tactile care/TI) AND (Anxiety/TH OR Anxiety/TI OR Indifference/TI
OR Aggression/TH OR Aggression/TI OR Psychomotor agitation/TH OR Irritable mood/ TH OR Hallucination/TH OR Hallucination/TI OR
Delusion/TH OR Delusion/TI OR Depression/TH or Depression/TI or Depression/TI OR Violence/TH or Violence/TI OR Wandering/TH or
Wandering/TI OR Restlessness/TI OR (Psychomotor agitation/TH AND Restlessness) OR Inappropriate sexual behavior/TI OR Sexual perversion/
TH OR ((Deviation OR Abnormality)AND Sexual behavior/TH) OR Sleep disorder/TH or Sleep disorder/TI OR Sleep disturbance/TI OR
Dyssomnia/TI OR Insomnia/TI OR Somnolence/TI OR Apathy/TH or Apathy/TI OR Delirium/TH or Delirium/TI)
Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday)#1 (Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug therapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”)) AND (“Apathy” [Mesh] OR apathy)
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/
TI OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Apathy/TH OR Apathy/TI)

Chapter 357

C | Interventions for Coexisting Diseases
CQ 3C-1

How is delirium treated?
Recommendation
Always remember to prevent delirium. When delirium has emerged, treat or remove the direct causative or inducing
factors. If symptoms do not respond to these interventions and treatments, consider treatment with atypical antipsychotics
such as quetiapine, perospirone, risperidone, and olanzapine. Also consider hospitalization for the purposes of detailed
investigations of the cause of delirium, smooth implementation of treatment, and ensuring safety of the patient. Clinicalguidelines for delirium have been prepared by the Japanese Society of General Hospital Psychiatry, refer to the guidelines
as needed.
2C

Comments and evidence

Since dementia is a risk factor for the development of delirium, it is necessary to be always vigilant for early detection andtreatment of delirium. The background factors of delirium include the following: (1) predisposing factors (current or past historyof organic brain disorder, old age); (2) precipitating factors (environmental factors such as hospitalization and noise; physicalfactors such as pain, dehydration, and malnutrition; sensory factors such as decreased vision and hearing; mental factors such as
psychological stress and anxiety; sleep-related factors such as disrupted circadian rhythm; (3) direct factors that may inducedelirium even as a single factor (stroke, electrolyte abnormality, infection, initiation or withdrawal of drug use) 1).
For treatment of delirium in dementia, refer to the clinical guidelines on delirium prepared by the Delirium Guideline
Revision Group of Japanese Society of General Hospital Psychiatry 2). First, always try to remove the precipitating factors.
Also, treat the direct factor, if possible. If delirium does not improve after these treatments, consider atypical antipsychotics(quetiapine, perospirone, risperidone, and olanzapine). The former two are recommended from the viewpoint of short halflife. The latter two have the advantage of being a liquid formulation and an orally disintegrating tablet, respectively. Use
haloperidol injection if intake of oral medication is difficult. Use the minimum required dose, and in principle administerin the evening. For treatment of delirium, also consider hospitalization for the purposes of detailed investigations of thecause, ensuring safety of the patient, smooth implementation of treatment, and provision of a calm environment.
In a multicenter randomized controlled trial (RCT) conducted in Japan, the frequency of delirium is reduced by taking ramelteon
from the time of admission 3). Therefore use of this drug may be considered. All of the drugs mentioned above are used off-label.
When prescribing these drugs, it is necessary to explain in detail to the patients and families, and to be aware of adverse events.

▪ References

1) Lipowski ZJ. Delirium: acute confusional states. London: Oxford Univ Press; 1990.
2) Japanese Society of General Hospital Psychiatry Delirium Guideline Revision Group. Japanese Society of General Hospital Psychiatry Treatment
Guideline 1: Treatment Guidelines for Delirium, Second Edition: Clinical Guidelines for Delirium. Tokyo: Seiwa Shoten; 2015. (In Japanese)
3) Hatta K, Kishi Y, Wada K, et al. Preventive e­ffects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014; 71(4):397-403.

▪ Search formula

PubMed search: June 23, 2015 (Tuesday)#1 ((Dementia [Mesh] AND (“drug therapy” [subheading] OR “Drug therapy” [Mesh])) OR (“Dementia/therapy” [Mesh] AND (“Antipsychotic
Agents” [Mesh] OR “Benzodiazepines” [Mesh] OR “Serotonin Uptake Inhibitors” [Mesh] OR “Antidepressive Agents” [Mesh] OR “Anticonvulsants”[Mesh] OR “Anticonvulsants” [PA] OR “Yi-Gan San” [Supplementary Concept] OR “Herbal Medicine” [Mesh] OR “Medicine, Kampo” [Mesh]
OR “ramelteon” [Supplementary Concept] OR “suvorexant” [Supplementary Concept])) OR ((dementia OR “alzheimer disease” OR “alzheimer’s
disease” OR “frontotemporal lobar degeneration”) AND (pharmacological OR drug OR medicine OR antipsychotics OR benzodiazepine OR“selective serotonin reuptake inhibitors” OR “serotonin-norepinephrine reuptake inhibitors” OR antidepressant* OR “mood stabilizer” OR
anticonvulsant* OR Yokukansan OR “Japanese herbal” OR “traditional herbal” OR kampo OR ramelteon OR suvorexant OR “orexin receptor
antagonist” OR “melatonin receptor agonist”))) AND (“Delirium” [Mesh]OR delirium)
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND ((SH = Pharmacotherapy)OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI
OR Therapeutic drug/ TI OR Kampo medicine/TH OR Antipsychotics/TH) AND (Delirium/TH or Delirium/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 3C-2

How epilepsy including seizures should be treated in patients with dementia?
Recommendation
The former antiepileptic drugs may worsen cognitive function, and should be used with caution in older patients withdementia. Novel antiepileptic drugs are relatively well tolerated and effective if the drug titration is applied.
2C

Comments and evidence
In dementia patients, the risk of both generalized and partial seizures is six times higher than in the control group 1, 2).
Especially in Alzheimer’s disease, the accumulation of amyloid β (Aβ) induces hyperexcitation of the cortical network in the
hippocampus, resulting in cognitive impairment, and the hippocampus can be the focus of epileptic seizures at the sametime 3, 4). In patients with Alzheimer’s disease, epilepsy with seizure focus in temporal lobe is common, and transient memory
impairment tends to occur especially if cognitive decline occurs at a younger age 5). In familial Alzheimer’s disease, several
cases with seizures and myoclonus have been reported 4). Cheng et al. 6) compared the age-adjusted annual incidence of
epilepsy between control and Alzheimer’s disease, and reported that the risk of epilepsy is increased by 1.85 times in patientswith Alzheimer’s disease at 3.6 years after the onset of dementia 6).
Because epileptic seizures worsen the prognosis of patients with dementia due to the higher risk of falls, trauma, and death,appropriate treatment with anti-epileptic drugs is required. However, the semiology of seizures is often non-convulsive,
subtle, and diverse, and often not recognized as seizures by the patient or the caregiver, which makes the diagnosis difficult.
Therefore, once a diagnosis of epilepsy is confirmed and the risk of seizure recurrence is high, it is necessary to startantiepileptic drug with monotherapy in a small dose at first and then upwardly titrating slowly 7). Since carbamazepine has
many drug interactions and adverse effects including cardiac conduction disorder, hyponatremia, and over-sedation, it
should be used with caution in older patients. Benzodiazepines, primidone, and phenobarbital are not recommended because
they worsen cognitive function. Sodium valproate has little effect on cognitive function, and it is effective for convulsive
seizures in older patients and for behavioral and psychological symptoms of dementia such as irritability, aggression andmood disorders.
New antiepileptic drugs (lamotrigine, levetiracetam, gabapentin, topiramate) are effective for seizures in older patientsand cause few adverse events. Among them, lamotrigine and levetiracetam are effective for epilepsy in patients with amnestic
mild cognitive impairment or early Alzheimer’s disease 5). In Japan, monotherapy of these drug is also indicated for thetreatment of epilepsy. Rowan et al. 8) recommend lamotrigine and gabapentin as antiepileptic drugs for older people withdementia, because they have less adverse effects compared with carbamazepine. Levetiracetam has been shown to be effective
and safe also in post-stroke epilepsy patients, and have less effect on cognitive function than carbamazepine 9).
In general, since older people often have lower serum albumin and liver and kidney dysfunctions, serum levels ofantiepileptic drugs can be readily elevated. Therefore, monotherapy of antiepileptic drugs starting with a low dose is highly
recommended. In addition, careful attention should be paid for drug interactions in older patients with dementia, because
they are usually taking multiple drugs.

▪ References
1) Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota.
Mayo Clin Proc. 1996; 71(6): 576-586.
2) Hesdor­er DC, Hauser WA, Annegers JF, et al. Dementia and adult-onset unprovoked seizures. Neurology. 1996; 46(3): 727-730.
3) Bell JS, Lonnroos E, Koivisto AM, et al. Use of antiepileptic drugs among community-dwelling persons with Alzheimer’s disease in Finland. J
Alzheimers Dis. 2011; 26(2): 231-237.
4) Born HA. Seizures in Alzheimer’s disease. Neuroscience. 2015; 286: 251-263.
5) Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013; 70(9):1158-1166.
6) Cheng CH, Liu CJ, Ou SM, et al. Incidence and risk of seizures in Alzheimer’s disease: A nationwide population-based cohort study. Epilepsy Res.
2015; 115: 63-66.
7) Hommet C, Mondon K, Camus V, et al. Epilepsy and dementia in the elderly. Dement Geriatr Cogn Disord. 2008; 25(4): 293-300.
8) Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.
Neurology. 2005; 64(11): 1868-1873.

Chapter 3599) Consoli D, Bosco D, Postorino P, et al. Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective
randomized open-label study (EpIC Project). Cerebrovasc Dis. 2012; 34(4): 282-289.

▪ Search formula
PubMed search: July 5, 2015 (Sunday)#1 (“Dementia” [Mesh] OR dementia OR “Cognition Disorders” [Mesh] OR cognition disorder* OR cognitive disorder*) AND (“Seizures/therapy”[Mesh] OR (seizure* AND (therapy OR therapeutic OR treatment OR prophylaxis OR prevention)) OR (“Seizures” [Mesh] AND “Anticonvulsants/
therapeutic use” [Mesh]) OR (anticonvulsant* AND (therapy OR therapeutic OR treatment OR prophylaxis OR prevention)))Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(Epilepsy/TH OR Epilepsy/TI OR Epilepsy/TI) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment) OR Treatment/TH OR Treatment/TI OR Therapy/TI OR Preventive/TI OR Anticonvulsive agent/TH OR Anti-convulsive agent/TI OR Anti-epileptic drug/TI OR Anti-convulsive agent/TI OR Anti-epileptic drug/TI OR Anticonvulsive drug/TI OR Anti-epileptic agent/TI OR Anti-convulsive drug/TI OR Anti-epileptic agent/TI)

60

Clinical Practice Guideline for Dementia 2017

CQ 3C-3

What are the interventions for dysphagia (including prevention of aspiration
pneumonia)?
Recommendation
To prevent the onset of aspiration pneumonia, angiotensin converting enzyme (ACE) inhibitor, amantadine, cilostazol(not covered by insurance), capsaicin, oral care, swallowing rehabilitation, chin down maneuver, maintaining sitting
position for 1 hour after eating, and influenza and pneumococcal vaccination are effective.
There is no data showing the usefulness of percutaneous endoscopic gastrostomy (PEG) in preventing aspiration
pneumonia or improving activities of daily living (ADL) and survival in patients with advanced stage dementia.

2D

Comments and evidenceIn frontotemporal lobar degeneration and Alzheimer’s disease dementia, abnormalities in eating behavior such as
overeating occur due to functional impairment of the limbic system and frontal lobe, and are particularly marked in theformer. Vascular dementia and dementia caused by parkinsonism often manifest impaired swallowing reflex, and aspiration
pneumonia is often caused by occult aspiration at night. On the other hand, in Alzheimer’s disease dementia, the swallowing
reflex is preserved until the late stage of the disease, and is often maintained even in a bed confined state.
Activation of the dopamine–substance P system is important for the prevention of aspiration pneumonia. Sensory stimulationof the oral cavity through oral care increases substance P, increases the sensitivity of the cough reflex, and consequently improves
the swallowing reflex 1, 2). Administration of ACE inhibitors that suppress substance P degradation is also useful 3). In addition,
cilostazol 4) and amantadine with dopamine release effect 5) have been reported to be effective in the prevention of aspiration
pneumonia. Furthermore, rivastigmine 6) and the Kampo herbal medicine “banxia houpo tang” 7) have been reported to improveswallowing function. Conversely, since cholinergic and dopaminergic systems act to maintain the swallowing function, drugs
with anticholinergic action and dopamine antagonistic action increase the risk of aspiration pneumonia 8).
In the advanced stage of dementia, use of PEG does not show benefit regarding survival duration, improvement of qualityof life (QOL), or reduction of aspiration pneumonia 9). Systematic reviews that evaluate the effect of PEG in dementia
patients with dysphagia have not found a survival-extending effect 10, 11).

▪ References
1) Yoshino A, Ebihara T, Ebihara S, et al. Daily oral care and risk factors for pneumonia among elderly nursing home patients. JAMA. 2001; 286(18):2235-2236.
2) Watando A, Ebihara S, Ebihara T, et al. Daily oral care and cough re­flex sensitivity in elderly nursing home patients. Chest. 2004; 126(4): 10661070.
3) Rafailidis PI, Matthaiou DK, Varbobitis I, et al. Use of ACE inhibitors and risk of community-acquired pneumonia: a review. Eur J Clin Pharmacol.
2008; 64(6): 565-573.
4) Shinohara Y. Antiplatelet cilostazol is effective in the prevention of pneumonia in ischemic stroke patients in the chronic stage. Cerebrovasc Dis.
2006; 22(1): 57-60.
5) Nakagawa T, Wada H, Sekizawa K, et al. Amantadine and pneumonia. Lancet. 1999; 353(9159): 1157.
6) Uwano C, Suzuki M, Aikawa T, Rivastigmine dermal patch solves eating problems in an individual with advanced Alzheimer’s disease. J Am Geriatr
Soc. 2012; 60(10): 1979-1980.
7) Iwasaki K, Wang Q, Nakagawa T, et al. The traditional Chinese medicine banxia houpo tang improves swallowing refl­ex. Phytomedicine. 1999;
6(2): 103-106.
8) Wada H, Nakajoh K, Satoh-Nakagawa T, et al. Risk factors of aspiration pneumonia in Alzheimer’s disease patients. Gerontology. 2001; 47(5): 271276.
9) Alagiakrishnan K, Bhanji RA, Kurian M. Evaluation and management of oropharyngeal dysphagia in different types of dementia: a systematic
review. Arch Gerontol Geriatr. 2013; 56(1): 1-9.
10) Goldberg LS, Altman KW. The role of gastrostomy tube placement in advanced dementia with dysphagia: a critical review. Clin Interv Aging. 2014;
9: 1733-1739.
11) Candy B, Sampson EL, Jones L. Enteral tube feeding in older people with advanced dementia: findings from a Cochrane systematic review. Int J
Palliat Nurs. 2009; 15(8): 396-404.

Chapter 3

61▪ Search formula
PubMed search: July 15, 2015 (Wednesday)#1 (“Dementia” [Mesh] OR dementia OR Alzheimer* OR “Cognition Disorders” [Mesh] OR cognition disorder* OR cognitive disorder*) AND(“Deglutition Disorders/therapy” [Mesh] OR ((deglutition disorder* OR swallowing disorder* OR dysphagia) AND (therapy OR therapeutic OR
treatment OR prophylaxis OR prevention)) OR “Pneumonia, Aspiration/therapy” [Mesh] OR (aspiration pneumonia* AND (therapy OR
therapeutic OR treatment OR prophylaxis OR prevention)))Ichushi search: July 15, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(dysphagia/TH or dysphagia/TI OR Pneumonia-aspiration/TH or aspiration pneumonia/TI) AND ((SH = Therapeutic use, treatment, drug
treatment, surgical treatment, transplantation, dietary treatment, psychiatric treatment, radiologic treatment, rehabilitation, prevention) OR
Treatment/TH OR Therapeutic use/TH OR Treatment/TI OR Therapy/TI OR Prevention/TI)

62

Clinical Practice Guideline for Dementia 2017

CQ 3C-4

What are the interventions for eating disorder and undernutrition?
Recommendation
In Alzheimer’s disease, eating difficulties may be caused by changes in eating behavior, loss of appetite, dysphagia, andautonomic disturbance. It is important to take history of the changes in body weight and quantity of food eaten; implement
nutritional assessment, prevention of aspiration, and review of medications; and examine the merits and demerits of oral
intake and tube feeding.
2C

Comments and evidence
Many people with dementia are affected by eating disorders, weight loss, and undernutrition.
Among people with mild Alzheimer’s disease, over 30% experience some changes in eating behavior, and 16% have lossof appetite 1). Riviere et al. 2) studied 224 people with moderate Alzheimer’s disease, and observed that 26% had eating
behavior disorders such as “getting up while eating” and “eating by hand”. In patients with severe dementia, 80% showed
weight loss, dysphagia, eating refusal, reduced food intake, and dehydration 2).
To investigate why people with Alzheimer’s disease lose appetite, Ismail et al. 3) observed reduced blood flow in various
regions including the anterior cingulate gyrus on blood flow SPECT, and speculated that these changes were related toappetite loss.
The adverse effects of cholinesterase inhibitors used as a treatment for Alzheimer’s disease include gastrointestinal
symptoms, although the symptoms are generally transient. There is a report suggesting that long-term administration ofthese agents may prevent weight loss 4).
In 2014, Goldberg et al. 5) conducted a systematic review on the usefulness of percutaneous endoscopic gastrostomy (PEG)
for severe dementia with dysphagia (publications from 1995 to 2012), and reported no evidence that PEG prolongs survival
long-term 5).
According to a review by Affoo et al. 6), while evidence suggests a possibility that dysphagia and autonomic nervous systemdysfunction may occur together in Alzheimer’s disease, the relationship between the two has not been clarified.

▪ References
1) Ikeda M, Brown J, Holland AJ, et al. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease.
J Neurol Neurosurg Psychiatry, 2002; 73(4): 371-376.
2) Riviere S, Gillette-Guyonnet S, Andrieu S, et al. Cognitive function and caregiver burden: predictive factors for eating behaviour disorders in
Alzheimer’s disease. Int J Geriatr Psychiatry. 2002; 17(10): 950-955.
3) Ismail Z, Herrmann N, Rothenburg LS, et al. A functional neuroimaging study of appetite loss in Alzheimer’s disease. J Neurol Sci. 2008; 271(1-2):
97-103.
4) Belmin J, Expert Panel and Organisation Committee. Practical guidelines for the diagnosis and management of weight loss in Alzheimer’s disease:a consensus from appropriateness ratings of a large expert panel. J Nutr Health Aging. 2007; 11(1): 33-37.
5) Goldberg LS, Altman KW. e­ role of gastrostomy tube placement in advanced dementia with dysphagia: a critical review. Clin Interv Aging. 2014;
9: 1733-1739.
6) Affoo RH, Foley N, Rosenbek J, et al. Swallowing dysfunction and autonomic nervous system dysfunction in Alzheimer’s disease: a scoping reviewof the evidence. J Am Geriatr Soc. 2013; 61(12): 2203-2213.

▪ Search formula
PubMed search: June 8, 2015 (Monday)#1 (“Dementia” [Mesh] OR dementia) AND (“Deglutition Disorders/therapy” [Mesh] OR (dysphagia AND (therapy OR therapeutic OR
treatment))) AND (“percutaneous endoscopic gastrostomy” OR PEG OR (“Endoscopy” [Mesh] AND “Gastrostomy” [Mesh] AND “percutaneous”)
OR “Enteral Nutrition” [Mesh] OR “tube feeding”)
Ichushi search: June 8, 2015 (Monday)#1 (Dementia/TH or Dementia/TI) AND (Eating dysfunction/TH or Eating disorder/TI) AND (Gastrostomy construction/TH OR PEG/TI OR
Gastrostomy/TH OR Gastrostomy/TI OR Enteral nutrition/TH or Tube feeding/TI)

Chapter 3

63

CQ 3C-5

What are the interventions for sarcopenia and frailty?
AnswerDementia tend to coexist with sarcopenia and frailty. Resistance training may be useful in improving sarcopenia andfrailty associated with dementia.
C

Comments and evidence
Sarcopenia is a common pathological condition seen in old age. Sarcopenia is defined as “a syndrome characterized byprogressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physicaldisability, poor quality of life and death” 1). The causes of sarcopenia include aging, reduced activity, poor nutrition, anddisease 1). Frailty is the decline of various physiological functions with ageing, and is a risk factor that leads to undesirable
outcomes such as falls, hospitalization, and death.
Sarcopenia and frailty tend to occur more frequently in older people with dementia than in older adults with normal
cognitive function. In recent years, the relationship between frailty and cognitive impairment has attracted attention 2).
Persons with Alzheimer’s disease in a nursing home who received the dual-task intervention of walking and conversation
showed less decline in physical function compared with persons given either conversation or walking intervention alone 3).
When frail persons with Alzheimer’s disease living at home participated in a home-based exercise program (aerobics, strength
training, and balance exercise) guided by the caregiver for 12 weeks, their hand function and lower extremity strength
significantly improved compared with the control group 4). A three-month resistance training program designed specifically for
older dementia persons significantly improved muscle strength and physical function compared with the control group 5). A
cohort study of frail older adults with dementia also found that 4 weeks of resistance exercise improved muscle strength andphysical functions 6). The above evidence shows that sarcopenia and frailty may be improved in people with dementia throughexercise customized for each individual.
Although there is no interventional study of nutrition therapy focused on people with dementia, nutritional supplementation
for sarcopenia generally improves muscle mass and muscle strength of older people 7). Hence, together with exercise,nutritional supplementation is important.

▪ References
1) Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on de­finition and diagnosis: Report of the European Working Groupon Sarcopenia in Older People. Age Ageing. 2010; 39(4): 412-423.
2) Halil M, Cemal Kizilarslanoglu M, Emin Kuyumcu M, et al. Cognitive aspects of frailty: mechanisms behind the link between frailty and cognitive
impairment. J Nutr Health Aging. 2015; 19(3): 276-283.
3) Tappen RM, Roach KE, Applegate EB, et al. Eff­ect of combined walking and conversation intervention on functional mobility of nursing homeresidents with Alzheimer disease. Alzheimer Dis Assoc Disord. 2000; 14(4): 196-201.
4) Steinberg M, Leoutsakos JM, Podewils LJ, et al. Evaluation of a home-based exercise program in the treatment of Alzheimer’s disease: the Maximizing
Independence in Dementia (MIND) study. Int J Geriatr Psychiatry. 2009; 24(7): 680-685.
5) Hauer K, Schwenk M, Zieschang T, et al. Physical training improves motor performance in people with dementia: a randomized controlled trial. J
Am Geriatr Soc. 2012; 60(1): 8-15.
6) Cadore EL, Moneo AB, Mensat MM, et al. Positive e­ffects of resistance training in frailty elderly patients with dementia after long-term physicalrestraint. Age (Dordr). 2014; 36(2): 801-811.
7) Malafarina V, Uriz-Otano F, Iniesta R, et al. E­ffectiveness of nutritional supplementation on muscle mass in treatment of sarcopenia in old age: asystematic review. J Am Med Dir Assoc. 2013; 14(1): 10-17.

▪ Search formula
PubMed search: June 8, 2015 (Monday)#1 (“Dementia” [Mesh] OR dementia) AND (“Sarcopenia/therapy” [Mesh] OR(sarcopenia AND “Muscular Atrophy” [Mesh]) OR (sarcopenia
AND (therapy OR therapeutic OR treatment)) OR (frailty AND (therapy OR therapeutic OR treatment)))
Ichushi search: June 8, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI) AND (sarcopenia/TI OR Sarcopenia/TH OR frailty/AL)

64

Clinical Practice Guideline for Dementia 2017

CQ 3C-6

What are the interventions and preventive measures for falls and fractures?
AnswerPeople with dementia have approximately 8 times higher risk for falls and approximately 3 times higher risk for fracturecompared with people without dementia. To prevent falls, use multi-faceted interventions including treatment ofunderlying diseases, adjustment of drugs, exercise, walking and balance training, training wearing aids, environmental
modification, and training to adjust to home environment. Also consider treatment for osteoporosis.
B

Comment and evidence
In older people, fracture caused by falling is one of the main causes of confining to bed, and falls lower the ability ofactivities of daily living (ADL) and motivation, and also induce delirium.
People with dementia have approximately 8 times higher risk for falls and approximately 3 times higher risk for fracturescompared with people without dementia 1). Dementia patients with orthostatic hypotension have a higher frequency of falls
compared to patients without orthostatic hypotension, with a hazard ratio of 2.13. For the incidence of falls, Parkinson’s
disease with dementia (PDD) was the highest, followed by dementia with Lewy bodies (DLB), vascular dementia, andAlzheimer’s disease (AD). For PDD and DLB, the high incidence may be related to orthostatic hypotension and autonomic
nervous system dysfunction 1).
A retrospective study conducted from 1988 to 2007 in the UK showed that the incidence of hip fracture was 17.4 per
1,000 people with dementia and 6.6 per 1,000 people without dementia, and the risk was 3.2 times higher in patients withdementia 2).
The guidelines for fall prevention prepared by the Orthopedic Surgery Committee of American Geriatric Society/ British
Geriatric Society3) recommends multifactorial interventions including minimization of medications, customized exercise
program, treatment of vision impairment, management of orthostatic hypotension, management of arrhythmia, vitamin D
supplementation, management of foot and footwear problems, modification of the home environment, and providing
education and information. However, there is insufficient evidence for supporting any single or multifactorial intervention
to reduce fall risk in older people with cognitive impairment. Subsequently, a meta-analysis of exercise interventions (7randomized controlled trials) was conducted, and found that exercise interventions reduce falls in people with dementia(odds ratio, 0.68) 4).
Although people with dementia are prone to osteoporosis-derived fractures, they are often not treated with drugs forosteoporosis. Consider appropriate assessment, treatment and guidance for osteoporosis 5). The risk of femoral neck fracture
is increased in older patients with Alzheimer’s disease who have vitamin K and vitamin D deficiency 6).

▪ References
1) Allan LM, Ballard CG, Rowan EN, et al. Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One. 2009; 4(5):e5521.
2) Baker NL, Cook MN, Arrighi HM, et al. Hip fracture risk and subsequent mortality among Alzheimer’s disease patients in the United Kingdom,
1988-2007. Age Ageing. 2011; 40(1): 49-54.
3) Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society. Summary of the Updated American
Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc. 2011; 59(1): 148157.
4) Chan WC, Yeung JW, Wong CS, et al. E­fficacy of physical exercise in preventing falls in older adults with cognitive impairment: a systematic review
and meta-analysis. J Am Med Dir Assoc. 2015; 16(2): 149-154.
5) Haasum Y, Fastbom J, Fratiglioni L, et al. Undertreatment of osteoporosis in persons with dementia? A population-based study. Osteoporos Int.
2012; 23(3): 1061-1068.
6) Sato Y, Honda Y, Umeno K, et al. The prevention of hip fracture with menatetrenone and risedronate plus calcium supplementation in elderly
patients with Alzheimer disease: a randomized controlled trial. Kurume Med J. 2011; 57(4): 117-124.

Chapter 3

65▪ Search formula
PubMed search: June 9, 2015 (Tuesday)#1 (“Dementia” [Mesh] OR dementia) AND (“Accidental Falls/prevention and control” [Mesh] OR (accident* AND (falls OR fall) AND (prevention
OR preventing)))
Ichushi search: June 9, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND (Falls/TI OR Falls/TH) AND (Accident prevention/TH OR (SH = Prevention) OR Prevention/TI OR
Prevention/TI)

66

Clinical Practice Guideline for Dementia 2017

CQ 3C-7

What are the interventions for pressure ulcers?
AnswerCurrently, there is no clear evidence for the therapeutic or preventive effects of supplements, tube feeding, and parenteralnutrition for pressure ulcers, and there is a lack of high-level evidence for comprehensive management. For local treatment,
refer to the “Evidence-based Guidelines for Local Treatment of Pressure Ulcers” published by the Japanese Society ofPressure Ulcers.
2C

Comment and evidence
Pressure ulcers are necrosis of ischemic cutaneous or subcutaneous tissues caused by blood circulation failure due tocontinuous pressure on localized skin area. Pressure sores are formed frequently in sites with bone protrusion and little
subcutaneous fat tissue, and are strongly affected by ageing, undernutrition, motor paralysis, joint contracture, and urinary
and fecal incontinence. Pressure ulcers tend to occur when activities of daily living (ADL) decrease accompanying progressionof dementia.
Although it has been reported that an increase in number of pressure ulcers is related to higher risk of death in people withadvanced dementia 1), there is currently no clear evidence for the therapeutic or preventive effects of supplements, tube
feeding, and parenteral nutrition for pressure ulcers 2).
A meta-analysis has indicated that the presence of increasing pain is more useful than purulent exudate, heat, and redness
for the diagnosis of pressure ulcer infection 3).

▪ References
1) Cintra MT, de Rezende NA, de Moraes EN, et al. A comparison of survival, pneumonia, and hospitalization in patients with advanced dementia
and dysphagia receiving either oral or enteral nutrition. J Nutr Health Aging. 2014; 18(10): 894-899.
2) Langer G, Fink A. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database Syst Rev. 2014; (6): CD003216.
3) Reddy M, Gill SS, Wu W, et al. Does this patient have an infection of a chronic wound? JAMA. 2012; 307(6): 605-611.

▪ Search formula
PubMed search: June 9, 2015 (Tuesday)#1 (“Dementia” [Mesh] OR dementia) AND (“Pressure Ulcer” [Mesh] OR “bed sore” OR bedsore OR “decubitus position” OR “decubitus ulcer”
OR “pressure sore” OR “pressure ulcer”)
Ichushi search: June 9, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND (Pressure ulcer/TI OR decubitus ulcer/TH)

Chapter 3

67

CQ 3C-8

What are the approaches to treat acute physical illness?
AnswerIn people with dementia, acute physical illness is difficult to detect because typical symptoms are frequently absent andthe patients cannot complain. In Alzheimer’s disease, as dementia becomes severe, the number of hospital admissions
increases and mortality also increases.
C

Comment and evidence

There is still no evidence for acute physical illness in people with dementia.
According to the 2014 data of the Fire and Disaster Management Agency of Japan 1), 61.6% (2.03 million) of the patientstransported to emergency department were elderly, which doubled the percentage of 28.8% in 1993. Among these cases,
cerebrovascular system, heart disease, and respiratory system accounted for 11% each. For people with dementia transported
to emergency department, the major causes are pneumonia, stroke, fractures of lower limbs, bruise or sprain, ileus, andgastrointestinal bleeding 2, 3). In addition, more than 70% of 107 cases of suffocation are secondary to neurological disorders
including dementia, cerebral infarction, schizophrenia, and Parkinson’s disease 4). Therefore, neurological disorders including
dementia can be considered to be risk factor of suffocation. People with Alzheimer’s disease have more hospital admissions
than the general elderly population, and people with severe Alzheimer’s disease are hospitalized 2.3 times more than thegeneral elderly population 5). Moreover, people with dementia who require emergency admission have high death rate 6).
When a person with dementia is admitted to the hospital, make sure that the patient is placed in a room that is withinwatching distance from the nurses, and avoid rooms near the entrance and exit of the ward. Ensure safety by using measures
such as a bed exit sensor and a protective cover to prevent needle removal. Provide care with consideration to monitorchanges in patient’s symptoms or conditions. People with dementia are prone to develop delirium due to anxiety and fear asa result of change in environment and physical distress. As a measure for delirium, provide care with special considerations
for patients with dementia: ask family members to accompany the patient, have the same nurse in charge of the patient,explain the nurse call and location of the toilet in simple language, tell patient the status repeatedly, resolve pain / anxiety /insomnia, and do not restrain actions. Consider medication as necessary.
When dementia is advanced, detection of urinary tract infection is difficult because typical symptoms are frequently
absent, and the patients cannot complain7).

▪ References

1) Homepage of Fire and Disaster Management Agency. Status of emergency actions. 
http://www.fdma.go.jp/neuter/topics/­eldList9_3.html (In Japanese)2) Kimbara, Y, Yamada H, Kitagawa Y, et al. A survey of clinical characteristics of medical and psychiatric comorbidity patients at Emergency Medical
Center, Nagoya Ekisaikai Hospital. Journal of Japanese Society for Emergency Medicine (Nihon Rinsho Kyukyu Igaku Gakkaishi) 2014; 17(5):675-679. (In Japanese)3) Kubota Y, Kameda M, Tamura Y, et al. Emergency medical care for older adults with dementia at emergency center. Japanese Journal of Geriatric
Psychiatry (Ronen Seishin Igakushi) 2007; 18(1): 1204-1209. (In Japanese)4) Michiwaki Y, Aikoh K, Inoue M, et al. Clinical factors and medical cost of 107 cases of suffocation by food. Japanese Journal of Gerodontology(Ronen Shika Igaku) 2012; 26(4): 453-459. (In Japanese)5) Albert SM, Costa R, Merchant C, et al. Hospitalization and Alzheimer’s disease: Results from a community-based study. J Gerontol A Biol Sci Med
Sci. 1999; 54(5): M267-M271.
6) Sampson EL, Blanchard MR, Jones L, et al. Dementia in the acute hospital: prospective cohort study of prevalence and mortality. Br J Psychiatry.
2009; 195(1): 61-66.
7) D’Agata E, Loeb MB, Mitchell SL. Challenges in assessing nursing home residents with advanced dementia for suspected urinary tract infections.
J Am Geriatr Soc. 2013; 61(1); 62-66.

▪ Search formula

PubMed search: June 10, 2015 (Wednesday)#1 (“Dementia” [Mesh] OR dementia) AND (“Pneumonia/therapy” [Mesh] OR (pneumonia AND (therapy OR therapeutic OR treatment)) OR“Acute Disease/therapy” [Mesh] OR “Emergency Medicine” [Mesh])
Ichushi search: June 10, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI) AND (Pneumonia/TH OR Pneumonia/TI OR Acute illness/TH OR Acute illness/TI OR Emergency
medicine/TH)

68

Clinical Practice Guideline for Dementia 2017

CQ 3C-9

How should decisions be made regarding invasive examinations and treatments
including dialysis and dental treatment?
AnswerWhen a person with dementia requires dialysis, refer to the “Proposal for the shared decision-making process regarding
initiation and continuation of maintenance hemodialysis” published by the Japanese Society for Dialysis Therapy. Dental
treatment and oral care are essential for people with dementia, and providing preventive and continuous oral hygiene
management is recommended.
D

Comments and evidence
As of the end of 2010, 9.9% of the total dialysis population had dementia (23,000 of 234,000 of all dialysis patients,
excluding those unknown and undocumented). For dialysis patients aged 90 years or above, 25-35% also have dementia andrequire support 1). As the number of people with dementia who require dialysis increase, there is also an increase in numberof patients who stand up or become restless during dialysis, impeding safe execution of dialysis. There are limits to sedationand caregiver attendance.
The “Proposal for the shared decision-making process regarding initiation and continuation of maintenance hemodialysis”
in Japan are recommendations on providing appropriate information to patients, giving support to patients when making
their own decisions, and obtaining written informed consent 2). Among the situations that require review of whether tosuspend dialysis, “extracorporeal circulation cannot be performed safely without restrain and sedation using medications”
and “oral intake not possible” and included, and these situations may arise in people with dementia.
As dementia emerges, self-cleaning behavior is impaired, and the state of oral hygiene worsens. People with dementia havemore caries and periodontal diseases than healthy people 4). Evidently oral care is important for the prevention of aspiration
pneumonia. In the clinical setting, patients with dementia often discontinue dental treatment because they do not understandthe meaning of the treatment. As a result, some patients require treatment under general anesthesia since the inflammation
cannot be controlled. Before dementia deteriorates to the above states, providing continuous preventive oral hygiene
management to people with dementia is recommended.

▪ References
1) Japanese Society for Dialysis Therapy. Data in Japan compiled by the Statistical Study Committee. http://docs.jsdt.or.jp/overview/index2011.html(In Japanese)
2) Watanabe Y, Hirakata H, Okada, et al. Proposal for the shared decision-making process regarding initiation and continuation of maintenancehemodialysis. Ther Apher Dial 2015; 19Suppl 1: 108-117.
3) Wu B, Plassman BL, Crout RJ, et al. Cognitive function and oral health among community-dwelling older adults. J Gerontol A Biol Sci Med Sci.
2008; 63(5): 495-500.

▪ Search formula
TraumaPubMed search: June 10, 2015 (Wednesday)#1 (“Dementia” [Mesh] OR dementia) AND (“Wounds and Injuries/therapy” [Mesh] OR ((fracture OR fractures OR trauma OR traumas) AND(therapy OR therapeutic OR treatment))
Ichushi search: June 10, 2015 (Wednesday)#1 (Dementia/MTH OR Dementia/TI) AND (Wound and injury/MTH OR Fracture/TI OR Trauma/TI)
Invasive examinations
PubMed search: June 12, 2015 (Friday)#1 (“Dementia/diagnosis” [Mesh] OR (dementia AND (diagnosis OR diagnostic))) AND (“Endoscopy” [Mesh] OR “Endoscopes” [Mesh] OR
endoscopy OR endoscopic OR endoscope* OR “invasive examination”)

Chapter 3

69

Ichushi search: June 12, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND (Endoscopy/TH OR ((Endoscope/TH OR Endoscope/AL) AND (Diagnosis OR Examination)) OR(Invasive examination/AL NOT (Non-invasive examination /AL OR Non-invasive examination/AL)))
Surgery or dialysis
PubMed search: June 12, 2015 (Friday)#1 (“Dementia” [Mesh] OR dementia) AND (“surgical indication” OR operability OR “Renal Dialysis” [Mesh] OR dialysis OR hemodialysis OR
dialyses OR hemodialyses) OR “Dementia/complications” [Mesh] AND (“Surgical Procedures, Operative” [Majr] OR “surgery” [Subheading])
AND “Risk” [Mesh]
Ichushi search: June 12, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND (Surgical indication/AL OR ((Surgery/MTH OR(SH = Surgical therapy) OR hemodialysis/TH OR
Dialysis/TI) AND Risk/TH))70

Clinical Practice Guideline for Dementia 2017

CQ 3C-10

What are the interventions for edema?
AnswerIn addition to interventions for immobility due to long-term bed confinement and undernutrition, provide treatments
for underlying diseases as well as for concomitant diseases such as skin infections and pressure ulcers. Pay attention to thepossibility of edema induced by drugs such as Yokukansan and antipsychotics, and consider discontinuation or dose
reduction of the causative drugs as appropriate.
C

Comments and evidence
Diseases that cause edema commonly seen in older people include: (1) causes of systemic edema; congestive heart failure,
renal disease, hepatic disease, and hypothyroidism, and (2) causes of localized edema; cerebrovascular disroder, deep veinthrombosis, knee osteoarthritis, and malignant tumors. Edema becomes more common with ageing, due to variability ofcapillary pressure, changes in interstitial components and reduced tissue pressure, lowered plasma osmotic pressure due todecreased serum albumin, and increased capillary permeability.
In people with dementia, it is necessary to consider the possibility of edema induced by drugs including antipsychotic
drugs 1) and Yokukansan 2), and to consider discontinuation or dose reduction of the causative drug as appropriate 2). According
to an observational study that examined the safety and efficacy of long-term use of Yokukansan in 163 patients who had beenprescribed Yokukansan for more than 6 months, edema appeared in 10.8% of the patients and many recovered by discontinuing
Yokukansan with no need for treatment 2).
Treatment of edema involves the treatment of underlying diseases identified by diagnosis of the cause as well as treatmentof coexisting illnesses such as skin infections and pressure ulcers. Especially in older people, extreme salt restriction andwater restriction to reduce edema may cause rapid intravascular dehydration, because of the low water and sodium retention
ability in older people. When using diuretics, monitor body weight to ensure that fluid is removed gradually. In addition,
since diuretics tend to disrupt electrolyte balance and cause hypotension, hypernatremia or hyponatremia, and hypokalemia,
close monitoring of blood electrolyte levels and urinary electrolyte excretion is necessary.

▪ References
1) Tan L, Tan L, Wang HF, et al. Efficacy and safety of atypical antipsychotic drug treatment for dementia: a systematic review and meta-analysis.
Alzheimers Res Ther. 2015; 7(1): 20.
2) Okahara K, Ishida Y. Safety and efficacy evaluation of long-term treatment with a traditional Japanese medicine, Yokukansan, on behavioral andpsychological symptoms of dementia. Dementia Japan. 2012; 26: 196-205. (In Japanese)▪ Search formula
PubMed search: June 12, 2015 (Friday)#1 (“Dementia” [Mesh] OR dementia) AND (“Edema” [Mesh] OR edema)
Ichushi search: June 12, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND (Edema/AL OR Edema/TH)

Chapter 3

71

CQ 3C-11

What are the interventions for urinary disorder?
AnswerMany people with dementia have functional urinary incontinence and urge urinary incontinence. Behavioral therapy
can be expected to be effective for urinary disorder, after ruling out underlying urological disorder. On the other hand,
there is no sufficient evidence for pharmacotherapy in people with dementia.
C

Comments and evidence
Carefully investigate the presence or absence of organic diseases causing urinary disorder, and rule out a diagnosis of suchdiseases. In people with dementia, functional urinary incontinence and urge urinary incontinence are common. Treat these
conditions by referring to guidelines (https://minds.jcqhc.or.jp/) 1-3).

1. Behavioral therapy 4-6)
The following interventions are recommended: (1) toileting assistance: [1] toileting at fixed time, [2] toileting according toan established voiding pattern, and [3] reeducating toileting habit; (2) bladder training; and (3) pelvic floor muscle
rehabilitation for stress urinary incontinence.

2. Pharmacotherapy for urinary disorder
For urge urinary incontinence in women, use anticholinergic drugs (propiverine and tolterodine). For prostatic hypertrophy
in overflow urinary incontinence, use the sympathetic selective α1 inhibitors (tamsulosin and naftopidil). For neurogenic
bladder, use cholinergic agonists (muscarinic receptor agonists; bethanechol). Attention should be paid to aggravation of
constipation and cognitive decline caused by anticholinergic drugs 7), and orthostatic hypotension caused by α1 inhibitors.
For overactive bladder with major symptoms of urinary urgency, urge incontinence, and frequent urination, use selective
muscarinic receptor antagonists (anticholinergic drugs) including fesoterodine, tolterodine, solifenacin, imidafenacin, andoxybutynin; and the β3 receptor agonist mirabegron 3). Oxybutynin is highly fat-soluble and crosses the blood-brain barrier,and the possibility of this drug of causing cognitive impairment has been suggested 8). In addition, combined use ofcholinesterase inhibitor and anti-cholinergic drug causes significant decline in activities of daily living compared withcholinesterase inhibitor monotherapy 9).

3. Other treatment methods1)
The following interventions have been recommended: (1) modify the environment depending on cognitive function andphysical function; (2) modify clothes; (3) use urinary catheter, suprapubic catheter, external urine receptacle, or urine
absorbent product; (4) use of bladder support device has been proposed; and (5) if urinary incontinence is detected, wipe thegenital area promptly to maintain cleanliness.

4. Drug-induced urinary disorder
Tricyclic antidepressants should be avoided as much as possible in male patients with urinary disorder 10). Among the
drugs for Parkinson’s disease, levodopa is recommended, whereas trihexyphenidyl and biperiden may cause urinary disorder.

▪ References
1) The Japanese Continence Society, Working Committee for Clinical Practice Guideline for Male Lower Urinary Tract Symptoms. Clinical Practice
Guideline for Male Lower Urinary Tract Symptoms. Tokyo: Blackwell Publishing; 2008. (In Japanese)
2) The Japanese Continence Society, Working Committee for Clinical Practice Guideline for Female Lower Urinary Tract Symptoms. Clinical Practice
Guideline for Female Lower Urinary Tract Symptoms. Tokyo: Blackwell Publishing; 2008. (In Japanese)3) The Japanese Continence Society, Working Committee for Guideline for Overreactive Bladder. Clinical Practice Guideline for Overreactive
Bladder. Tokyo: RichHill Medical Inc.; 2015. (In Japanese)4) Drennan VM, Greenwood N, Cole L, et al. Conservative interventions for incontinence in people with dementia or cognitive impairment, living at
home: a systematic review. BMC Geriatr. 2012; 12: 77.
5) Goode PS, Burgio KL, Richter HE, et al. Incontinence in older women. JAMA. 2010; 303(21): 2172-2181.
6) Hagglund D. A systematic literature review of incontinence care for persons with dementia: the research evidence. J Clin Nurs. 2010; 19(3-4): 303-312.

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Clinical Practice Guideline for Dementia 2017

7) Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern
Med. 2015; 175: 401-407.
8) Paquette A, Gou P, Tannenbaum C. Systematic review and meta-analysis: do clinical trials testing antimuscarinic agents for overactive bladderadequately measure central nervous system adverse events? J Am Geriatr Soc. 2011; 59(7): 13321339.
9) Sink KM, Th­ omas J 3rd, Xu H, et al. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive
outcomes. J Am Geriatr Soc. 2008; 56(5): 847-853.
10) Thompson S, Herrmann N, Rapoport MJ, et al. Efficacy and safety of antidepressants for treatment of depression in Alzheimer’s disease: ametaanalysis. Can J Psychiatry. 2007; 52(4): 248-255.

▪ Search formula
PubMed search: June 12, 2015 (Friday), July 18, 2015 (Saturday)#1 (“Dementia” [Mesh] OR dementia OR alzheimer* [TI]) AND (“Urinary Incontinence/therapy” [Mesh] OR “Urinary disorders/therapy” [Mesh]
OR “Urinary Bladder Diseases/therapy” [Mesh] OR “Dysuria/therapy” [Mesh] OR ((“urinary incontinence” OR urinary disorder* [TI] OR urinary
incontinence* [TI] OR urinary bladder disease* [TI] OR bladder dysfunction* [TI] OR neurogenic bladder* [TI] OR dysuria [TI]) AND (therapy
OR therapeutic OR treatment OR management OR care OR training OR intervention)))Ichushi search: June 12, 2015 (Friday), July 18, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI) AND (urinary disorder/TH OR urinary disorder/TI OR Urinary incontinence/TI OR Bladder disease/TH
OR Bladder disease/TI OR Micturition pain/TH OR Micturition pain/TI OR Neurogenic bladder/TI OR Overactive bladder/TI)

Chapter 373

CQ 3C-12

What are the interventions for constipation?
AnswerConstipation is a common disease among people with dementia, and may impair quality of life (QOL) and causedelirium. Differentiate constipation from organic diseases, and use laxatives when diet (high fiber foods) and exercise do
not improve the constipation.
C

Comments and evidence
Constipation impairs QOL of people with dementia, causes irritability, decreases appetite, and may even result in delirium.
The rates of constipation by subtype of dementia are 43% in dementia with Parkinson’s disease, 28% in Lewy body disease,and 26% in vascular dementia, and were all higher than the rate of 2% in controls; whereas the rate is 3% in Alzheimer’s
disease and not significantly different from controls 1).
Constipation becomes more common with aging, due to weakness of the pelvic floor muscles, autonomic disturbances,
and abnormalities in the colon wall. Constipation is classified into functional (atonic, convulsive, rectal), organic,
symptomatic (such as diabetes and cerebrovascular disorder), and drug-induced. Atonic constipation is the most common,and is classified as functional constipation. Organic constipation is caused by colon cancer or scarring. Medications associatedwith constipation include anticholinergic drugs, antidepressants, antipsychotic drugs, antiparkinsonian drugs, antihistamines,
diuretics, and opioids 2). Symptoms of nausea/vomiting, abdominal distension, and retention of feces and gas suggest ileus.
Change in stool caliber, occult blood in stool, bloody stool, iron deficiency anemia, and weight loss are signs of suspectedorganic constipation 2).
After ruling out the above conditions, use non-pharmacological interventions such as lifestyle modification and diettherapy. Recommend patients to (1) eat a fiber-rich diet, (2) keep regular eating and defecation habits, and (3) do walking
exercise. For convulsive constipation, it is important to remove stress. For atonic constipation, advice patients to drink
sufficient water to prevent hard stool, and to take water-soluble vitamins such as vitamins B1 and B2, as well as to increasebifidobacteria in the bowel. If there is no improvement despite the above interventions, prescribe pharmacotherapy. Laxatives
include osmotic laxatives (magnesium oxide), colonic stimulants (such as senna, sennoside, Daio, and sodium picosulfate),
chloride channel activator (lubiprostone) that promotes water secretion in the intestinal tract, Daikenchuto suppository, andenemas. Select medications according to the number of defecations and the nature of the stool.
Although enema is widely used, the rates of complications such as perforation, hyperphosphatemia, and sepsis are
particularly high in older patients, and should be used with caution 3).

▪ References
1) Allan L, McKeith I, Ballard C, et al. The prevalence of autonomic symptoms in dementia and their association with physical activity, activities ofdaily living and quality of life. Dement Geriatr Cogn Disord. 2006; 22: 230-233.
2) Lindberg G, Hamid SS, Malfertheiner P, et al. World Gastroenterology Organisation global guideline: Constipation- a global perspective. J Clin
Gastroenterol. 2011; 45(6): 483-487.
3) Niv G, Grinberg T, Dickman R, et al. Perforation and mortality after cleansing enema for acute constipation are not rare but are preventable. Int J
Gen Med. 2013; 6: 323-328.

▪ Search formula
PubMed search: June 12, 2015 (Friday), July 18, 2015 (Saturday)#1 (“Dementia” [Mesh] OR dementia OR alzheimer* [TI]) AND (“Constipation/therapy” [Mesh] OR “Colonic Diseases, Functional/therapy”[Mesh] OR ((constipation [TI] OR bowel dysfunction* [TI] OR colonic disease* [TI] OR neurogenic bowel*[TI]) AND (therapy OR therapeutic
OR treatment OR management OR care OR training OR intervention)))Ichushi search: June 12, 2015 (Friday), July 18, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI) AND (Constipation/TH OR Constipation/TI OR Defecation disorder/TH OR Defecation disorder/TI OR
Colonic disease-functional/ TH OR Functional colonic disease/TI OR Neurogenic bowel/TI OR irritable colon/TI)

74

Clinical Practice Guideline for Dementia 2017

CQ 3C-13

How should diabetes, hypertension and other lifestyle-related diseases
be managed?
Recommendation
Individualized approach to diabetes control is recommended, with consideration of the severity of dementia andphysical dysfunction, coexisting diseases, frailty, and other factors. Although there is little evidence regarding the effects
of antihypertensive treatment for hypertensive patients with dementia, treatment that does not excessively reduce bloodpressure should be considered.
2C

Comments and evidence

It has been pointed out that lifestyle-related diseases (or vascular risk factors) such as hypertension, diabetes, dyslipidemia,
and obesity that coexist with dementia may potentially modify the progression of cognitive dysfunction. Proper treatmentof vascular risk factors accompanying Alzheimer’s disease dementia has been shown to mitigate the deterioration of Mini
Mental State Examination (MMSE) score 1).
For glycemic control in older diabetic patients who have developed dementia, set the treatment target ​considering theactivities of daily living (ADL), coexisting diseases, and risk of severe hypoglycemia. Hypoglycemia, falls and fractures
increase when HbA1c is less than 7.0%; and cognitive decline, frailty, and geriatric syndrome increase gradually when
HbA1c exceeds 8.0%. In older people with diabetes, setting HbA1c target for individual patient is recommended, taking
into consideration not only the presence or absence and severity of dementia, but also the coexisting diseases, basic ADL(BADL) and instrumental ADL (IADL), frailty, and risk of severe hypoglycemia 2). Current recommendation is HbA1c 7.0%
to below 7.5% for older people with normal cognitive and physical functions, below 8.0% for mild to moderate dementia,
and below 8.5% for moderate to severe dementia or severely impaired physical function. Furthermore, according to the
proposal of the Joint Committee in Japan, lower limits of the targets have been set to avoid hypoglycemia in patients using
drugs for which severe hypoglycemia is a concern (such as insulin, sulphonylureas, and glinides).
There is little evidence for the effect of antihypertensive agents in hypertensive patients with dementia. An observational
study finds that antihypertensive therapy prevents the progression of mild cognitive impairment to Alzheimer’s disease
dementia 3). Antihypertensive treatment should be considered 4). However, although there are no descriptions for therecommended blood pressure targets for older people with frailty or dementia, care should be taken not to excessively lower
blood pressure in older people with dementia receiving antihypertensive treatment 5).

▪ References
1) Deschaintre Y, Richard F, Leys D, et al. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology. 2009;73(9): 674-680.
2) The Japan Diabetes Society / Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes. Glycemic targets for
elderly patients with diabetes. 2016. (In Japanese)
3) Li J, Wang YJ, Zhang M, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology. 2011;76(17): 1485-1491.
4) Japan Society for Hypertension Committee for Guidelines for the Management of Hypertension. Guidelines for the Management of Hypertension
2014 (JSH 2014). Tokyo: LifeScience Shuppan; 2014. (In Japanese)5) Mossello E, Pieraccioli M, Nesti N, et al. E­ffects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs.
JAMA Intern Med. 2015; 175(4): 578-585.

▪ Search formula

PubMed search: July 3, 2015 (Friday)#1 (“Dementia/prevention and control” [Majr] OR (dementia [TI] AND (prevent* OR control*)) OR “Cognition Disorders/prevention and control” [Majr]
OR ((cognition disorder* [TI] OR “cognitive dysfunction” [TI]) AND (prevent* OR control*))) AND (“Diabetes Mellitus” [Mesh] OR “Hypertension”[Mesh] OR ((“diabetes mellitus” [TI] OR hypertension [TI])) OR “Life Style” [Majr] OR lifestyle related disease* [TI] OR lifestyle disease* [TI])
Ichushi search: July 3, 2015 (Friday)#1 (Dementia/MTH OR Dementia/TI OR Cognitive impairment/MTH OR Cognitive impairment/TI) AND ((SH = Therapeutic use, treatment,
drug treatment, surgical treatment, transplantation, dietary treatment, psychiatric treatment, radiotherapy, rehabilitation, prevention)OR
Pharmacotherapy/TH OR Pharmacological effect/TH OR Treatment/TI OR Therapy/TI OR Control/TI OR Prevention/TI) AND (Lifestyle
related disease /TH OR Lifestyle related disease /TI OR Diabetes/TH OR Diabetes/ TI OR Hypertension/TH OR Hypertension/TI)

Chapter 375

Chapter 4
Clinical Course and Treatment

A | Risk Factors and Protective Factors of Dementia
CQ 4A-1

What are the risk factors and protective factors of dementia?
AnswerRisk factors for dementia include ageing, genetic risk factors (APP, PS1, PS2, APOEε4), vascular risk factors(hypertension, diabetes, dyslipidemia), lifestyle-related factors (such as smoking), and related diseases (metabolic
syndrome, sleep apnea syndrome, depression, and bipolar disorder). Protective factors include moderate exercise, dietaryfactors, leisure activities, social participation, mental activity, and cognitive training. Acquired elements include education
history and head trauma.

Comments and evidence
Risk factors that can be modified to prevent dementia include (midlife) hypertension, diabetes, (midlife) obesity,
dyslipidemia, smoking, low physical activity, and depression 1-3).
The effects of hypertension on dementia and cognitive impairment vary with age. Since midlife hypertension is a risk
factor for dementia and cognitive impairment in older age, active treatment is recommended from the viewpoint of dementia
prevention.
Diabetes is a risk factor for dementia (Alzheimer’s disease dementia, vascular dementia, and mixed dementia); especially,
glycemic control in midlife is necessary to prevent the onset of dementia.
Midlife dyslipidemia, especially hypercholesterolemia, has been shown to be a risk factor for Alzheimer’s disease dementia,
and strict control of dyslipidemia in midlife is desirable. In older people, report has indicated that higher serum cholesterollevel is associated with a lower risk of developing Alzheimer’s disease dementia. Therefore, statins have to be used withcaution in older people.
An increasing number of reports suggest a relationship of metabolic syndrome with ageing-associated cognitive impairment,
mild cognitive impairment, and vascular dementia, but the association with Alzheimer’s disease dementia is not consistent.
Many reports have shown that metabolic syndrome in midlife, in particular, is associated with cognitive impairment.
Smoking aggravates dementia [risk ratio (RR) 1.30], vascular dementia (RR 1.38), and Alzheimer’s disease dementia (RR1.40).
Many observational studies on exercise therapy have reported that regular physical activity prevents the onset of dementia
and Alzheimer’s disease dementia. Interventional trials on the effect of physical activity in older people report the protective
effect of physical activity against cognitive impairment, and recommends active incorporation of exercise 4).
Several observational studies report that a past history of depression and bipolar disorder increases the risk of dementia
onset in later life 5-7).
Leisure activities comprise intellectual, physical, and social elements. Many reports show that leisure activities haveprotective effects against the development of dementia and Alzheimer’s disease dementia.
High-calorie diets containing mainly carbohydrates, low-protein diets, and low-fat diets tend to increase the risk of mild
cognitive impairment and dementia. Moderate drinking has been reported to prevent dementia. Hyperhomocysteinemia has
been reported to be a risk factor for Alzheimer’s disease dementia and other types of dementia 1). Sleep apnea syndrome andsleep-disordered breathing are known to be vascular risk factors associated with cognitive impairment.
A shorter education history is associated with increase in the risk of Alzheimer’s disease dementia 2).
Head injury increases the odds ratio (OR) of a pathological diagnosis of Alzheimer’s disease dementia in men (OR 1.47),
but not in women (OR 1.18) 8).

▪ References
1) Deckers K, van Boxtel MPJ, Schiepers OJG, et al. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on
the evidence from observational studies. Int J Geriatr Psychiatry. 2015; 30(3): 234-246.
2) Beydoun MA, Beydoun HA, Gamaldo AA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic78

Clinical Practice Guideline for Dementia 2017

review and meta-analysis. BMC Public Health. 2014; 14: 643-676.
3) Plassman BL, Williams JW Jr, Burke JR, et al. Systematic review: Factors associated with risk for and possible prevention of cognitive decline in later
life. Ann Intern Med. 2010; 153(3): 182-193.
4) So F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011; 269(1):107-117.
5) da Silva J, Goncalves-Pereira M, Xavier M, et al. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry. 2013;
202(3): 177-186.
6) Jorm AF. History of depression as a risk factor for dementia: an updated review. Aust N Z J Psychiatry. 2001; 35(6): 776-781.
7) Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis.
Arch Gen Psychiatry. 2006; 63(5): 530-538.
8) Abner EL, Nelson PT, Schmitt FA, et al. Self-reported head injury and risk of late-life impairment and AD pathology in an AD center cohort.
Dement Geriatr Cogn Disord. 2014; 37(5-6): 294-306.

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79

CQ 4A-2

Are hypertension control and antihypertensive drugs effective in dementia
prevention?
Recommendation
Hypertension in midlife is a risk factor for dementia, and should be treated actively. However, large-scale studies havenot clearly shown the preventive effect of antihypertensive therapy against onset of dementia and cognitive impairment.

2C

Comments and evidence
The effect of hypertension on dementia and cognitive impairment varies with age. In particular, hypertension in midlife
is a risk factor for dementia in old age. Therefore, active treatment is recommended from the viewpoint of dementia prevention 1).
In a 12-year follow-up study of adults with no dementia at baseline, blood pressure at baseline had a greater effect on the
speed of cognitive decline in subjects who were in midlife (aged under 65 years) at the start of the study compared with those
who were in old age (aged 65 years or above). This finding suggests that blood pressure control in midlife has a pronounced
effect on cognitive function 2).
The relationship between hypertension and dementia in old age is not consistent.
The dementia preventive effect of antihypertensive medications has been observed for dementia in general and for vasculardementia.
A Cochrane review reports a meta-analysis of large-scale double-blind interventional trials (SHEP, Syst-Eur, SCOPE,
HYVET). The subjects of the analysis were older people (mean age 75 years) with hypertension. Blood pressure wasadequately lower in the intervention group compared with the control group. However, with regard to the onset of dementia,
the intervention group showed only a tendency of preventive effect [odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74
to 1.07] 3).
A pooled meta-analysis of 8 large-scale clinical trials found that blood pressure lowering had no significant dementia
prevention effect overall, but diuretics and calcium antagonists were effective 4).
In a pooled meta-analysis of 14 longitudinal studies on the relationship between antihypertensive therapy and onset ofdementia or cognitive impairment in subjects without dementia at baseline, use of antihypertensive drugs had no significant
preventive effect on the development of Alzheimer’s disease dementia and cognitive impairment. However, there was a
preventive effect on vascular dementia and dementia in general 5).
In a meta-analysis based on 19 randomized controlled trials (RCTs) and 11 observational studies on the prevention effects
of antihypertensive drugs in patients with no history of stroke, the risk of developing dementia was significantly reduced by
9%. In a sub-analysis of the antihypertensive classes, angiotensin II receptor blocker (ARB) tended to be beneficial for
cognitive function 6).
In another meta-analysis of 12 studies in older subjects without dementia or cerebrovascular disorders (4,076 subjects),
hypertension significantly reduced episodic memory and global cognition 7).
In the Honolulu-Asia Aging Study, 2,197 male hypertensive patients (mean age 77 years) without dementia or cognitive
impairment were followed. The risk of progression of cognitive decline was reduced in patients taking β-blockers as
antihypertensive drug (incidence ratio 0.69, 95% CI 0.50 to 0.94) 8).
In the Hisayama study, the relative risk of developing vascular dementia increased linearly with increasing blood pressure
from midlife to late life 9).

▪ References
1) Launer LJ, Hughes T, Yu B, et al. Lowering midlife levels of systolic blood pressure as a public health strategy to reduce late-life dementia:
perspective from the Honolulu Heart Program/Honolulu Asia Aging Study. Hypertension. 2010; 55(6): 1352-1359.
2) Kohler S, Baars MA, Spauwen P, et al. Temporal evolution of cognitive changes in incident hypertension: prospective cohort study across the adultage span. Hypertension. 2014; 63(2): 245-251.
3) McGuinness B, Todd S, Passmore P, et al. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive
impairment and dementia. Cochrane Database Syst Rev. 2009; (4): CD004034.
4) Staessen JA, Thijs L, Richart T, et al. Placebo-controlled trials of blood pressure-lowering therapies for primary prevention of dementia. Hypertension.

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Clinical Practice Guideline for Dementia 2017

2011; 57(2): e6-e7.
5) Chang-Quan H, Hui W, Chao-Min W, et al. e association of antihypertensive medication use with risk of cognitive decline and dementia: a metaanalysis of longitudinal studies. Int J Clin Pract. 2011; 65(12): 1295-1305.
6) Levi Marpillat N, Macquin-Mavier I, Tropeano AI, et al. Antihypertensive classes, cognitive decline and incidence of dementia: a network metaanalysis. J Hypertens. 2013; 31(6): 1073-1082.
7) Gifford KA, Badaracco M, Liu D, et al. Blood pressure and cognition among older adults: a meta-analysis. Arch Clin Neuropsychol. 2013; 28(7):649-664.
8) Gelber RP, Ross GW, Petrovitch H, et al. Antihypertensive medication use and risk of cognitive impairment: The Honolulu-Asia Aging Study.
Neurology. 2013; 81(10): 888-895.
9) Ninomiya T, Ohara T, Hirakawa Y, et al. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study. Hypertension.
2011; 58(1): 22-28.

▪ Search formula
PubMed search: June 13, 2015 (Saturday)#1 ((“Dementia/prevention and control” [Mesh]) OR (dementia AND prevent*) OR “Cognition Disorders/prevention and control” [Mesh] OR(“cognition disorder*” AND prevent*)) AND (“Antihypertensive Agents” [Mesh] OR “Antihypertensive Agents” [Pharmacological Action] OR
antihypertensive agent*)
Ichushi search: June 13, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Antihypertensive agents/TH OR
Antihypertensive agents/TI OR Antihypertensive agents /TI) AND (Prevention/TI OR Control/TI OR (SH = Prevention))

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81

CQ 4A-3

Is diabetes control effective in dementia prevention?
Recommendation
In many reports, including meta-analyses, diabetes is a risk factor for Alzheimer’s disease dementia, vascular dementia,
and mixed dementia. Especially, glycemic control in midlife is necessary for prevention of dementia onset.
2C

Comments and evidence
Many meta-analysis and systematic reviews of observational studies have reported that diabetes is a risk factor for dementia(Alzheimer’s disease dementia, vascular dementia, and mixed dementia) 1-9)
A 9-year follow-up of older people aged 75 years and above, comprising 963 subjects with normal cognitive function and302 subjects with mild cognitive impairments (120 with amnestic mild cognitive impairments, 182 without dementia buthaving other cognitive impairment), the rate of conversion to dementia was 2.87 times in the diabetes group and 4.96 times
in the pre-diabetes group 1).
The mechanisms by which diabetes affects the pathology of Alzheimer’s disease dementia presumably involve cell biologicaland molecular interactions of multiple factors including hyperinsulinemia and impaired insulin secretion 2). It remains
unclear whether endogenous or exogenous insulin adversely affects cognitive function.
According to the results of the Hisayama study, diabetes is a significant risk for the development of Alzheimer’s disease
dementia and vascular dementia. The risk of developing vascular dementia increased with increased level of glucose tolerance
impairment, and the risk of developing Alzheimer’s disease dementia increased significantly with increased severity of
diabetes (hazard ratio 2.1) 3).
A report indicates that controlling diabetes together with hypertension and lipids can reduce vascular events, and improve
cognitive decline related to vascular dementia 4).

▪ References
1) Xu W, Caracciolo B, Wang HX, et al. Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes. 2010;
59(11): 2928-2935.
2) Kopf D, Frolich L. Risk of incident Alzheimer’s disease in diabetic patients: a systematic review of prospective trials. J Alzheimers Dis. 2009; 16(4):677-685.
3) Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011; 77(12):1126-1134.
4) McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet. 2012; 379(9833): 2291-2299.
5) Palta P, Schneider AL, Biessels GJ, et al. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains
and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc. 2014; 20(3): 278-291.
6) Cheng G, Huang C, Deng H, et al. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies.
Intern Med J. 2012; 42(5): 484-491.
7) Luchsinger JA. Diabetes, related conditions, and dementia. J Neurol Sci. 2010; 299(1-2): 35-38.
8) Reijmer YD, van den Berg E, Ruis C, et al. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev. 2010; 26(7): 507-519.
9) Exalto LG, Whitmer RA, Kappele LJ, et al. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol. 2012; 47(11):858-864.

▪ Search formula
PubMed search: June 13, 2015 (Saturday)#1 ((“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR “cognition disorder*” [TI]) AND (“Diabetes Mellitus” [Majr] OR“diabetes mellitus” [TI] OR “Insulin Resistance” [Majr] OR “Insulin” [Majr] OR insulin [TI])) OR ((“Dementia/prevention and control” [Mesh]
OR (dementia AND prevent*) OR “Cognition Disorders/prevention and control” [Mesh] OR (“cognition disorder*” AND prevent*)) AND(“Diabetes Mellitus/ therapy” [Mesh] OR (“diabetes mellitus” AND (therapy OR therapeutic OR treatment))))Ichushi search: June 13, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Diabetes/TH OR Diabetes/TI OR
Insulin resistance/TH OR Insulin resistance/TI OR Insulin resistance/TI) AND (Prevention/TI OR Control/TI OR (SH = Prevention))

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Clinical Practice Guideline for Dementia 2017

CQ 4A-4

Is treatment for dyslipidemia effective for dementia prevention?
Recommendation
Dyslipidemia in midlife is a risk factor for dementia, especially Alzheimer’s disease dementia. Statins have been reported
to reduce the risk of dementia, and lipid control in midlife is desirable. Since the effects of serum cholesterol level on
dementia in older people remain uncertain, statins should be used with caution in older people.
2C

Comments and evidence
Research so far has shown that hypercholesterolemia is a risk for Alzheimer’s disease dementia 1). Therefore, many studies
have been conducted to examine the effect of administration of statins, therapeutic drugs for dyslipidemia, in preventing
development of dementia including Alzheimer’s disease dementia. However, the results of these studies are not consistent. In
general, randomized controlled trials (RCT) have not yielded effective results, and data indicating effectiveness are largely
reported by observational studies.
In a Cochrane review that analyzed two RCTs in patients with dyslipidemia and risk of developing dementia (cardiovascularand cerebrovascular disorder, lifestyle-related diseases), administration of statins was not associated with the onset ofdementia, changes in various neuropsychological tests, or occurrence of adverse events 2).
Regarding the prevention of further cognitive decline by statin administration in persons with Alzheimer’s disease
dementia (including suspected cases), a Cochrane review reported a meta-analysis of only three large-scale RCTs with 748
subjects. No significant preventive effect of disease progression was observed in any of the three batteries: Alzheimer’s
Disease Assessment Scale cognitive subscale (ADAS-cog), Mini Mental State Examination (MMSE), and Clinician’s Global
Impression of Change (CGIC) 3).
In a systematic review of observational studies that examined the effects of statins other than improvement of dyslipidemia
in the general population, the incidence of dementia among statin users was low in 13 meta-analysis 5).
In a meta-analysis based on 8 prospective observational studies, statins reduced the risk of dementia by 38% [relative risk
(RR) 0.62, 95% confidence interval (CI) 0.4 to 0.81] 6).
In a meta-analysis based on 20 studies (16 observational studies, 3 case-control studies, 1 RCT), statins reduced the riskof developing dementia by 38% (RR 0.62, 95% CI 0.43 to 0.82). Even when the endpoint was limited to Alzheimer’s disease
dementia, the risk of developing dementia was reduced by 24% (RR 0.76, 95% CI 0.65 to 0.90) 7).
The effect of dyslipidemia on cognitive decline varies with age. Midlife dyslipidemia, especially hypercholesterolemia, hasbeen shown to be a risk factor for Alzheimer’s disease dementia, and strict control of lipid abnormalities in midlife isdesirable. There are also reports that higher serum cholesterol level in older people is associated with lower risk of developing
Alzheimer’s disease dementia. Therefore, statins have to be used with caution in older people.
In one report, statin treatment for mild cognitive impairment reduced the hazard risk of developing Alzheimer’s disease
dementia by 67% 8).
In another report, statin administration to older people with vascular risk factors did not prevent cognitive decline orprevent dementia 9).

▪ References
1) Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies.
Arch Neurol. 2011; 68(10): 1239-1244.
2) McGuinness B, Craig D, Bullock R, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2009; (2): CD003160.
3) McGuinness B, O’Hare J, Craig D, et al. Cochrane review on ‘Statins for the treatment of dementia’. Int J Geriatr Psychiatry. 2013; 28(2): 119-126.
4) Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med. 2013; 159(10): 688-697.
5) Macedo AF, Taylor FC, Casas JP, et al. Unintended effects of statins from observational studies in the general population: systematic review andmeta-analysis. BMC Med. 2014; 12: 51.
6) Song Y, Nie H, Xu Y, et al. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013;13(4): 817-824.
7) Wong WB, Lin VW, Boudreau D, et al. Statins in the prevention of dementia and Alzheimer’s disease: a meta-analysis of observational studies andan assessment of confounding. Pharmacoepidemiol Drug Saf. 2013; 22(4): 345-358.
8) Sparks DL, Kryscio RJ, Connor DJ, et al. Cholesterol and cognitive performance in normal controls and the influence of elective statin use after

Chapter 483

conversion to mild cognitive impairment: results in a clinical trial cohort. Neurodegener Dis. 2010; 7(1-3): 183-186.
9) McGuinness B, Craig D, Bullock R, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016; (1): CD003160.

▪ Search formula
PubMed search: June 13, 2015 (Saturday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR “cognition disorder*” [TI]) AND (“Hypolipidemic Agents” [Majr]
OR “antilipemic agent*” [TI] OR “hypolipidemic agent*” [TI]) OR ((“Dementia/ prevention and control” [Mesh] OR dementia AND prevent* OR“Cognition Disorders/prevention and control” [Mesh] OR(“cognition disorder*” AND prevent*))) AND (“Hypolipidemic Agents” [Mesh] OR“Hypolipidemic Agents” [Pharmacological Action] OR ((“antilipemic agent*” OR “hypolipidemic agent*”) AND (therapy OR therapeutic OR
treatment)))
Ichushi search: June 13, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Hypolipidemic agents/TH OR
Hypolipidemic agents/TI OR Lipid improving agents/TI OR Antilipemic agent/TI OR Antilipidemic agent/TI OR Antilipidemic drug/TI OR
Antilipemic drug/TI OR Antilipemic drug/ TI OR Antilipemic agent/TI OR Antilipemic drug/TI OR Antilipidemic drug/TI OR Lipid-lowering
drug/TI OR Anticholesteremic agent/TI OR Anticholesteremic drug/TI OR Anticholesteremic agent/TI OR Anticholesteremic drug/TI) AND(Prevention/TI OR Control/TI OR (SH = Prevention))

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Clinical Practice Guideline for Dementia 2017

CQ 4A-5

Does metabolic syndrome worsen dementia?
Recommendation
There are many reports indicating that metabolic syndrome and its factors (abnormal glucose tolerance, obesity,
hypertension, and dyslipidemia) are associated with ageing-related cognitive decline, mild cognitive impairment, andvascular dementia. However, opinions on Alzheimer’s disease dementia are divided.
2C

Comments and evidence
Many reports have shown that metabolic syndrome, especially in midlife, is associated with cognitive decline. Obesity in
midlife is associated with an increase in risk of dementia [risk ratio (RR) 1.41], although the risk decreases at age 65 andabove (RR 0.83) 1).
In one study of adults aged below 65 years, metabolic syndrome was associated with memory impairment, visuospatial
impairment, and impaired executive function 2). In a 25-year longitudinal study of 3,555 subjects, patients who fulfilled
multiple items of metabolic syndrome had increased risk of dementia, particularly vascular dementia, but no increase in riskof Alzheimer’s disease dementia 3).
According to a 3.5-year longitudinal study of 2,097 persons aged 65 to 84 years, among subjects with mild cognitive
impairment, those who had coexisting metabolic syndrome had a significantly higher risk of developing dementia comparedwith those without metabolic syndrome 3).
When 837 persons with mild cognitive impairment were observed for 5 years, 352 (42.1%) converted to Alzheimer’s
disease dementia, and these patients had significantly more vascular risk factors than those who remained having mild
cognitive impairment (2.33 vs 1.15, p < 0.001) 4). In the group treated for all the vascular risk factors (hypertension, diabetes,and dyslipidemia) during the stage of mild cognitive impairment, the rate of conversion to Alzheimer’s disease dementia waslower compared to the group not treated at all 4).
Persons with Alzheimer ’s disease dementia who had no cerebrovascular disorders and were treated for hypertension,
diabetes, and dyslipidemia have slower decline in cognitive function compared with persons without any risk factors 5).
Even in persons with metabolic syndrome, treating risk factors for arteriosclerosis may prevent cognitive decline 6).

▪ References
1) Pedditizi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review andmeta-analysis of longitudinal studies. Age Ageing. 2016; 45(1): 14-21.
2) Yates KF, Sweat V, Yau PL, et al. Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler Thromb Vasc
Biol. 2012; 32(9): 2060-2067.
3) Panza F, Frisardi V, Capurso C, et al. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms.
J Alzheimers Dis. 2010; 21(3): 691-724.
4) Li J, Wang, YJ, Zhang M, et al. Chongqing Ageing Study Group: Vascular risk factors promote conversion from mild cognitive impairment toAlzheimer disease. Neurology. 2011; 76(17): 1485-1491.
5) Deschaintre Y, Richard F, Leys D, et al. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology. 2009;73(9): 674-680.
6) Arai A. Correction of metabolic syndrome and dementia prevention. Japanese Journal of Clinical Medicine (Nihon Rinsho) 2011; 69(1012 suppl10): 202-206. (In Japanese)▪ Search formula
PubMed search: June 13, 2015 (Saturday)#1 ((“Dementia” [Majr] OR dementia [TI] OR “Alzheimer’s disease” [TI] OR “Alzheimer disease” [TI] OR “Cognition Disorders” [Majr] OR“cognition disorder*” [TI]) AND (“Metabolic Syndrome X” [Majr] OR “metabolic syndrome” [TI])) OR ((“Dementia/prevention and control”[Mesh] OR ((dementia OR “Alzheimer’s disease” OR “Alzheimer disease”) AND prevent*) OR “Cognition Disorders/prevention and control”[Mesh]OR(“cognition disorder*” AND prevent*)) AND (“Metabolic Syndrome X” [Mesh] OR “metabolic syndrome”))
Ichushi search: June 13, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer’s disease/TI OR Alzheimer’s disease/TI OR Cognitive impairment/TH OR Cognitive
impairment/TI) AND (Metabolic syndrome/TH OR Metabolic syndrome/TI OR Metabolic syndrome/TI) AND (Risk factor/TH OR Risk
factor/TI OR Risk factor/TI)

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CQ 4A-6

Does smoking worsen dementia?
Recommendation
Smoking worsens all-cause dementia, vascular dementia, and Alzheimer’s disease dementia.

1B

Comments and evidence
The results of 37 large-scale studies show that smoking worsens dementia [risk ratio (RR) 1.30], vascular dementia (RR1.38), and Alzheimer’s disease dementia (RR 1.40). The risk of Alzheimer’s disease dementia is significantly higher in current
smokers who are APOE ε4 non-carriers. People aged between 65 and 75 who smoke have an increased risk of all-cause
dementia and Alzheimer’s disease dementia compared with those who do not smoke 1-3).
Smoking 20 cigarettes a day increases the risk of all-cause dementia (RR 1.34) 1). Persons who have ever smoked are athigher risk for all-cause dementia (RR 1.13) and vascular dementia (RR 1.25) than those who never smoke. On the other
hand, those who smoked before but have quitted smoking do not have an increased risk for all-cause dementia 1).
In recent large-scale trials, smoking is often reported as a risk factor for all-cause dementia 1, 3).
The global smoking rate is 27.4%. The increase in risk of Alzheimer’s disease dementia due to smoking has a RR of 1.59,
and the population attributable risk (PAR) is 13.9%. Approximately 14% of Alzheimer’s disease dementia worldwide isreported to be caused by smoking 3).

▪ References
1) Zhong G, Wang Y, Zhang Y, et al. Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies withinvestigation of potential effect modifiers. PLoS One. 2015; 10(3) : e0118333.
2) Cataldo JK, Prochaska JJ, Glantz SA. Cigarette smoking is a risk factor for Alzheimer’s Disease: an analysis controlling for tobacco industry
affiliation. J Alzheimers Dis. 2010; 19(2) : 465-480.
3) Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011; 10(9) : 819-828.

▪ Search formula
PubMed search: June 13, 2015 (Saturday)#1 ((“Dementia” [Majr] OR dementia [TI] OR “Alzheimer’s disease” [TI] OR “Alzheimer disease” [TI] OR “Cognition Disorders” [Majr] OR“cognition disorder*” [TI]) AND (“Smoking” [Majr] OR smoking [TI])) OR ((“Dementia/ prevention and control” [Mesh] OR ((dementia OR“Alzheimer’s disease” OR “Alzheimer disease”) AND prevent*) OR “Cognition Disorders/prevention and control” [Mesh] OR (“cognition
disorder*” AND prevent*)) AND (“Smoking” [Mesh] OR “smoking”))
Ichushi search: June 13, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Alzheimer’s disease/TI OR Alzheimer’s disease/TI OR Cognitive impairment/TH OR Cognitive
impairment/TI) AND (Smoking/TH OR Smoking/TI) AND (Risk factor/TH OR Risk factor/TI OR Risk factor/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 4A-7

Is exercise effective in preventing dementia?
Recommendation
Many observational studies have reported that regular physical activity is associated with reduced incidence of all-cause
dementia and Alzheimer’s disease dementia. Interventional studies in older persons without dementia and older persons
with mild cognitive impairment report that physical activity protects against cognitive decline. Active incorporation of
exercise is recommended.
1B

Comments and evidence
Decreased walking speed and reduced grip strength in middle-aged to older persons are related to cognitive impairment 1).
Physical activity and habitual exercise during middle age to old age have been shown to be associated with reduced incidence
of dementia and Alzheimer’s disease dementia 2, 3).
A meta-analysis has reported that intervention of physical activity for older persons without dementia improves attention
and judgment 4). In a meta-analysis of 14 randomized controlled trials (RCT) that studied older people aged 65 years andabove with mild cognitive impairment or Mini Mental State Examination (MMSE) scores of 24-28 points, exercise
intervention significantly improved verbal fluency, but did not significantly improve executive function, memory or
information processing 5). In a RCT studying older Japanese persons with mild cognitive impairment, implementation of a
combination of physical exercise and cognitive tasks that stimulate attention and memory (such as calculation and word
chain), so-called “cognicise”, improved logical memory and MMSE score as well as prevented the progression of hippocampal
atrophy 6).

▪ References
1) Clouston SA, Brewster P, Kuh D, et al. The dynamic relationship between physical function and cognition in longitudinal aging cohorts. Epidemiol
Rev. 2013; 35: 33-50.
2) Morgan GS, Gallacher J, Bayer A, et al. Physical activity in middle-age and dementia in later life: Findings from a prospective cohort of men in
Caerphilly, South Wales and a meta-analysis. J Alzheimers Dis. 2012; 31(3): 569-580.
3) Sofi F, Valecchi D, Bucci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011; 269(1):107-117.
4) Kelly ME, Loughrey D, Lawlor BA, et al. The impact of exercise on the cognitive functioning of healthy older adults: a systematic review and metaanalysis. Ageing Res Rev. 2014; 16: 12-31.
5) Gates N, Fiatarone Singh MA, Sachdev PS, et al. The effect of exercise training on cognitive function in older adults with mild cognitive impairment:
a meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry. 2013; 21(11): 1086-1097.
6) Suzuki T, Shimada H, Makizako H, et al. A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment.
PLoS One. 2013; 8(4): e61483.

▪ Search formula
PubMed search: June 2, 2015 (Tuesday)#1 ((“Dementia/prevention and control” [Mesh] OR “Cognition Disorders/prevention and control” [Mesh] OR “Alzheimer Disease/therapy” [Majr]
OR “Mild Cognitive Impairment/therapy” [Majr]) AND (“Exercise” [Majr] OR “Exercise therapy” [Majr])) OR ((“Dementia/prevention andcontrol” [Majr] OR “Cognition Disorders/prevention and control” [Majr]) AND (“Exercise” [Mesh] OR “Exercise therapy” [Mesh]))Ichushi search: June 2, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI) AND (Preventive medicine/TH OR (SH = Prevention) OR Prevention/TI) AND (Physical exercise/TH OR
Sports/TH OR Exercise therapy/TH)

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CQ 4A-8

Are leisure activities, social participation, mental activities, cognitive training,
and artistic activities such as music effective in preventing dementia andcognitive decline in older people?
Recommendation
The effect of cognitive training is not consistent. While some reports show that cognitive training is effective inpreventing cognitive decline, other reports find no significant difference. Cognitive training and exercise reduce the riskof cognitive decline. For leisure activities, since the definitions are not clear, further analysis is needed in the future.

2C

Comments and evidence
Leisure activities include intellectual elements (such as games, chess, mahjong, and going to movies or theater), physicalelements (such as sports, walking, and aerobics, etc.), and social elements (such as meeting friends, volunteer activities, andtravelling). Many reports have shown that leisure activities are effective in preventing the onset of dementia and Alzheimer’s
disease dementia. Although observational studies 1, 2) report that leisure activities from middle age to old age reduce the risk ofdeveloping Alzheimer’s disease dementia, the definition of leisure activity is not clear 3). Therefore, further analysis is necessary.
While reports have indicated a possibility that cognitive training (see CQ3A-7-1) is effective in preventing functional
decline with respect to memory 4, 5), other report shows no significant difference 6). Some randomized controlled trials (RCT)
report that cognitive training and exercise reduce the risk of cognitive impairment 7-9).
There are 12 reports on meditation therapy, including 6 RCTs. The results suggest that mediation may prevent cognitive
decline 10).
The preventive effect of music therapy for cognitive decline is unknown, but a meta-analysis of RCTs in patients withdementia finds that rather than cognitive function, music therapy is effective in improving behavioral and psychologicalsymptoms of dementia (BPSD) as well as anxiety 11).
There are only case reports and reports of small-scale study on the effect of art therapy 12,13).

▪ References
1) Stern C, Munn Z. Cognitive leisure activities and their role in preventing dementia: a systematic review. Int J Evid Based Healthc. 2010; 8(1): 2-17.
2) Wang HX, Jin Y, Hendrie HC, et al. Late life leisure activities and risk of cognitive decline. J Gerontol A Biol Sci Med Sci. 2013; 68(2): 205-213.
3) Wang HX, Xu W, Pei JJ. Leisure activities, cognition and dementia. Biochim Biophys Acta. 2012; 1822(3): 482-491.
4) Gates NJ, Sachdev PS, Fiatarone Singh MA, et al. Cognitive and memory training in adults at risk of dementia: a systematic review. BMC Geriatr.
2011; 11: 55-69.
5) Smith GE, Housen P, Yaffe K, et al. A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory
with Plasticity-based Adaptive Cognitive Training (IMPACT)study. J Am Geriatr Soc. 2009; 57(4): 594-603.
6) Martin M, Clare L, Altgassen AM, et al. Cognition-based interventions for healthy older people and people with mild cognitive impairment.
Cochrane Database Syst Rev. 2011; (1): CD006220.
7) Bherer L. Cognitive plasticity in older adults: effects of cognitive training and physical exercise. Ann N Y Acad Sci. 2015; 1337: 1-6.
8) Middleton LE, Yaffe K. Promising strategies for the prevention of dementia. Arch Neurol. 2009; 66(10): 1210-1215.
9) Barnes DE, Santos-Modesitt W, Poelke G, et al. The Mental Activity and eXercise (MAX)trial: a randomized controlled trial to enhance cognitive
function in older adults. JAMA Intern Med. 2013; 173(9): 797-804.
10) Gard T, Holzel BK, Lazar SW. The potential effects of meditation on age-related cognitive decline: a systematic review. Ann N Y Acad Sci. 2014;
1307: 89-103.
11) Chang YS, Chu H, Yang CY, et al. The efficacy of music therapy for people with dementia: A meta-analysis of randomised controlled trials. J Clin
Nurs. 2015; 24(23-24): 3425-3440.
12) Chancellor B, Duncan A, Chatterjee A. Art therapy for Alzheimer’s disease and other dementias. J Alzheimers Dis. 2014; 39(1): 1-11.
13) Hattori H, Hattori C, Hokao C, et al. Controlled study on the cognitive and psychological effect of coloring and drawing in mild Alzheimer’s
disease patients. Geriatr Gerontol Int. 2011; 11(4): 431-437.

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Clinical Practice Guideline for Dementia 2017

▪ Search formula
PubMed search: June 15, 2015 (Monday)#1 (“Dementia/prevention and control” [Mesh] OR (dementia AND prevent*) OR “Cognition Disorders/prevention and control” [Mesh] OR(“cognition disorder*” AND prevent*)) AND (“Leisure Activities” [Mesh] OR leisure activity* OR “Learning” [Mesh] OR “memory training” OR
cognitive activity* OR “Neuronal Plasticity” [Mesh] OR “cognitive plasticity” OR (physical AND social component*) OR “Psychotherapy” [Mesh]
OR “music therapy” OR “art therapy”)
Ichushi search: June 15, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Leisure activities/TH OR Leisureactivities/TI OR Leisure/TI OR Social participation/TH OR Social participation/TI OR Social participation/TI OR mental activities/AL OR
Cognitive training/AL OR Perceptive art therapy/TH OR Art therapy/TI OR Music therapy/TI) AND (Prevention/TI OR Management/TI OR(SH = Prevention))

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89

CQ 4A-9

Are there dietary factors associated with dementia?
Recommendation
There are many reports on dementia, diet and nutrition. High-calorie diets composed mainly of carbohydrates, lowprotein diets and low-fat diets tend to increase the risk of mild cognitive impairment and dementia. No definitive results
are available for individual nutrients.
2C

Comments and evidence
Many studies on dementia and dietary factors have been reported, most of which are observational studies. While theseobservational studies have accumulated a vast amount of knowledge about the relationship between diet, nutrition andcognitive function, no definitive conclusions have been reached on the specific foods, nutrients, or dietary patterns that
increase the risk of developing dementia or prevent the development of dementia. Some randomized controlled trials (RCTs)
have been performed, but they have not yielded any definitive results so far.
High-calorie diets composed of mainly carbohydrates may increase the risk of mild cognitive impairment and dementia.
As a possible cause, diets with high blood glucose load may have adverse effects on glucose and insulin metabolism. On theother hand, low-protein diets and low-fat diets also tend to increase the risk of mild cognitive impairment and dementia 1).
According to reports of the Hisayama study on the relation between dietary patterns and risk of dementia, consumptionof soybeans, soybean products, vegetables, seaweed, milk and dairy products reduces the risk of dementia, while consuming
larger quantity of rice increases the risk of dementia 2, 3).
The Rotterdam study reports on the relation between antioxidants and dementia. Consumption of foods high in vitamin
E slightly reduces the risk of dementia over the long term. On the other hand, vitamin C, beta-carotene, and flavonoids are
not associated with the risk of dementia. Furthermore, consumption of fish and omega-3 fatty acid is also not related to therisk of dementia 4, 5).
Opinions are divided on caffeine, coffee, and tea. In general, the degree of cognitive decline tends to be lower in consumersof the above products. However, the level of consumption related to this effect remains unclear 6).

▪ References
1) Roberts RO, Roberts LA, Geda YE, et al. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. J Alzheimers
Dis. 2012; 32(2): 329-339.
2) Ozawa M, Ohara T, Ninomiya T, et al. Milk and dairy consumption and risk of dementia in an elderly Japanese population: the Hisayama Study.
J Am Geriatr Soc. 2014; 62(7): 1224-1230.
3) Ozawa M, Ninomiya T, Ohara T, et al. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin
Nutr. 2013; 97(5): 1076-1082.
4) Devore EE, Grodstein F, van Rooij FJ, et al. Dietary intake of fish and omega-3 fatty acids in relation to long-term dementia risk. Am J Clin Nutr.
2009; 90(1): 170-176.
5) Devore EE, Grodstein F, van Rooij FJ, et al. Dietary antioxidants and long-term risk of dementia. Arch Neurol. 2010; 67(7): 819-825.
6) Arab L, Khan F, Lam H. Epidemiologic evidence of a relationship between tea, coffee, or caffeine consumption and cognitive decline. Adv Nutr.
2013; 4(1): 115-122.

▪ Search formula
PubMed search: June 15, 2015 (Monday)#1 (“Dementia/etiology”[Mesh] OR “Dementia/epidemiology”[Mesh] OR (dementia AND (etiology* OR epidemiology*)) OR “Cognition
Disorders/etiology” [Mesh] OR “Cognition Disorders/epidemiology” [Mesh] OR (“cognition disorder*” AND (etiology* OR epidemiology*)))AND (“Food and Beverages” [Mesh] OR food OR beverage*) AND (“Risk” [Mesh] OR risk)
Ichushi search: June 15, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Foods and drinks/TH OR Foods/TI
OR Drinks/TI OR Diet/TH OR Diet/TI) AND (Risk/TH OR Risk/TI OR Risk/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 4A-10

Is moderate drinking effective in preventing cognitive decline and dementia?
Recommendation
A report has shown that moderate drinking of alcoholic drinks has preventive effect on dementia. Caution should be
exercised in interpreting this finding, because the definition of “moderate drinking” differs depending on race and on
individuals. This should not be recommended to persons who cannot drink.
2C

Comments and evidence
Alcohol is inherently neurotoxic, and heavy drinking causes atrophy of the brain. On the other hand, moderate drinking
has been reported to prevent dementia. In particular, appropriate consumption of red wine has been reported to prevent
cognitive decline.
According to observational studies in persons with a healthy lifestyle, low to moderate alcohol consumption reduces theodds ratio of cognitive decline or dementia 1), but heavy alcohol consumption increases the risk of conversion from mild
cognitive impairment to dementia 2). While red wine has a preventive effect against cognitive decline, other alcoholic
beverages such as beer, white wine, fortified wine (wine with high alcohol content), spirits (such as gin and vodka) have nosuch effect, suggesting that ingredients other than alcohol in red wine may have a preventive effect 3). In addition, a casecontrol study has found that habitual drinking in older people protects against the development of vascular dementia (oddsratio 0.48) 4).
Note that the relationship between drinking and cognitive function has not been proven by randomized controlled trial(RCT) due to ethical restrictions.

▪ References
1) Elwood P, Galante J, Pickering J, et al. Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort
study. PLoS One. 2013; 8(12): e81877.
2) Xu G, Liu X, Yin Q, et al. Alcohol consumption and transition of mild cognitive impairment to dementia. Psychiatry Clin Neurosci. 2009; 63(1):43-49.
3) Nooyens AC, Bueno-de-Mesquita HB, van Gelder BM, et al. Consumption of alcoholic beverages and cognitive decline at middle age: theDoetinchem Cohort Study. Br J Nutr. 2014; 111(4): 715-723.
4) Takahashi PY, Caldwell CR, Targonski PV. Effect of alcohol and tobacco use on vascular dementia: a matched case control study. Vasc Health Risk
Manag. 2011; 7: 685-691.

▪ Search formula
PubMed search: June 15, 2015 (Monday)#1 (“Dementia/prevention and control” [Mesh] OR (dementia AND prevent*) OR “Cognition Disorders/prevention and control” [Mesh] OR(“cognition disorder*” AND prevent*)) AND (“Alcohol Drinking” [Mesh] OR alcohol drinking* OR “Alcoholic Beverages” [Mesh] OR alcoholic
beverage*)
Ichushi search: June 15, 2015 (Monday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Alcoholic beverage/TH OR Alcohol/
TI OR Drinking/TH OR Drinking/TI)

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CQ 4A-11

Does sleep apnea syndrome worsen cognitive function?
Recommendation
Sleep apnea syndrome, while being a vascular risk factor, is also associated with cognitive impairment. Continuous
positive airway pressure therapy improves cognitive impairment.
2C

Comments and evidence
Many observational studies have shown that sleep apnea syndrome and sleep-disordered breathing are vascular risk factors,
and at the same time are associated with cognitive decline. In addition, although continuous positive airway pressure therapy,
which is used as a treatment for sleep apnea syndrome, is expected to contribute to the improvement of cognitive function,
there remain many unclear aspects about the relationship between severity and therapeutic effect.
A report from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study has shown that the presence of sleep apnea
syndrome accelerates the development of mild cognitive impairment and Alzheimer’s disease dementia, and that treatment
with continuous positive airway pressure delays the progression of dementia 1).
A meta-review of reports suggesting that sleep apnea syndrome affects cognitive function indicates that sleep apnea isrelated to deficits in attention, long-term visual and verbal memory, visuospatial cognitive function, and executive function,
but does not affect language ability and psychomotor function 2, 3). In older women, reports have shown that shortened sleep
time, hypoxia during sleep, and sleep apnea increase the risk of cognitive decline 4, 5).
Several observational studies 1, 2) and randomized controlled trials (RCT) 6, 7) have reported that continuous positive airway
pressure therapy improves the decline of cognitive functions associated with sleep apnea.

▪ References
1) Osorio RS, Gumb T, Pirraglia E, et al. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology. 2015; 84(19): 1964-1971.
2) Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology. 2013; 18(1): 61-70.
3) Yaffe K, Falvey CM, Hoang T. Connections between sleep and cognition in older adults. Lancet Neurol. 2014; 13(10): 1017-1028.
4) Chang WP, Liu ME, Chang WC, et al. Sleep apnea and the risk of dementia: a population-based 5-year follow-up study in Taiwan. PLoS One. 2013;8(10): e78655.CQ 4A.11 141
5) Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women.
JAMA. 2011; 306(6): 613-619.
6) Sanchez AI, Martinez P, Miro E, et al. CPAP and behavioral therapies in patients with obstructive sleep apnea: effects on daytime sleepiness, mood,and cognitive function. Sleep Med Rev. 2009; 13(3): 223-233.
7) Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea
patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2012; 35(12): 1593-1602.

▪ Search formula
PubMed search: June 17, 2015 (Wednesday)#1 (“Dementia” [Mesh] OR dementia OR “Cognition Disorders” [Mesh] OR cognition disorder*) AND (“Sleep Apnea Syndromes” [Mesh] OR“sleep apnea syndrome”)
Ichushi search: June 17, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (sleep apnea syndrome/TH OR sleep
apnea syndrome/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 4A-12

Are depression and bipolar disorder risk factors for dementia?
Recommendation
Multiple observational studies have reported that a history of depression
associated with increased risk of developing dementia.

1B

or bipolar disorder2C

isComments and evidence
Many studies have reported that a history of depression is associated with increased risk of developing dementia in older
age 1, 2). Although the possibility that depression symptoms per se may be the initial symptoms of dementia has been noted,
the relationship between early-onset depression and development of dementia in old age, as well as the relationship between
the number of episodes of depressive symptoms and the risk of dementia have been reported 3), supporting the notion that
depressive symptoms are a risk factor for dementia.
While many studies focus on Alzheimer’s disease dementia, there are reports indicating that a history of depression is also
a risk factor for vascular dementia (VaD).
A few reports have shown that a history of bipolar disorder increases the development of dementia, but there is opinion
that a bias may be present since patients with bipolar disorder are in an environment that facilitates a diagnosis of dementia
compared to control patients 1). Although observational studies have reported that the rate of developing dementia decreases
with continuous treatment with antidepressants for depression and lithium for bipolar disorder 4, 5), there is no clear evidence
from interventional study that these treatments reduce the development of dementia.

▪ References
1) da Silva J, Goncalves-Pereira M, Xavier M, et al. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry. 2013;
202(3): 177-186.
2) Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011; 10(9): 819-828.
3) Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment.
Neurology. 2010; 75(1): 27-34.
4) Kessing LV, Forman JL, Andersen PK. Do continued antidepressants protect against dementia in patients with severe depressive disorder? Int Clin
Psychopharmacol. 2011; 26(6): 316-322.
5) Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar Disord. 2010; 12(1): 87-94.

▪ Search formula
PubMed search: June 3, 2015 (Wednesday)#1 (“Dementia/etiology” [Mesh] AND (“Mood Disorders/complications” [Mesh] OR “Depression/complications” [Mesh]) AND “Risk Factors”[Mesh]) OR (“Dementia/epidemiology” [Majr] AND (“Mental Disorders/epidemiology” [Majr] OR “Mood Disorders/epidemiology” [Majr]) AND“Age Factors” [Mesh] AND “Epidemiologic Methods” [Mesh] AND risk [TI]) OR (risk [TI] AND dementia [TI] AND (depression OR “bipolar
disorder”))
Ichushi search: June 3, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI) AND (Depression OR Depression OR bipolar disorder) AND (Risk factor OR Risk)

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B | Mild Cognitive Impairment
CQ 4B-1

What are the prevalence and incidence of mild cognitive impairment (MCI)?
AnswerAlthough the data vary from study to study, the prevalence of MCI is estimated to be 15-25% in older people aged 65
years and above, and the incidence is estimated to be 20-50 per 1,000 people per year.

Comments and evidence
1. Prevalence 1-4)

The original diagnostic criteria for MCI was published by Petersen et al.1). Since then, various criteria for diagnosis of mild
cognitive impairment have been used in epidemiological studies, which greatly affect the prevalence and incidence obtained
from these studies. Since a large amount of epidemiological data focuses on amnestic mild cognitive impairment, which is asubtype of mild cognitive impairment restricted to memory impairment, this situation also causes some confusion. Moreover,the prevalence would differ depending on whether subject recruitment of an epidemiological study is community-based or
population-based. The range of the results obtained also differs depending on the magnitude (how high or how low) and therange of the subjects’ ages.
If one only views the data without considering the above factors, the statistics would yield a prevalence of approximately
15-25% in most studies. When limited to amnestic mild cognitive impairment, prevalence with a range from 2.4% to 28.3%
in those aged 65 and above has been reported.

2. Incidence 4, 5)
Since the age of the cohort participating in survey varies from study to study, the incidence ranges from 20 to 50 per 1,000
person per year. When limited to amnestic mild cognitive impairment, the incidence has been reported to be 9.9-40.6 per
1,000 persons per year.
The prevalence is higher in recent reports.

▪ References
1) Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999; 56(3): 303-308.
2) Petersen RC. Early diagnosis of Alzheimer’s disease: is MCI too late? Curr Alzheimer Res. 2009; 6(4): 324-330.
3) Luck T, Luppa M, Briel S, et al. Incidence of mild cognitive impairment: a systematic review. Dement Geriatr Cogn Disord. 2010; 29(2): 164-175.
4) Ward A, Arrighi HM, Michels S, et al. Mild cognitive impairment: disparity of incidence and prevalence estimates. Alzheimers Dement. 2012; 8(1):14-21.
5) Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med. 2013; 29(4): 753-772.

▪ Search formula
PubMed search: June 5, 2015 (Friday)#1 (“Mild Cognitive Impairment/epidemiology” [Mesh] OR “Mild Cognitive Impairment” AND “Cognition Disorders/epidemiology” [Mesh])
AND “Morbidity” [Mesh]
Ichushi search: June 5, 2015 (Friday)#1 (mild cognitive impairment/TH OR mild cognitive impairment/TI) AND (prevalence OR incidence OR incidence)

94

Clinical Practice Guideline for Dementia 2017

CQ 4B-2

What is the conversion rate from mild cognitive impairment (MCI)
to dementia, and the reversion rate from MCI to cognitive normal?
AnswerThe conversion rate from mild cognitive impairment to dementia is estimated to be approximately 5-15% per year. The
reversion rate is estimated to be approximately 16-41% per year.

Comments and evidence
The data for conversion from mild cognitive impairment to dementia varies from study to study. In addition, it should be
noted that the results differ depending on whether the study involves follow-up by medical specialists or is communitybased. Naturally, the conversion rate would be high if follow-up is done by specialists. Conversion occurs at a rate of
approximately 5-15% per year. By type of dementia, the rate of conversion diagnosed by specialists is 8.1% for Alzheimer’s
disease dementia and 1.9% for vascular dementia. In community-based studies, the conversion rates for the two types are
6.8% and 1.6%, respectively, with higher rate for Alzheimer’s disease dementia.
On the other hand, the reversion rates from mild cognitive impairment to a cognitive normal state range widely from 16
to 41% per year.

▪ Further reading
1) Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia--meta-analysis of 41 robust inception cohort studies.
Acta Psychiatr Scand. 2009; 119(4): 252-265.
2) Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med. 2013; 29(4): 753-772.

▪ Search formula
PubMed search: June 5, 2015 (Friday), August 14, 2015 (Friday)#1 ((“Mild Cognitive Impairment” [Mesh] OR (“Mild Cognitive Impairment” AND “Cognition Disorders” [Mesh])) AND “Dementia” [Mesh]
AND(“conversion rate” OR “conversion rates” OR “reversion rate” OR “reversion rates” OR ((convert [TI] OR conversion [TI] OR reversion [TI]
OR revert [TI]) AND (rate [TI] OR rates [TI])))) OR ((“Mild Cognitive Impairment/epidemiology” [Majr] OR (“Mild Cognitive Impairment” [TI]
AND “Cognition Disorders/epidemiology” [Majr])) AND “Dementia/epidemiology” [Mesh] AND (“Incidence” [Mesh] OR “Prevalence” [Mesh]))Ichushi search: June 5, 2015 (Friday)#1 (mild cognitive impairment/TH OR mild cognitive impairment/TI) AND (Dementia/TH OR Dementia/TI) AND (Convert OR Conversion
OR Revert OR Reversion)

Chapter 4

95

CQ 4B-3

What are the useful biomarkers for predicting conversion of mild cognitive
impairment (MCI) to dementia?
AnswerAbnormal cerebrospinal fluid levels of Aβ42, phosphorylated tau, and total tau; presence of APOE gene ε4 polymorphism;
and abnormal findings on amyloid PET and 18FDG-PET have been considered to be useful biomarkers for predicting
conversion from mild cognitive impairment (MCI) to dementia. BComments and evidence
Most studies on risk factors for conversion of mild cognitive impairment to dementia focus on Alzheimer’s disease. The
clinical state of MCI due to Alzheimer’s disease coincides with the pathological stage of completion of Aβ and phosphorylated
tau accumulation in the brain. Persons showing an Alzheimer’s disease pattern in biomarker study tend to convert todementia.

1. Humoral markers
a. Cerebrospinal fluid 1)
In a meta-analysis that analyzed 10 studies, cerebrospinal fluid biomarkers predicted conversion from MCI to dementia
with the following performance: abnormal Aβ42 level with 79% sensitivity and 72% specificity, abnormal total tau levelwith 72% sensitivity and 70% specificity, abnormal phosphorylated tau with 84% sensitivity and 93% specificity, andabnormal ratio of Aβ42/phosphorylated tau with 85% sensitivity and 79% specificity.
b. Genes 2)
A meta-analysis of 8 studies found that carriers of APOE ε4 polymorphism tended to convert from MCI to dementia, witha relative risk of 2.09.
c. Blood
Reports of research on various blood biomarkers including proteins and microRNA have been published, but none of thebiomarkers showed consistent performance that is reproducible in multiple studies.

2. Imaging biomarkers
a. MRI
Cohort studies have reported that the volumes of hippocampus, amygdala, and entorhinal cortex at the start of study werereduced in the group showing conversion compared to the group that did not convert. Moreover, higher atrophy rates ofhippocampus, entorhinal cortex, and temporal cortex depicted on serial images taken over time were associated with higher
rate of conversion. However, no conclusion has been reached as to the site and size of atrophy, and the rate of atrophy thatbest predicts conversion 3-7).
b. FDG-PET 8)
In a meta-analysis analyzing 14 studies, 18FDG-PET predicted conversion with 76% sensitivity and 82% specificity.
c. Amyloid PET 9)
In a meta-analysis that analyzed 11 studies using 11C-labelled Pittsburgh Compound-B (11C-PIB)-PET, this method
predicted conversion of MCI to dementia with 96% sensitivity and 58% specificity. There is no meta-analysis of studies using
18
F ligand preparations.
d. SPECT 10)
Although SPECT is a frequently used examination in Japan, this method is not widely used globally. In a meta-analysisof 8 studies, this test predicts conversion with 83.8% sensitivity and 70.4% specificity.

96

Clinical Practice Guideline for Dementia 2017▪ References
1) Ferreira D, Rivero-Santana A, Perestelo-Perez L, et al. Improving CSF biomarkers’ performance for predicting progression from mild cognitive
impairment to Alzheimer’s disease by considering different confounding factors: a meta-analysis. Front Aging Neurosci. 2014; 6: 287.
2) Fei M, Jianhua W. Apolipoprotein ε4-allele as a significant risk factor for conversion from mild cognitive impairment to Alzheimer’s disease: a metaanalysis of prospective studies. J Mol Neurosci. 2013: 50(2): 257-263.
3) Davatzikos C, Bhatt P, Shaw LM. et al. Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification. Neurobiol
Aging. 2011; 32(12): 2322. e19-e27.
4) Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology.
2009; 73(4): 294-301.
5) Gomar JJ, Conejero-Goldberg C, Davies P, et al. Extension and refinement of the predictive value of different classes of markers in ADNI: Four-year
follow-up data. Alzheimer’s & Dementia. 2014; 10(6): 704-712.
6) Risacher SL. Shen L, West JD, et al. Longitudinal MRI atrophy biomarkers: Relationship to conversion in the ADNI cohort. Neurobiology ofAging. 2010; 31(8): 1401-1418.
7) Risacher SL. Saykin AJ. West JD. et al. Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Current Alzheimer
Research. 2009; 6(4): 347-361.
8) Smailagic N, Vacante M, Hyde C, et al. 18F-FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people withmild cognitive impairment (MCI). Cochrane Database Syst Rev. 2015; 1: CD010632.
9) Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, Feng J. 11C-PIB-PET for the early diagnosis of Alzheimer’s disease
dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2014; 7: CD010386.
10) Yuan Y. Gu ZX. Wei WS. Fluorodeoxyglucose-positron-emission tomography, single-photon emission tomography, and structural MR imaging forprediction of rapid conversion to Alzheimer disease in patients with mild cognitive impairment: a meta-analysis. AJNR Am J Neuroradiol. 2009;30(2): 404-410.

▪ Search formula
PubMed search: June 27, 2016 (Monday)#1 (“Mild Cognitive Impairment” [Mesh] OR Mild Cognitive Impairment* [TIAB]) AND (convert [TIAB] OR conversion [TIAB] OR reversion[TIAB] OR revert [TIAB]) AND (“Biomarkers” [Mesh] OR biomarker* [TIAB] OR marker* [TIAB] OR predict* [TIAB] OR marked* [TIAB])
Ichushi search: June 27, 2016 (Monday)#1 (mild cognitive impairment/TH OR mild cognitive impairment/TI) AND (Convert OR Conversion OR Revert OR Reversion) AND(Biomarker/TH OR Marker)

Chapter 4

97

CQ 4B-4

What rating scales are recommended when mild cognitive impairment (MCI)
is suspected?
Answer
The Mini Mental State Examination (MMSE) is not adequate to detect mild cognitive impairment (MCI). Therefore,
the Montreal Cognitive Assessment-Japanese version (MoCA-J) is recommended. Instead of MMSE alone, adding slightly
complex memory tasks such as sentence memorization facilitates the diagnosis of amnestic mild cognitive impairment.
C

Comments and evidence
The MoCA-J is more challenging than MMSE because the memory task requires recall of five words and the scale also
includes tests of frontal lobe function., and is therefore suitable for the diagnosis of MCI. When the cutoff score for MoCA
was set at 25/26 out of 30, MCI is diagnosed with 95% sensitivity and 50% specificity for the English version, and 93%
sensitivity and 87% specificity for the Japanese version 1, 2)
Addenbrooke’s Cognitive Examination-Revised (ACE-R) is an MMSE test with the addition of other elements including
anterograde/retrograde memory, naming words, and visuospatial cognitive function. When the cut-off score is 88/100,
ACE-R differentiates MC1 with better sensitivity and specificity than MMSE 3).
Amnestic MC1 can be detected more easily by adding detailed memory tests such as Wechsler Memory Scale-Revised(WMS-R) and Rey Auditory Verbal Learning Test (RAVLT). Although the clock drawing test is widely used, this test has
been reported to be unsuitable for the discrimination of MCI because of low sensitivity (58.2%) and specificity (57.3%) 4).
Regarding evaluation based on questionnaires and interviews with caregivers, reports have indicated the effectiveness ofquestionnaires on instrumental activities of daily living and total score of Clinical Dementia Rating (CDR) for diagnosing
MCI 5, 6). Some studies use CDR 0.5 as a test for MCI, for convenience. Cognitive Function Instrument (CFI), which asks
the patient and the family about changes in cognitive activities compared to one year ago, has been reported to be useful forthe evaluation of functional abilities before onset of Alzheimer’s disease dementia 7).

▪ References
1) Smith T, Gildeh N, Holmes C. e Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry 2007; 52(5):329-332.
2) Fujiwara Y, Suzuki H, Yasunaga M, et al. Brief screening tool for mild cognitive impairment in older Japanese: validation of the Japanese version of
the Montreal Cognitive Assessment. Geriatr Gerontol Int. 2010; 10(3): 225-232.
3) Crawford S, Whitnall L, Robertson J, et al. A systematic review of the accuracy and clinical utility of the Addenbrooke’s Cognitive Examinationand the Addenbrooke’s Cognitive Examination-Revised in the diagnosis of dementia. Int J Geriatr Psychiatry 2012; 27(7): 659-669.
4) Ehreke L, Luppa M, Luck T, et al. Is the clock drawing test appropriate for screening for mild cognitive impairment?― Results of the German study
on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Dement Geriatr Cogn Disord. 2009; 28(4): 365-372.
5) Zoller AS, Gaal IM, Royer CA, et al. SIST-M-IR activities of daily living items that best discriminate clinically normal elderly from those with mild
cognitive impairment. Curr Alzheimer Res. 2014; 11(8): 785-791.
6) Duara R, Loewenstein DA, Greig-Custo MT, et al. Diagnosis and staging of mild cognitive impairment, using a modification of the clinicaldementia rating scale: the mCDR. Int J Geriatr Psychiatry. 2010; 25(3): 282-289.
7) Amariglio RE, Donohue MC, Marshall GA, et al. Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease
dementia: the Alzheimer’s Disease Cooperative Study Cognitive Function Instrument. JAMA Neurol. 2015; 72(4): 446-454.

98

Clinical Practice Guideline for Dementia 2017

CQ 4B-5

How is mild cognitive impairment (MCI) diagnosed?
AnswerMild cognitive impairment (MCI) is originally a concept centered on memory impairment. MCI is classified into
amnestic MCI and non-amnestic MCI by the presence or absence of memory impairment. Furthermore, it is divided into
single-domain or multiple-domain depending on whether the impairment involves a single cognitive function domain or
multiple domains. Similar concept is also found in Clinical Dementia Rating (CDR) 0.5; mild neurocognitive disorder in
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5); and mild cognitive disorder (MCD) in
International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10).

Comments and evidencePetersen established the concept that the state of mild cognitive impairment may represent the prodrome stage of dementia 1).
The diagnostic criteria for MCI were defined in 1995 2). Since then, some additions and corrections have been made based on
research and books, but the fundamental concept remains unchanged. As subtypes of mild cognitive impairment, amnestic
mild cognitive impairment is defined as predominantly memory impairment, and non-amnestic mild cognitive impairment
is defined as impairment of other functions including execution, attention, language, and visuospatial cognition 3). It should
be noted that MCI is a diagnosis based on symptoms, and the pathological background is diverse.

1. Criteria of Petersen 2, 4, 5)
Mild cognitive impairment is a concept centered on memory impairment, and refers to a state (not dementia) in a person
who complains of memory loss and who has low scores in memory tests adjusted for age and years of education. The detailed
criteria are as follows.
• Cognitive function has declined compared to before, which is reported by the patient and corroborated by informant
and experienced clinical doctor.
• Has impairment in at least one of the following cognitive function domains: memory, execution, attention, language,
and visuospatial cognition.
• Is independent in activities of daily living. May require more time than before, or become inefficient, or make mistakes.
• Not dementia.

2. Diagnostic criteria of DSM-5 6)
In DSM-5, dementia is renamed major neurocognitive disorder, and mild cognitive impairment is termed mild
neurocognitive disorder. The diagnostic criteria for mild neurocognitive disorder in DSM-5 include mild decline in one ormore cognitive domains that can be confirmed from cognitive function tests and a reliable informant, but the impairment
does not interfere with daily life. These criteria are not much different from other diagnostic criteria. On the other hand,regarding the results of neuropsychological test battery, the decline in cognitive function is described as -1 to -2SD. This
range differs slightly from the NIA-AA criteria, which will be described later.

3. Diagnostic criteria of ICD-10 7)
In ICD-10, mild cognitive disorder (MCD) is adopted as a concept equivalent to mild cognitive impairment.

4. Clinical Dementia Rating (CDR) 0.5 8)
The CDR evaluates memory, orientation, judgment and problem-solving, community affairs, home and hobbies, andpersonal care; each scored on a 5-grade scale of 0, 0.5, 1, 2, and 3. The overall score is determined after weighting. An overall
score of 0.5 corresponds to mild cognitive impairment.

5. Diagnostic criteria of National Institute on Aging–Alzheimer’s Association workgroup (NIA-AA) 9, 10)
In addition to clinical diagnostic criteria, biomarker criteria are provided in the NIA-AA criteria. The degree of cognitive
decline based on the neuropsychological test battery is described as -1 to -1.5 SD compared with age- and education-matchedpeers, which is slightly different from that described in DSM-5.

Chapter 499

6. Criteria of International Working Group-2 11)
In the diagnostic criteria for Alzheimer’s disease published in 2014, an attempt was made to change the conventional
division of “preclinical Alzheimer’s disease”, “prodromal Alzheimer’s disease”, and “Alzheimer’s disease dementia” into twogroups: “preclinical Alzheimer’s disease” and “Alzheimer’s disease”. In other words, the concept is not to distinguish between
mild cognitive impairment and dementia based on the pathological background of Alzheimer’s disease, but to diagnosis
Alzheimer’s disease when clinical symptoms are present, including amnesia alone.

▪ References
1) Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment clinical characterization and outcome. Arch Neurol. 1999; 56(3): 303-308.
2) Petersen RC, et al., Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA. 1995;
273(16): 1274-1278.
3) Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004; 256(3): 183-194.
4) Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001; 58(12): 1985-1992.
5) Petersen RC. Clinical practice. Mild cognitive impairment. New Engl J Med. 2011; 364(23): 2227-2234.
6) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington VA: American
Psychiatric Association; 2013.
7) World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th Revision. Geneva: World HealthOrganization; 1993.
8) Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993; 43(11): 24122414.
9) Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the
National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3):270-279.
10) Arai H. Diagnosis of mild cognitive impairment with Alzheimer’s disease in the background: proposal from the National Institute on Aging–
Alzheimer’s Association workgroups. Cognition Dementia 2012; 11(3): 19-27. (In Japanese)
11) Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;
13: 614-629.

▪ Search formula
PubMed search: June 5, 2015 (Friday), August 26, 2015 (Wednesday)#1 “Mild Cognitive Impairment/diagnosis” [Majr] OR (“Mild Cognitive Impairment” AND “Cognition Disorders/diagnosis”[Majr]) OR ((“Mild
Cognitive Impairment” [TI] AND “Cognition Disorders/diagnosis”[Mesh] AND criteria [TIAB]) AND (“Diagnosis, Differential” [Mesh] OR(“diagnostic criteria”)) OR (“Alzheimer Disease/diagnosis” [Majr] AND “diagnostic criteria” [TI]) OR (“clinical dementia rating” AND “Dementia/psychology” [Majr] AND “Psychiatric Status
Rating Scales” [Majr]))
Ichushi search: June 5, 2015 (Friday)#1 (mild cognitive impairment/MTH OR mild cognitive impairment/TI) AND (SH = Diagnostic use, diagnosis, diagnostic imaging, X ray
diagnosis, radionuclide diagnosis, ultrasound diagnosis)

100

Clinical Practice Guideline for Dementia 2017

CQ 4B-6

Are there methods to prevent progression from mild cognitive impairment(MCI) to dementia?
Recommendation
Control of hypertension, diabetes, dyslipidemia and other risk factors, as well as continued practice of moderate exercise
are recommended. There is no sufficient evidence that anti-dementia drugs should be used for the purpose of preventing
progression to dementia in persons with mild cognitive impairment.
2C

Comments and evidence
Methods for preventing progression from mild cognitive impairment to dementia include pharmacotherapy, nonpharmacological therapies, and interventions for risk factors.
For pharmacotherapy, the effect of cholinesterase inhibitors in improving cognitive function has been confirmed inpatients with mild cognitive impairment, but the effect of preventing progression from mild cognitive impairment todementia remains unclear 1-3). Estrogen therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), extract from leaves ofginkgo tree (Ginkgo biloba), and vitamin E have been studied, but the effect of preventing progression from mild cognitive
impairment to dementia has not been confirmed for any of these treatments.
Non-pharmacological therapies including moderate physical activity, aerobic exercise, Mediterranean diet, cocoa, andsmoking cessation have been suggested to be effective, but most studies were conducted in a small number of subjects andhence do not provide sufficient evidence 4-6). Several studies suggest that cognitive rehabilitation or cognitive training iseffective in maintaining and improving cognitive function, but further intervention studies are needed to standardize
intervention and assessment methods 7-10) (see CQ4A).
Studies have clarified that a history of hypertension, diabetes, dyslipidemia (hypercholesterolemia) or cerebrovasculardisorders is a risk factor that promotes progression from mild cognitive impairment to dementia, not only for vasculardementia but also for Alzheimer’s disease dementia 11). Although there is still insufficient evidence that controlling these risk
factors can prevent progression to dementia, appropriate control is recommended for patients with these risk factors (seeCQ4A).

▪ References
1) Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology.
2009; 72(18): 1555-1561.
2) Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment: Cochrane Database Syst Rev. 2012; (9): CD009132.
3) Tricco AC, et al. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis.
CMAJ. 2013; 185: 1393-1401.
4) Baker LD, Frank LL, Foster-Schubert K, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010; 67(1):71-79.
5) Etgen T, Sander D, Bickel H, et al. Mild cognitive impairment and dementia: the importance of modifiable risk factors. Dtsch Arztebl Int. 2011;
108(44): 743-750.
6) Scarmeas N, stern Y, Mayeux R, et al. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009; 66(2): 216-225.
7) Teixeira CVL, Gobbi LT, Corazza DI, et al. Non-pharmacological interventions on cognitive functions in older people with mild cognitive
impairment (MCI). Arch Gerontol Geriatr. 2012; 54(1): 175-180.
8) Simon SS, Yokomizo JE, Bottino CM, et al. Cognitive intervention in amnestic Mild Cognitive Impairment: a systematic review. Neurosci Biobehav
Rev. 2012; 36(4): 1163-1178.
9) Gates NJ, Sachdev PS, Fiatarone Singh MA, et al. Cognitive and memory training in adults at risk of dementia: a systematic review. BMC Geriatr.
2011; 11: 55. doi: 10.1186/1471-2318-11-55.
10) Law LL, Barnett F, Yau MK, et al. Effects of functional tasks exercise on older adults with cognitive impairment at risk of Alzheimer’s disease: arandomised controlled trial. Age Ageing. 2014; 43(6): 813-820.
11) Li J, Wang YJ, Zhang M, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology. 2011;76(17): 1485-1491.

Chapter 4101▪ Search formula
PubMed search: July 17, 2015 (Friday), August 26, 2015 (Wednesday)#1 (“Mild Cognitive Impairment” [Majr] OR ((“mild cognitive impairment” [TI] OR MCI [TI]) AND (prevent* OR improvement OR therapy OR
therapeutic OR treatment OR training OR rehabilitation OR intervention OR program OR prophylaxis*)) OR ((“mild cognitive impairment” [TI]
OR MCI [TI]) AND “Cognition Disorders/therapy” [Mesh])) AND (“Dementia/prevention and control” [Mesh] OR (dementia AND (prevent*OR prophylaxis*)) OR “Cognition Disorders/prevention and control” [Mesh] OR ((cognition disorder* OR cognitive disorder*) AND (prevent* OR
prophylaxis*))) OR ((“mild cognitive impairment” [TI] OR MCI [TI]) AND “Cognition Disorders” [Majr] AND “Dementia/epidemiology” [Majr]
AND prevent*)
Ichushi search: July 17, 2015 (Friday)#1 (Mild cognitive impairment/TH OR Mild cognitive impairment/TI OR MCI/TI) AND ((SH = Therapeutic use, Treatment, Drug treatment,
Surgical treatment, Transplantation, Dietary treatment, Psychiatric treatment, Radiologic treatment, Rehabilitation, Prevention) OR Treatment/
TH OR Treatment/TI OR Therapy/TI OR Rehabilitation/TI OR Training/TI OR Training/TI OR Program/TI) AND (Dementia/TH OR
Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI ) AND ((SH = Prevention) OR
Prevention/TH OR Prevention/TI)

102

Clinical Practice Guideline for Dementia 2017

CQ 4B-7

What kinds of guidance and support are available for people with mild
cognitive impairment (MCI)?
Answer
It is necessary to provide proper information about mild cognitive impairment to the patients as well as caregivers inorder to promote correct understanding of the disease.
Provide support to enable the patients to continue living independently for as long as possible by introducing assistive
devices utilizing information technology (IT), practicing the use of calendars and notebooks, and modifying the living
environment.
C

Comments and evidence
Unlike those with dementia, persons at the stage of mild cognitive impairment (MCI) are independent in basic activities
of daily living (ADL). Therefore, daily care and support for these persons are not necessary. However, in situations such asheart failure where self-care is required, MCI may worsen the prognosis.
The memory support system (MSS) that trains patients to enter schedules and events in calendars and notebooks can be
expected to improve ADL and self-efficacy of patients with MCI and reduce the burden on caregivers 1). Acquiring a habit ofusing calendars and notebooks would also be helpful in the future when mild cognitive impairment has progressed todementia.
Risk factors for lifestyle-related diseases such as hypertension, diabetes, and dyslipidemia can become risk factors that
promote progression from mild cognitive impairment to dementia. Therefore, it is necessary to provide guidance on lifestylemodification and medication management.
It is necessary to first of all help the patient and family understand correctly that mild cognitive impairment is an unstablecondition that may progress to dementia or may return to normal cognition, and then provide guidance to prepare forprogression to dementia in the future.
See also CQ3A-1.

▪ References
1) Greenaway MC, Duncan NL, Smith GE. e memory support system for mild cognitive impairment: randomized trial of a cognitive rehabilitationintervention. Int J Geriatr Psychiatry. 2013; 28(4): 402-409.

▪ Search formula
PubMed search: July 18, 2015 (Saturday), July 23, 2015 (Thursday)#1 ((“Mild Cognitive Impairment” [Mesh] OR “mild cognitive impairment” [TI] OR MCI [TI]) AND ((“Patient Care” [Mesh] AND management*)
OR “Health Education” [Mesh] OR education [TI] OR support* [TI] OR guidance[TI] OR instruction [TI] OR service* [TI])) OR ((“Mild
Cognitive Impairment” [Mesh] OR “mild cognitive impairment” [TI] OR MCI [TI]) AND (“Health Education” [Mesh] OR education [TI] OR
support* [TI] OR guidance [TI] OR instruction [TI] OR service* [TI]) AND (“Patient Care” [Mesh] OR “Patient Care Management” [Mesh] ORpatient* [TI] OR management* [TI] OR care [TI]))
Ichushi search: July 17, 2015 (Friday)#1 (Mild cognitive impairment/TH OR <Mild cognitive impairment/TI OR MCI/TI) AND (Patient care management/TH OR Health education/
TH OR Home care support service/TH OR Social support/TH OR Mental support/TH) AND (Support/TI OR Guidance/TI OR Education/TI
OR Support/TI OR Support/TI OR Guidance/TI OR Instruction/TI OR Service/TI)

Chapter 4103

C | Disease Severity and Interventions According to Severity
CQ 4C-1

What kind of guidance and support can be given to persons with mild
to moderate dementia?
AnswerCase management (care management) has been reported to be effective in reducing admission to care facilities and costsof care in the short term. Education on dementia and peer support are effective in improving the patients’ depressive stateand quality of life (QOL).
C

Comments and evidence
Case management is carried out by professionals such as nurses and social workers, and involves a variety of activities
including coordination of care and formulation of a care plan according to the needs of the persons with dementia living in
the community. According to a review of 13 randomized controlled trials (RCTs), case management is effective in reducing
admission to care facilities and long-term care costs in the short term, but the long-term effect is uncertain 1).
Social support groups for people with dementia provide a venue for education related to dementia, mutual assistance, peer
support, and information exchange. They are effective in improving the patients’ depression state, QOL, and self-esteem 2).
A multi-disciplinary educational program for persons with early-stage dementia and their families should contain a corecomponent of medical knowledge about the symptoms and progression of dementia 3).
Many cognitive training or cognitive rehabilitation programs are conducted for the purpose of improving cognitive
function centered on memory. Cognitive rehabilitation has been suggested to improve ADL in patients with mild Alzheimer’s
disease dementia 4). Cognitive training provides training of specific tasks targeting cognitive functions, while cognitive
rehabilitation introduces compensatory approaches to meet patients’ needs.
Many research articles have suggested the effectiveness of non-pharmacological therapies such as reminiscence therapy,
validation therapy, music therapy, exercise, aromatherapy 5), and light therapy 6). However, there are issues in these reports
concerning the quality of evidence. Therefore these therapies cannot be actively recommended.
Assistive devices using computer and robotic assistance for ADL and entertainment activities are being evaluated inclinical trials, and future development can be expected. A system that prompts bathing and other activities at specific timeis effective for persons with mild dementia 7). In a study of persons with moderate Alzheimer’s disease dementia, presenting
pictorial step-by-step instructions of work procedures on a computer allowed the patients to make coffee and snacks bythemselves 8). In addition, the patients were able to enjoy music by choosing from music options by themselves 8).

▪ References
1) Reilly S, Miranda-Castillo C, Malouf R, et al. Case management approaches to home support for people with dementia. Cochrane Database Syst
Rev. 2015; 1: CD008345.
2) Leung P, Orrell M, Orgeta V. Social support group interventions in people with dementia and mild cognitive impairment: a systematic review of theliterature. Int J Geriatr Psychiatry. 2015; 30(1): 1-9.
3) Seike A, Sumigaki C, Takeda A, et al. Developing an interdisciplinary program of educational support for early-stage dementia patients and theirfamily members: an investigation based on learning needs and attitude changes. Geriatr Gerontol Int. 2014; 14 Suppl 2: 28-34.
4) Bahar-Fuchs A, Clare L, Woods B. Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer’s disease and vascular dementia.
Cochrane Database Syst Rev. 2013; (6): CD003260.
5) Forrester LT, Maayan N, Orrell M, et al. Aromatherapy for dementia. Cochrane Database Syst Rev. 2014; (2): CD003150.
6) Forbes D, Blake CM, Thiessen EJ, et al. Light therapy for improving cognition, activities of daily living, sleep, challenging behaviour, and psychiatricdisturbances in dementia. Cochrane Database Syst Rev. 2014; (2): CD003946.
7) Mokhtari M, Aloulou H, Tiberghien T, et al. New trends to support independence in persons with mild dementia: a mini-review. Gerontology.
2012; 58(6): 554-563.
8) Lancioni GE, Singh NN, O’Reilly MF, et al. Persons with moderate Alzheimer’s disease use simple technology aids to manage daily activities andleisure occupation. Res Dev Disabil. 2014; 35(9): 2117-2128.

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▪ Search formula
PubMed search: July 17, 2015 (Friday), August 26, 2015 (Wednesday)#1 ((“Dementia” [Majr] OR dementia [TI] OR alzheimer* [TI]) AND (“early stage” [TI] OR mild [TI] OR moderate [TI] OR “Patient Acuity”[Mesh])) OR ((dementia OR alzheimer*) AND (“early stage” OR mild OR moderate)) AND (“Patient Care” [Mesh] OR “Health Education”[Mesh]) AND (education [TI] OR support* [TI] OR guidance [TI] OR instruction [TI] OR service* [TI] OR management [TI])
Ichushi search: July 17, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND (Mild/TI OR Moderate/TI OR severity/TH) AND (Patient care management/TH OR Healtheducation/TH OR Home care support service/TH OR Social support/TH OR Mental support/TH) AND (Support/TI OR Guidance/TI OR
Education/TI OR Support/TI OR Support/TI OR Guidance/TI OR Instruction/TI OR Service/TI)

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105

CQ 4C-2

What kind of guidance and support can be given to caregivers of persons
with mild to moderate dementia?
Answer
Educational support for caregivers of persons with dementia is effective in lessening their care burden and depressive
state. Telephone counseling and Internet educational programs are also effective.
C

Comments and evidence
Caregivers of persons with dementia often report feeling the care burden and depressive symptoms. According to a metaanalysis of studies that provide educational interventions for caregivers of persons with dementia, a moderate beneficial effecton care burden and a small beneficial effect on the depressive state were observed, but the effects of improving quality of life
(QOL) and reducing admission to care facilities were not clear 1).
A meta-analysis on counseling using telephone found a significant effect in improving the caregivers’ depressive state 2).
There is also a study suggesting the effectiveness of caregiver education via the Internet 3), and this method may be further
developed by the widespread use of the Internet.
An Italian study was conducted using reduction of caregiver burden and avoidance of admission of persons with dementia
to care facilities as markers of effectiveness of an intervention program for caregivers. In this study, case management, visits
by nurses, and introduction of technological devices were effective in reducing care burden and avoiding admission to carefacilities 4).
A meta-analysis of 78 studies on caregiver interventions showed significant improvements in caregivers’ feeling of careburden, depression, subjective well-being, satisfaction, and ability/knowledge, as well as care receivers’ symptoms. Theintervention effect for caregivers of persons with dementia was less than that for other groups of caregivers. Psychoeducationalor psychotherapeutic interventions showed the most consistent short-term effects 5).
See also CQ3A-1.

▪ References
1) Jensen M, Agbata IN, Canavan M, et al. Effectiveness of educational interventions for informal caregivers of individuals with dementia residing in
the community: systematic review and meta-analysis of randomised controlled trials. Int J Geriatr Psychiatry. 2015; 30(2): 130-143.
2) Lins S, Hayder-Beichel D, Rucker G, et al. Efficacy and experiences of telephone counselling for informal carers of people with dementia. Cochrane
Database Syst Rev. 2014; (9): CD009126.
3) Blom MM, Zarit SH, Groot Zwaaftink RB, et al. Effectiveness of an Internet intervention for family caregivers of people with dementia: results ofa randomized controlled trial. PLoS One. 2015; 10(2): e0116622.
4) Chiatti C, Rimland JM, Bonfranceschi F, et al. The UP-TECH project, an intervention to support caregivers of Alzheimer’s disease patients in Italy:
preliminary findings on recruitment and caregiving burden in the baseline population. Aging Ment Health. 2015; 19(6): 517-525.
5) Sorensen S, Pinquart M, Duberstein P. How effective are interventions with caregivers? An updated meta-analysis. Gerontologist. 2002; 42(3): 356372.

▪ Search formula
PubMed search: July 17, 2015 (Friday)#1 (((“Dementia” [Majr] OR dementia [TI] OR alzheimer* [TI]) AND (“early stage” [TI] OR mild [TI] OR moderate [TI])) AND (“Caregivers”[Mesh] OR “Family” [Mesh] OR caregiver* [TI] OR family* [TI]) AND (“Patient Care” [Mesh] OR “Health Education” [Mesh] OR education[TI] OR support* [TI] OR guidance [TI] OR instruction [TI] OR service* [TI])) OR ((dementia OR alzheimer*) AND (“early stage” OR mild OR
moderate) AND (caregiver* OR family) AND (education OR support* OR guidance OR instruction OR service*))
Ichushi search: July 17, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND (Mild/TI OR Moderate/TI OR severity/TH) AND (Caregiver/TH OR Caregiver/TI OR Carepersonnel/TI OR Family/TH OR Family/TI) AND (Patient care management/TH OR Health education/TH OR Home care support service/TH
OR Social support/TH OR Mental support/TH OR Support/TI OR Guidance/TI OR Education/TI OR Support/TI OR Support/TI OR
Guidance/TI OR Instruction/TI OR Service/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 4C-3

What kind of guidance and support can be given to persons with severe dementia?
Answer
For persons with severe dementia, it is desirable to help them receive medical and long-term care continuously withoutchanging their living environment or lifestyle as far as possible.
C

Comments and evidence
Persons with severe dementia have increased frequencies of physical symptoms including loss of appetite, sleep disturbance,
urinary disorders such as incontinence, defecation disorders such as constipation, and gait disturbance. There are also more
emergency admissions for infections, cerebrovascular disorders, and undernutrition. A study has found when these patientsrequire emergency admission, admission to a special ward cared by a team comprising doctor, nurse, physiotherapist, social
worker, and counselor, and then having the same team in charge of home care after discharge resulted in significantly lessbehavioral disturbance, use of fewer antipsychotic drugs, and less caregiver stress compared to admission to a general ward 1). It
is desirable to coordinate the system to enable patients to receive continuous medical and long-term care, so that they can receive
medical care in a familiar environment without changing their lifestyle.
For persons with severe dementia, admission to care facilities is an important consideration. A report has shown that while
appropriate home care management can delay admission to care facilities, it is ultimately impossible to avoid facility admission
for persons with severe dementia 2). In addition, it is also known that the cost of nursing care increases as the severity ofdementia increases 3). Compared to mild and moderate cases, the difference between the costs of institutional care and thecosts of home care is small.
There is no research with high-level evidence on the treatment of pneumonia and nutritional disorders in persons withsevere dementia. For management of dysphagia, hand feeding of small portions by a caregiver (comfort feeding by hand)with mouth care is preferable to tube feeding 4).
In a survey of a nursing home in the United States, patients with severe dementia were given quinolone and cephalosporin
antibiotics without adequate evidence, resulting in extensive colonization of multidrug-resistant bacteria. Comfort is thegoal of care for many patients with advanced dementia, and more sensible use of antibacterial drugs is desirable 5, 6).

▪ References
1) Tibaldi V, Aimonino N, Ponzetto M, et al. A randomized controlled trial of a home hospital intervention for frailty elderly demented patients:
behavioral disturbances and caregiver’s stress. Arch Gerontol Geriatr Suppl. 2004; (9): 431-436.
2) Eloniemi-Sulkava U, Notkola IL, Hentinen M, et al. Effects of supporting community-living demented patients and their caregivers: a randomized
trial. J Am Geriatr Soc. 2001; 49(10): 1282-1287.
3) Lopez-Bastida J, Serrano-Aguilar P, Perestelo-Perez L, et al. Social-economic costs and quality of life of Alzheimer disease in the Canary Islands,
Spain. Neurology. 2006; 67(12): 2186-2191.
4) Arcand M. End-of-life issues in advanced dementia: Part 2: management of poor nutritional intake, dehydration, and pneumonia. Can Fam
Physician. 2015; 61(4): 337-341.
5) Mitchell SL, Shaffer ML, Loeb MB, et al. Infection management and multidrug-resistant organisms in nursing home residents with advanced
dementia. JAMA Intern Med. 2014; 174(10): 1660-1667.
6) Yates E, Mitchell SL, Habtemariam D, et al. Interventions associated with the management of suspected infections in advanced dementia. J Pain
Symptom Manage 2015; 50(6): 806-813.

▪ Search formula
PubMed search: July 17, 2015 (Friday)#1 (((“Dementia” [Majr] OR dementia [TI] OR alzheimer* [TI]) AND (advanced [TI] OR severe [TI])) OR ((dementia OR alzheimer*) AND(advanced OR severe))) AND ((“Patient Care” [Mesh] OR “Health Education” [Mesh]) AND (education [TI] OR support* [TI] OR guidance [TI]
OR instruction [TI] OR service* [TI] OR management [TI]))
Ichushi search: July 17, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND Advanced/TI AND (Patient care management/TH OR Health education/TH OR Home care support
service/TH OR Social support/TH OR Mental support/TH) AND (Support/TI OR Guidance/TI OR Education/TI OR Supprt/TI OR Support/
TI OR Guidance/TI OR Instruction/TI OR Service/TI)

Chapter 4

107

CQ 4C-4

What kind of guidance and support can be given to caregivers of persons
with severe dementia?
Answer
Providing support to caregivers can help maintain the quality of life (QOL) of the caregivers and reduce their
psychological burden. Support given by a multidisciplinary team is recommended to enable patients with dementia toreceive continuous medical and long-term care.
C

Comments and evidence
A family booklet about comfort care for persons with severe dementia may be useful 1). The contents of the booklet consistof symptoms, decision-making, and treatments accompanying progression of Alzheimer’s disease dementia, and the booklet
is perceived as acceptable and useful by bereaved families of persons with dementia in Canada, Holland and Italy.
Support through telephone is also effective. Sixteen telephone conversations in six months from therapists who provided
educational instructions to caregivers systematically improved caregivers’ depressive symptoms and reactions to carerecipients’ behaviors 2).
Since caring for persons with severe dementia imposes heavy burden on caregivers 24 hours a day, 365 days a year, the useof respite care is recommended. However, there are few high-quality studies on respite care, and the benefits and adverse
effects have not been clarified so far 3).

▪ References
1) van der Steen JT, Arcand M, Toscani F, et al. A family booklet about comfort care in advanced dementia: three-country evaluation. J Am Med Dir
Assoc. 2012;13(4): 368-375.
2) Tremont G, Davis JD, Papandonatos GD, et al. Psychosocial telephone intervention for dementia caregivers: A randomized, controlled trial.
Alzheimers Dement. 2015;11(5): 541-548.
3) Maayan N, Soares-Weiser K, Lee H. Respite care for people with dementia and their carers. Cochrane Database Syst Rev. 2014;(1): CD004396.

▪ Search formula
PubMed search: July 17, 2015 (Friday)#1 ((“Dementia” [Majr] OR dementia [TI] OR alzheimer* [TI]) AND (advanced [TI] OR severe [TI])) AND (“Caregivers” [Mesh] OR “Family”[Mesh] OR caregiver* [TI] OR family* [TI]) AND (“Patient Care” [Mesh] OR “Health Education” [Mesh] OR education [TI] OR support* [TI]
OR guidance [TI] OR instruction [TI] OR service* [TI] OR management* [TI]) OR ((dementia OR alzheimer*) AND (advanced OR severe) AND(caregiver* OR family) AND (education OR support* OR guidance OR instruction OR service* OR management*))
Ichushi search: July 17, 2015 (Friday)#1 (Dementia/TH OR Dementia/TI) AND Severity/TI AND (Caregiver/TH OR Caregiver/TI OR Care personnel/TI OR Family/TH OR
Family/TI) AND (Patient care management/TH OR Health education/TH OR Home care support service/TH OR Social support/TH OR Mental
support/TH OR Support/TI OR Guidance/TI OR Education/TI OR Support/TI OR Support/TI OR Guidance/TI OR Instruction/TI OR
Service/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 4C-5

How should end-of-life care be given to persons with dementia?
AnswerIn the terminal stage of persons with advanced dementia, providing medical care and general care with an emphasis on
alleviating the person’s pain is desirable.
C

Comments and evidence
The survival prognosis for persons with advanced dementia is extremely poor. A survey conducted at nursing homes in the
United States on 323 persons (median age 86.0 years) with Global Deterioration Scale (GDS) stage 7 dementia found a
24.7% probability of death within 6 months and a median survival duration of 478 days, which was equivalent to the life
expectancy of metastatic breast cancer and stage IV congestive heart failure 1).
No method has been established to predict the survival prognosis of persons with dementia 2). Medicare in the UnitedStates requires Functional Assessment Staging (FAST) stage 7c as a requirement for initiation of palliative care, but this is
not a reliable predictor of death after 6 months 2).
Persons with advanced dementia may experience pain, breathing difficulty, and anorexia, as in patients with terminal
stage cancer, but control of these conditions is extremely inadequate in persons with dementia 3). In the terminal stage of
persons with advanced dementia, care based on advance care planning (ACP) 4) aiming at comfort of the person rather thanprolonging life is desirable, but the introduction of ACP is not easy in clinical practice 5). According to observational studies,tube feeding is not recommended because the benefits are unclear. Report suggests the effectiveness of palliative care or
hospice care 4). Appropriate assessment and management of pain as well as effective management of behavioral problems canimprove the quality of life (QOL) of persons with severe dementia 6).
Persons with advanced dementia often have difficulties with self-determination and confirmation of intent. As an alternative,
decision has to be based on presumed intent, proxy intent, or prior intent. Based on the opinions of the family, speculate thepatient’s intent as far as possible and respect it. As a tool that supports the decision-making process through discussions between
the parties concerned, the Japan Geriatrics Society has published the “Guidelines for the decision-making process in medical
and long-term care for the elderly: focusing on the initiation of artificial hydration and nutrition” 7).
The family plays an important role in end-of-life care. At the same time, since the family is under great mental and physical stress,
support for the family is important. In addition, after the person with dementia has died, grief care for the family is necessary.

▪ References
1) Mitchell SL, Teno JM, Kiely DK, et al. The clinical course of advanced dementia. N Engl J Med. 2009;361(16): 15291538.
2) Brown MA, Sampson EL, Jones L, et al. Prognostic indicators of 6-month mortality in elderly people with advanced dementia: a systematic review.
Palliat Med. 2013;27(5): 389-400.
3) Sampson EL. Palliative care for people with dementia. Br Med Bull. 2010;96: 159-174.
4) Mitchell SL. Clinical Practice. Advanced dementia. N Engl J Med. 2015;372(26): 2533-2540.
5) Sampson EL, Jones L, Thune-Boyle IC, et al. Palliative assessment and advance care planning in severe dementia: an exploratory randomized
controlled trial of a complex intervention. Palliat Med. 2011;25(3): 197-209.
6) Cordner Z, Blass DM, Rabins PV, et al. Quality of life in nursing home residents with advanced dementia. J Am Geriatr Soc. 2010;58(12): 2394-2400.
7) Japan Geriatrics Society. Guidelines for the decision-making processes in medical and long-term care for the elderly: focusing on the initiation of
artificial hydration and nutrition. Japanese Journal of Geriatrics. (Nihon Ronen Igakkai Zasshi) 2012; 49(5): 632– 645 (In Japanese)▪ Search formula
PubMed search: July 17, 2015 (Friday)#1 ((“Dementia” [Mesh] OR dementia [TI] OR alzheimer* [TI]) AND (advanced [TI] OR severe [TI]) AND (“Terminal Care” [Mesh] OR“Advance Care Planning” [Mesh] OR “Palliative Care” [Mesh] OR “terminal care” [TI] OR hospice [TI] OR “palliative care” [TI] OR “end of life”[TI] OR bereavement* [TI])) OR ((dementia OR alzheimer*) AND (advanced OR severe) AND (“terminal care” OR hospice OR “palliative care”
OR “end of life” OR bereavement*))
Ichushi search: July 18, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI) AND (Severe/TI OR Advanced dementia/AL OR End-stage dementia/AL) AND (Terminal care/TH OR
Terminal care/TI OR Advance care plan/TH OR Advance care plan/TI OR Palliative care/TH OR Palliative care/TI OR Hospice/TH OR
Hospice/TI OR Bereavement/TH OR Bereavement/TI)

Chapter 4109

Chapter 5
Various Systems and Social Resources
for Supporting Persons with Dementia
and Their Families

A | Various Systems and Social Resources for Supporting
Medical and Long-term Care for Persons with Dementia
CQ 5A-1

What are the functions and roles of the medical center for dementia?
Answer
The Medical Center for Dementia is required to provide two key functions: specialized medical functions (specialized
medical consultation, differential diagnosis of dementia and initial response, and emergent responses for behavioral/
psychological symptoms of dementia and physical comorbidities) and community liaison hub functions (establishment
and operation of the Local Liaison Council for Dementia Care, and organizing workshops). In each prefecture, theMedical Center for Dementia is expected to design the hub function, deployment, and method of liaison, which matchthe characteristics of local communities, and to manage the quality of the activities.

Comments and evidence
The objective of the Medical Center for Dementia is “to build a functional system for people with dementia, which canprovide comprehensive health care services in the community ranging from prevention of disease progression to support forcommunity living. Specifically, the Medical Center for Dementia supports differential diagnosis for dementia-related diseases
and initial response; emergent responses for acute treatments of behavioral/psychological symptoms, and physicalcomorbidities; and specialized medical consultations, while also conducts training for community health and nursing carepersonnel”. Currently, there are three types of Medical Center for Dementia: “core type”, “regional type”, and “liaison type”.
The functions required of the Medical Center for Dementia include (1) specialized medical services (1. differential
diagnosis of dementia and initial response, 2. emergent response for behavioral/psychological symptoms and physicalcomorbidities, 3. specialized medical consultations) and (2) community liaison hub functions (1. establishment and operationof Local Liaison Council for Dementia Care, 2. organizing workshops).
Specialized medical consultations take place in a medical consultation room staffed with psychiatric social worker, publichealth nurse, and other personnel. In response to telephone or face-to-face consultations from persons with dementia, theirfamilies or related organizations, the staff of the medical consultation room makes medical appointments or arranges forreferral to medical institutions 1). Following the diagnosis, staff of the medical consultation room provides information to thepersons with dementia and their families, liaises and coordinates with relevant organizations, and supports them in using theservices they need 1). The medical consultation room plays an important role in improving the functions of the Medical
Center for Dementia 2). To support differential diagnosis and initial response, the medical consultation room is staffed withspecialized doctors and equipped with testing facilities. The staff also provides information to persons with dementia andtheir families after the diagnosis, and liaises with primary care physicians to secure continuous medical care. To support
emergent response for behavioral/psychological symptoms and physical comorbidities, the medical consultation room
responds to emergent cases by coordinating with hospitals with general or psychiatric beds, as well as with psychiatric andgeneral emergency systems.
The Local Liaison Council for Dementia Care is a council formed and operated by local health and medical professionals,
the Community General Support Center, long-term care insurance personnel, and experts related to dementia medical care.
The aim is to promote the establishment of a community-based dementia support system. Workshops are organized fortraining local professionals as well as families and community residents. Training of medical specialists and specialized staff
knowledgeable in a wide range of activities stipulated by the Medical Center for Dementia is an important responsibility of
the core-type Medical Center for Dementia 3). In addition, organization of regular training programs including case studies
with active participation by primary care physicians and certified dementia support doctors will contribute to maintain ahigh level of dementia medical care in the region 4).

112

Clinical Practice Guideline for Dementia 2017▪ References
1) Awata S. Roles of Medical Center for Dementia in the community. Japanese Journal of Geriatrics. (Nihon Ronen Igakkai Zasshi) 2009; 46(3): 203206. (In Japanese)
2) Awata S. New national health program against dementia in Japan: the medical center for dementia. Psychogeriatrics, 2010; 10(2): 102-106.
3) Ikeda M, Kojima S, Tomioka O. Roles of Medical Center for Dementia and future direction: Focusing on Kumamoto model. Japanese Journal of
Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2010; 21(11): 1189-1192. (In Japanese)4) Kojima S, Ikeda M. Roles of Core Medical Center for Dementia in dementia medical care and issues. Japanese Journal of Geriatric Psychiatry(Ronen Seishin Igaku Zasshi) 2014; 25(7): 738-743. (In Japanese)▪ Search formula
PubMed search: July 14, 2015 (Tuesday)#1 (“Dementia/therapy” [Majr] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition Disorders/therapy” [Majr] OR (cognition disorder* [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) AND (“Health Services for the Aged”[Mesh] OR “Community Health Services” [Mesh] OR “Community Health Centers” [Mesh])
Ichushi search: July 14, 2015 (Tuesday)#1 Medical Center for Dementia/TH OR Medical Center for Dementia/TI

Chapter 5

113

CQ 5A-2

What are the roles of certified dementia support doctors?
Answer
The roles of certified dementia support doctors (dementia support doctor hereinafter) are: (1) to support primary caredoctors and care professionals involved in medical and long-term care for people with dementia; (2) to facilitate
multidisciplinary liaison mainly at the Community General Support Center; and (3) to train primary care doctors aiming
to improve dementia managing skills and to educate residents of the community. Dementia support doctors are expected
to promote collaboration between different medical disciplines and between medical care and long-term care in thecommunity.
C

Comments and evidence
Accompanying aging of the population, the number of people with dementia has increased rapidly, and dementia is now
considered a common disease. Under such circumstances, there is an urgent need to establish a support system for older
people from the early stage of dementia with the participation of primary care doctors, and to educate doctors and care staff.
By the end of 2015, a total of 5,085 dementia support doctors were certified. The roles of dementia support doctors are as
follows: (1) to support primary care doctors and care professionals involved in medical and long-term care for persons withdementia; (2) to facilitate multidisciplinary liaison mainly at the Community General Support Center; and (3) to serve aslecturers in training of primary care doctors aiming to improve dementia managing skills and to educate residents of thecommunity 1). Compared with general primary care doctors, dementia support doctors possess superior capabilities indifferential diagnosis of dementia, management of behavioral and psychological symptoms of dementia (BPSD) in outpatientsetting, and community liaison and long-term care 2). In a survey of dementia support doctors, 84% are engaged in liaisonand 64% in training and educational activities 3).

▪ References
1) Washimi Y, Horibe K, Takeda A, et al. Educational program in Japan for Dementia Support Doctors who support medical and care systems as
liaisons for demented older adults in the community. Geriatr Gerontol Int. 2014; 14(Suppl 2): 11-16.
2) Awata S. Consideration of National Policies to Support the Development of Medical Services for Dementia. Psychiatria et Neurologia Japonica(Seishin Shinkeigaku Zasshi) 2014; 116(5): 378-387. (In Japanese)
3) NLI Research Institute. FY 2012 Ministry of Health, Welfare and Labour Health Project Promotion Grant: Report of study on the functions ofdementia support doctor and training system and teaching materials. Tokyo: NLI Research Institute; 2013.

▪ Search formula
PubMed search: June 17, 2015 (Wednesday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR “cognition disorder*” [TI]) AND “Japan” [Mesh] AND (doctor
OR doctors)
Ichushi search: June 17, 2015 (Wednesday)#1 Dementia support doctor/AL

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Clinical Practice Guideline for Dementia 2017

CQ 5A-3

What are the roles of long-term care insurance system for persons
with dementia and their caregivers?
Answer
The long-term care insurance is the foundation that supports the living of people with dementia and their families. The
long-term care insurance provides diverse services including consultation support services mainly at the Community
General Support Center; home-visit services such as home help service, home-visit bathing, and home-visit nursing; andfacility services such as day care and day rehabilitation service; as well as community-based services such as group homefor older people with dementia and small-scale multifunctional in-home care.
A

Comments and evidence

1. Outline of long-term care insurance system
a. Basic design of the system
Based on the Long-term Care Insurance Act enacted in 1997, the long-term care insurance system was started in 2000 as
the fifth social insurance system. The insured persons are those aged 40 years and above (65 years and above: primary insured
persons, 40-64 years: secondary insured persons), and the insurer is a municipality. The insured persons can receive insurance
benefits (use of services) if they are judged as requiring long-term care or requiring support, after going through a screening/
evaluation process of “whether or not they are in a state of needing long-term care”. The screening/evaluation process is called“certification of long-term care need”. The process consists of (1) application submitted by the insured person to the insurer;(2) investigation of physical condition (primary screening by computer); (3) report written by the family doctor from the
medical viewpoint [secondary screening, considering also (2)]. There are seven levels of certification, ranging from mild tosevere: “support needed” levels 1-2 to “care needed” levels 1-5. Those certified as “support needed” can use the preventive
care services, and those certified as “care needed” can utilize the care services.
b. Long-term care insurance services
Over 20 services are provided by the long-term care insurance, and they are broadly classified as follows: (1) home services,(2) facility services, and (3) community-based services that utilize multiple home services in a package 1). (1) Home services
and (3) community-based services, with some exceptions, are provided based on a monthly service utilization plan (careplan). The care plan is basically prepared by a care support specialist (care manager). In principle, the plan is prepared by
combining services within the monthly payment limit (use limit) which is determined depending on the level of care needed.
Although the usefulness of all these services has not been verified, disappearance or reduction of behavioral and psychologicalsymptoms was observed by using day care for dementia, which is a facility service for dementia 2).

2. System reform in 2015 and fee revision 3)
The long-term care insurance system is operated based on a project plan developed by the insurer every three years, andinsurance premiums and care fees (unit price for service) are revised every three years. In addition, if necessary, the system
will be reformed accompanying revision of the Act. In fiscal year 2015, the system was reformed in response to the Act for
Securing Comprehensive Medical and Long-term Care (Tax and Social Security Integrated Reform), and the fees were also
revised following the usual 3-year schedule.

▪ References
1) Awata S. Therapeutic approach for dementia in long-term care insurance. Japanese Journal of Psychiatric Treatment (Seishinka Chiryogaku) 2014;29(8): 1051-1057. (In Japanese)
2) Social Welfare Corporation Yokufukai Dementia Care Research & Training Tokyo Center. A study on the approach of day services for persons withdementia. Surveys related to verification of the effects of long-term care fees and research in FY 2013 (FY 2013 survey), 2014. (In Japanese)3) Ministry of Health, Labour and Welfare. Outline of the long-term care insurance system reform: revision of the Long-term Care Insurance Act andrevision of long-term care fees. 2006 . http:www.mhlw.go.jp/topics/kaigo/topics/0603/dl/data.pdf (In Japanese)

Chapter 5115▪ Search formula
PubMed search: June 17, 2015 (Wednesday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR cognition disorder* [TI]) AND (“Insurance, Long-Term Care”[Mesh] OR “long-term care insurance” [TI])
Ichushi search: June 17, 2015 (Wednesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Long-term care insurance/TH OR
Long-term care insurance/TI)

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CQ 5A-4

What are the functions and roles of Community General Support Center?
Answer
The Community General Support Center was established in 2006. The contents of operation for dementia are notnecessarily clearly defined so far, but the Center has played an important role as the core facility to provide support for
persons with dementia in the following work areas: (1) general consultation/support, (2) protection of patients’ rights, (3)comprehensive and continuous case management support, and (4) preventive benefits and preventive care management.
In the future, its importance will increase as a core organization for the community-based comprehensive care system.
A

Comments and evidenceWith the revision of the Long-term Care Insurance Act in 2006, Community General Support Center was established ineach municipality as a base for promoting comprehensive community care. The center is mandated as a facility that “aims tocomprehensively support the improvement of health care and promotion of welfare by providing assistance necessary for
maintaining physical and mental health and stabilizing lives of residents living in the community”. Specifically, a teamconsisting of three professionals: social worker, chief care manager, and public health nurse or nurse with experience incommunity care, is responsible for the following work areas: (1) general consultation/support, (2) protection of patients’rights, (3) comprehensive and continuous case management support, and (4) preventive benefits and preventive caremanagement. However, some problems have been identified 1), which include 1) issue of support for households withoutfamily care capability, 2) issue related to daily life support with the rapid increase in households of single persons without
relatives, 3) issue related to certification of long-term care need for dementia, and 4) issue of medical collaboration incommunity care for dementia 2-5). As indicated in another section, the installation of an initial-phase intensive support teamfor dementia in the Community General Support Center is expected to be one solution to these issues.

▪ References
1) Yamamoto S. The future of community general support center: focusing on various issues in community care for dementia. Japanese Journal of
Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2012; 23(Suppl. 1): 126-131. (In Japanese)
2) Awata S, Sano Y, Fukumoto M. Status of works related to dementia in community general support center of suburban city, especially from theperspectives of medical resources and collaboration. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2010; 21(3): 356-363.
(In Japanese)3) Konagaya Y. Status and issues of consultations related to dementia in community general support center. Japan Medical Journal (Nihon Iji Shinpo)
2012; (4610): 84-88. (In Japanese)
4) Kikuchi K, Sato S, Yamaguchi K, et al. Functions of community general support center: present status and issues. Japanese Journal of Geriatric
Psychiatry (Ronen Seishin Igaku Zasshi) 2012; 23(3): 299-304. (In Japanese)5) Takeda A. Evaluation of the usefulness of building community support system. Proceedings of the 54th Annual Meeting of Japan Geriatric Society.
Japanese Journal of Geriatrics. (Nihon Ronen Igakkai Zasshi) 2013; 50(2): 197-199. (In Japanese)▪ Search formula
PubMed search: June 17, 2015 (Wednesday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR cognition disorder* [TI]) AND (“Comprehensive Health Care”[Mesh] OR “integrated care”) AND (“Community Health Centers” [Mesh] OR “community based”)
Ichushi search: June 17, 2015 (Wednesday), July 7, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Community general care center/AL OR
Community General Support Center/TH OR Community General Support Center/TI OR Community general center/AL OR (Community/TI
AND Comprehensive/TI AND Center/TI))

Chapter 5

117

CQ 5A-5

What are the functions and roles of the initial-phase intensive support teamfor dementia?
AnswerMedical and general care for dementia in the future is expected to base on early and proactive response aiming toprevent crisis, and to be equipped with functions for early support and support to avoid crisis. The initial-phase intensive
support team for dementia is a promising mechanism to fulfill these functions. An expert team visits persons withdementia and provides comprehensive support at an early stage to enable them to continue living in the community. The
model project started in 2012, and activities in all municipalities were scheduled to begin by the end of 2017.
C

Comments and evidence

The mission of the initial-phase intensive support team for dementia is to visit persons with dementia and provide
comprehensive support at the earliest possible stage to enable them to continue living in the community. “Initial” in this casedoes not necessarily denote the initial stage of the disease, but means “first touch”. Furthermore, “intensive” refers to visiting
the persons with dementia and their families, providing assessment and family support comprehensively and intensively (forapproximately 6 months), and after providing support for independent living, referring them back to their usual medical andgeneral care team. Persons who should be targeted are those who have not received medical services or long-term careservices, or who have stopped receiving these services. Some examples of such cases are those (1) who have not received aclinical diagnosis of dementia-related disease; (2) who are not receiving continuous medical services; (3) who are notconnected to long-term care insurance services, (4) who were diagnosed with dementia but have stopped receiving long-termcare services, or those who despite receiving medical and long-term care services are struggling to cope with behavior andpsychological symptoms of dementia (BPSD).
Model projects were conducted at 14 locations nationwide in 2013 1), and at 41 locations nationwide in 2014 2). The results
showed that persons targeted for visit and support were identified centrally through the Community General Support Centers,
but details of the route of identification showed that consultations from the families and the patients accounted for 50%,
indicating that the persons concerned requested consultation. In addition, 85-90% of the patients continued to live at home
after receiving intervention from the team, showing that the team did not respond to difficult cases simply by hospitalization
and admission to care facilities. Furthermore, improvement in the care burden scale has been reported 2, 3). From 2015, theinitial-phase intensive support team was scheduled to start operation in all the municipalities in which this initiative was feasible
as a community support project. By the end of 2017, the team was scheduled to start in all municipalities nationwide. Resultsof a study show that the initial-phase intensive support team for dementia is useful in enabling persons with dementia to
continue living at home, and can be expected to be an attempt that improves the overall community care 4). However, since thisproject has just been started, further verification is needed in the future.

▪ References

1) National Center for Geriatrics and Gerontology. Grant-in-aid for the promotion of health services for the elderly 2013. Research project on thedevelopment of an initial-phase intensive support service model to achieve early diagnosis and early intervention for dementia: project report. 2014.
(In Japanese)2) National Center for Geriatrics and Gerontology. Grant-in-aid for the promotion of health services for the elderly 2014. Research project on the
installation and operation of an initial-phase intensive support service model to achieve early diagnosis and early intervention for dementia: project
report. 2015(2): 138-146. (In Japanese)
3) Washimi Y. Dementia and community collaboration: on the initial-phase intensive support team. Japanese Journal of Geriatrics. (Nihon Ronen
Igakkai Zasshi) 2015; 52(2): 138-146. (In Japanese)
4) Awata S. Orange Plan and challenge from the community: initial-phase support for dementia: especially the outreach issues (home-visit care).
Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2013; 24(9): 883-889. (In Japanese)▪ Search formula

PubMed search: June 17, 2015 (Wednesday)#1 (“Dementia” [Majr] OR dementia [TI] OR “Cognition Disorders” [Majr] OR cognition disorder* [TI]) AND “Patient Care Team” [Mesh] AND“Intensive Care” [Mesh]
Ichushi search: June 17, 2015 (Wednesday)#1 Dementia initial-phase intensive support team/AL OR ((Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive
impairment/TI) AND Initial-phase intensive/AL AND (Support team/TI OR Team care/TH OR Team care/TI))

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B | Advocacy for People with Dementia
CQ 5B-1

Is it possible to evaluate the abilities of judgment and decision-making
in persons with dementia?
AnswerWhen obtaining consent for performing a medical action or considering the use of the adult guardianship system,
doctors need to determine the mental capacity (abilities of judgement and decision-making) of a person with dementia.
The mental capacity has a three-layer structure: (1) functional ability, (2) capacity, and (3) competence. Doctors are able
to determine the mental capacity of an individual with dementia by assessing the cognitive function (functional ability)
associated with a specified legal action and assessing the underlying clinical state (capacity).

Comments and evidence
Mental capacity is the ability to effectively express an intention and understand the result of one’s actions (abilities of
judgment and decision-making). Capacity to act refers to a legal status or legal qualification that a person can execute aneffective legal act alone. In routine medical care for persons with dementia, it is necessary to evaluate the mental capacity ofthese individuals when obtaining consent for a medical action or when considering the use of the adult guardianship system.

1. Structure of assessment of mental capacity
The structure of assessing mental capacity has three levels: (1) functional ability, (2) capacity, and (3) competence.
Functional ability is the mental function required at each stage of the psychological process leading to decision-making, andis a phenomenon that can be measured as a continuous variable, as for cognitive function. Capacity is the clinical state judged
by a doctor, and is a categorical phenomenon related to whether a person can make meaningful decision under the circumstancesin which the person is placed. For example, a medical diagnosis of severe dementia state belongs to this category. Competence
is a legal status which is judged by a legal personnel, especially a judge, and is a categorical phenomenon judged by thedichotomy of “yes” or “no” regarding whether a person possesses the ability required to execute a legal act alone.

2. Practical judgment of mental capacity
The conventional judgment of mental capacity used for determining capacity for criminal responsibility consists of thefollowing procedures: (1) confirm the psychiatric diagnosis (biological factor), (2) determine whether or not the psychiatricdisorder is severe enough to impede legal action (psychological factor), and (3) make a legal judgment based on the above. On
the other hand, Igarashi 1) advocates that since not all the persons diagnosed with dementia lack mental capacity and ability toact, the following procedures are more appropriate in the era of normalization: (1) assess functional ability related to a specificlegal action; (2) next, evaluate capacity as an underlying factor; and (3) entrust the judgment of competence to a judge.
There are various approaches to the assessment of the functional ability of a person with dementia: (1) an approach that
focuses on cognitive function, (2) an approach that focuses on the ability to execute a specific action, and (3) an approachbased on observation of daily actions 2). The approach focusing on cognitive function employs Mini Mental State Examination(MMSE), but there is insufficient evidence regarding the relationship with mental capacity 3). For the approach focusing on
the ability to execute a specific action (related to consent to treatment), Applebaum et al. 4) advocated a concept consisting offour steps: (1) understand the information related to decision making (understanding), (2) rationally process the information
obtained (rational thinking), (3) recognize the situation in which decision is made and the result of decision-making(recognition), and (4) express the result of decision-making to others (statement of choice). Based on this concept, they
developed a scale for measuring the ability to consent to treatment 5). In addition, Marson et al. 6) have developed the“Financial Capacity Instrument”.

Chapter 5119

3. Issues related to informed consent and medical consent for persons with dementia
Individuals who receive medical care have the right to make decisions about receiving the medical care. A doctor mustobtain the patient’s consent before performing the medical action, and as a premise, the doctor should give an explanationnecessary for obtaining the consent. In other words, medical actions must be performed based on informed consent.
From this perspective, a person who has been diagnosed with dementia is entitled to receive explanations including thediagnosis (name of disease), symptoms, predicted clinical course, treatments, and systems and services available. In addition, asa premise of such explanations, the patient has the right of self-determination about receiving (or rejecting) the medical action.
If a person with dementia lacks the ability to consent to medical care, the health care personnel customarily obtains
consent from the family or relatives, and then conducts the medical practice. However, if there are no family members or
relatives who can cooperate with consent to medical care, medical decision for a person with dementia who lacks the ability
to consent to medical care becomes a difficult problem. In Japan, there is currently no legislation on medical consent for
adults who lack the ability to consent.
In Japan, from the legal side, the Japan Federation of Bar Associations has published “Outline of the act on proxy medical
consent for persons lacking medical consent ability” (2011), and the Legal-Support Adult Guardianship Center has publishedthe “Interim report on consent to medical action” (2009). From the medical side, the Japan Geriatrics Society has issued a“Position Statement” on “End-of-life medical and general care for the elderly” (2012). From the administration side, the“Guidelines on the decision-making process of medical care at the end of life” (2015) has been published. In addition, themethod of (written) advance healthcare directive is increasingly being used to decide in advance the contents of medical carethat one wishes to receive (or not to receive).

▪ References
1) Igarashi Y. Adult guardianship system and structure of judging mental capacity. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku
Zasshi) 2003; 14(10): 1228-1239. (In Japanese)
2) Matsuda O. Aspects of aging society (9) Aging society and judgment ability; evaluation of normal aging and pathological aging. Japanese Journalof Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2009; 20(6): 681-687. (In Japanese)
3) Matsuda O, Saito M. Protection of rights and ability assessment of elderly people with dementia: study of the degree of agreement between the
results of intelligence tests and cognitive function tests and the execution of daily living activities including financial capacity. Japanese Journal of
Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2011; 22: 723-733. (In Japanese)
4) Applebaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988; 319(25): 1635-1638.
5) Grisso T, Appelbaum PS. The MacArthur Treatment Competence Study. III: Abilities of patients to consent to psychiatric and medical treatments.
Law Hum Behav. 1995; 19: 149-174.
6) Marson DC, Sawrie SM, Snyder S, et al. Assessing financial capacity in patients with Alzheimer disease: a conceptual model and prototype
instrument. Arch Neurol. 2000; 57: 877-884.

▪ Search formula
PubMed search: July 14, 2015 (Tuesday)#1 (“Dementia/diagnosis” [Mesh] OR dementia [TI] OR “Cognition Disorders/diagnosis” [Mesh] OR cognition disorder* [TI] OR cognitive
disorder* [TI]) AND (“Neuropsychological Tests” [Majr] OR neuropsychological test* [TI] OR “Disability Evaluation” [Majr] OR disability
evaluation* [TI] OR disability assessment* [TI]) AND (“Liability, Legal” [Mesh] OR legal liability* [TI] OR “Forensic Psychiatry” [Mesh] OR“Decision Making” [Mesh] OR decision making* [TI] OR “Executive Function” [Mesh] OR functional ability* [TI] OR “Mental Competency”[Mesh] OR competency* [TI] OR capacity* [TI])
Ichushi search: July 14, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Neuropsychological examination/TH
OR Neuropsychological examination/TI OR Neuropsychological test/TI) AND (Legal responsibility/TH OR Legal responsibility/TI OR Legalability to act/TI OR Decision making/TH OR Decision making/TI OR “Executive function (awareness process)”/TH OR Executive function/TI
OR Functional ability/TI OR Mental ability/TH OR Mental ability/TI OR Judgment ability/TI OR competence/TI OR capacity/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 5B-2

How can the adult guardianship system be used to protect the rightsof people with dementia?
AnswerIndividuals with dementia are vulnerable to infringement of their rights due to decline of judging ability. The adultguardianship system is a system that supports all legal activities including asset management and contract related topersonal custody for a person who lacks sufficient judgment ability, by appointing an assistant (such as adult guardian)
who protects the rights of the persons with dementia. However, there are many issues in the current adult guardianshipsystem including the following: the guardian does not have the right to consent to medical actions; there are insufficientmeasures against asset embezzlement by the guardian; the utilization rate is low; and there is a shortage of persons willingto take on the role as guardian.

Comments and evidence
Persons with dementia are vulnerable to having their rights infringed due to decline in judgment ability 1, 2). In order toprevent such infringement of rights, persons with dementia can utilize the programs for supporting independence in dailyliving and the adult guardianship systems. In both systems, the crucial point is to support daily living while respecting theperson’s self-determination 3).

1. Outline of the program for supporting independence in daily living
For persons whose ability of judgment is impaired due to dementia, intellectual disability, mental disability, and othercauses, and who experience difficulties in managing the contracts of utilizing welfare services by themselves, these persons
can utilize the “Program for supporting independence in daily living (former: Community welfare rights protection project)”that provides assistance for using welfare services, management of everyday finance, custody of important documents, andother services based on the contract signed with the person with dementia. However, in order to use this project, there is acondition that “the person himself/herself has the ability to understand the contents of the program and sign a contract”.

2. Outline of the adult guardianship system
The adult guardianship system is a system that supports all legal activities including contracts related to asset management
and personal custody (taking care of personal affairs) for a person who lacks sufficient judgment ability, by selecting an assistant(such as a guardian) who protects the rights of the person with dementia. There are two systems: a statutory guardianship system
and a voluntary guardianship system. The statutory guardianship system is a system that protects and assists the person withdementia (hereinafter referred to as the person) by the following framework: an adult guardian appointed by the family court(adult guardian, curator, or assistant), while considering the interests of the person, acts on behalf of the person to execute legal
acts such as contracts (proxy right), give consent when the person conducts legal acts by himself/herself (consent right), or cancel
a legal act after the person has committed an unbeneficial legal act without consent from the adult guardian (right to rescind).
On the other hand, the voluntary guardianship system operates as follows: to prepare for the future when judgment ability
becomes inadequate, the person while still having adequate judgment ability selects a proxy (voluntary guardian), and concludes
a contract granting proxy right for legal acts related to the person’s own asset management and personal custody (voluntary
guardianship contract), which is a notarized document prepared by a notary.
Application to use the statutory guardianship system is filed by the person, spouse, relative within the fourth degree,
public prosecutor, or (if there is no relative) the municipal mayor. There are three types of statutory guardianship: guardian,curator, and assistant. In the case of “a general state of lacking judgment capability”, a guardian is appointed, and theguardian is able to exercise all proxy rights and rights to rescind. In the case of “markedly inadequate judgment capability”,
a curator is appointed. The curator is able to exercise rights to consent and rights to rescind on specific matters (debt, lawsuit,approval/waiver of inheritance, new construction/renovation, etc. listed in Civil Code Article 13). In addition, the curator
may be granted proxy rights for certain legal acts (such as bank cash management, asset management, long-term care
contract, hospitalization contract, etc.) according to the request of the person. In the case of “inadequate judgment capability”,
an assistant is appointed, and the assistant can exercise rights to consent or rights to rescind for a part of specific matters

Chapter 5121according to the request of the person.
However, the proxy rights that a guardian can exercise are limited to asset management and personal custody. For example,
the guardian cannot exercise proxy rights regarding divorce/marriage/adoption, consent to medical actions, surety, andguarantor. In addition, there are other issues such as insufficient measures against asset embezzlement by the guardian, lowutilization rate per population compared to European and American countries, and shortage of persons willing to take on
the role as guardian.

▪ References
1) Ikeda E. To prevent economic damage: how to support elderly persons living alone. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku
Zasshi) 2011; 22(7): 815-824. (In Japanese)
2) Akanuma Y. How to protect the rights of persons with dementia? Rights protection for dementia. Naika 2012; 109(5): 825-827. (In Japanese)3) Arai M. Rights protection for patients with dementia. Roles of the adult guardianship system. The Journal of the Japanese Society of Internal
Medicine (Nihon Naika Gakkai Zasshi) 2011; 100(8): 2195-2199. (In Japanese)▪ Search formula
PubMed search: July 14, 2015 (Tuesday)#1 “Dementia” [Mesh] OR dementia [TI] OR “Cognition Disorders” [Mesh] OR cognition disorder* [TI] OR cognitive disorder* [TI] AND(“Legal Guardians” [Mesh] OR adult guardian* [TI]) AND (“Patient Advocacy” [Mesh] OR “Patient Rights” [Mesh] OR advocacy [TI] OR right*[TI])
Ichushi search: July 14, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Adult guardianship system/TH or
Adult guardianship system/TI) AND (Patients’ rights protection /TH OR Rights protection/TI OR Patients’ rights/TH)

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CQ 5B-3

What role does the Prevention of Elder Abuse Act play in preventing abuseto persons with dementia?
Answer
The Prevention of Elder Abuse Act sets forth national responsibilities for preventing elder abuse, protection measuresfor older people who have been abused, and support measures to prevent abuse of older people by caregivers. Cognitive
impairment is a major factor that increases the risk of abuse. Anyone finding an older person who appears to be abusedhas the obligation to report or the obligation to make efforts to report to the municipalities (Community General Support
Centers), depending on the severity of abuse.

Comments and evidence
The “Act on the Prevention of Elder Abuse, Support for Caregivers of Elderly Persons and Other Related Matters”(hereinafter “Prevention of Elder Abuse Act”) was approved in November 2005 and enforced in April 2006. To protect therights of older people, this law sets forth the responsibilities of the country to prevent elder abuse, protection measures forolder persons who have been abused, and support measures to prevent abuse of older persons by caregivers (such as by
reducing caregiver burden) aiming to promote policies related to support for prevention of elder abuse and support for
caregivers 1).

1. Outline of the law
In this law, an elderly person is defined as a person who is aged 65 years or older, and elder abuse is classified into “elder
abuse by a caregiver” and “elder abuse by care facility staff”. Caregivers are assumed to include family members, relatives,and persons living with the elderly person, who are taking care of the elderly person. Care facility staff is assumed to be
employee working in a “care facility” or “care business”.
Elder abuse is defined as “an elderly person placed in a state where his/her rights and interests are infringed, or in a state
where his/her life, health, or living is impaired by inappropriate treatment from others”.
A person finding an older person who appears to be abused has the obligation to report or the obligation to make efforts
to report to the municipalities (Community General Support Centers), depending on the severity of abuse. In addition,municipalities are primarily responsible for the prevention of abuse, protection of the older persons, and support for theabuse perpetrators. Even if it is difficult to determine whether a case is abuse, the municipality should take necessary assistantmeasures according to the Prevention of Elder Abuse Act, when it is speculated that the rights of an older person may be
infringed, or his/her life, health, or living may be impaired.

2. Factors for elder abuse
The risk factors for abuse in community-dwelling older persons include (1) factors related to the older person (75 years ofage and older, female, ethnicity, poor economic or health status, cognitive impairment, behavioral problems such as
aggression and care refusal, high level of dependence due to functional decline, psychiatric illness or psychological problems,poor physical health or frailty); (2) factors related to the perpetrator (psychiatric illness or psychological problems, careburden, and stress) (3) relationship (family disharmony, poor or conflictual relationship), and (4) environmental factors(poor social support, living with others) 2).

3. Situation of response to the Prevention of Elder Abuse Act
Since 2007, the Ministry of Health, Labor and Welfare has reported the “Survey results on the status of responses basedon the Act on the Prevention of Elder Abuse, Support for Caregivers of Elderly Persons and Other Related Matters”.

4. Limitations of the Prevention of Elder Abuse Act
A survey of long-term care insurance facilities and daycare facilities for dementia finds that cases of suspected abuse
constituted approximately 10 to 20%, but speculates that a considerable number of cases did not get notified 3). Althoughelder abuse is attracting attention because of the intent, there are many cases in the gray zone that are difficult to prove as

Chapter 5123abuse. Also, there is no provision in the current law for self-neglect. The necessity of proposing a law that can deal with awide range of infringements, including self-neglect, has been pointed out 4). Regarding elder abuse by care facility staff andothers, it is necessary to more clearly define the importance of efforts aiming to improve the quality of care, reduce theoccupational stress on workers, and implement appropriate organizational management. On the other hand, dementia care
workers need to detect signs of abuse by caregivers and provide appropriate care management and family support 5).

▪ References
1) Takizawa K. Outline of the Act on the Prevention of Elder Abuse. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2008;19(12): 1301-1306. (in Japanese)
2) Johannesen M, LoGiudice D. Elder abuse: a systematic review of risk factors in community-dwelling elders. Age Ageing. 2013; 42(3): 292-298.
3) Yoshikawa Y. Elder abuse and physical restraint by care facility workers: 5 years after enactment of the law. Japanese Journal of Gerontology (Ronen
Shakai Kagaku) 2012; 34(1): 71-76. (in Japanese)
4) Nomura S. A study of the legal system to prevent and support self-neglected elderly: Issues regarding enactment of law for elderly advocacy including
self-neglect. Journal of the Japan Academy for the Prevention of Elder Abuse (Koreisha Gyakutai Boshi Gakkai) 2011; 7(1): 82-99. (in Japanese)5) Yoshikawa Y. Prevention of elder abuse in dementia care: from the viewpoint of prevention before occurrence. Journal of Japanese Society for
Dementia Care (Nihon Ninchishokea Gakkaishi) 2013; 11(4): 765-771. (in Japanese)▪ Search formula
PubMed search: July 14, 2015 (Tuesday)#1 (“Dementia” [Mesh] OR dementia [TI] OR “Cognition Disorders” [Mesh] OR cognition disorder* [TI] OR cognitive disorder* [TI]) AND“Elder Abuse/prevention and control” [Mesh]
Ichushi search: July 14, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Elder abuse prevention law/TH OR
Elder abuse prevention law/TI) AND ((Elder abuse/TH OR Elder abuse/TI) AND ((SH = Prevention) OR Prevention/TI OR Prevention/TI))

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C | Early-onset Dementia
CQ 5C-1

What is early-onset dementia?
AnswerFrom the medical viewpoint, early-onset dementia refers to onset of dementia younger than 65 years of age. In terms ofutilization of support system, the term refers to a person younger than 65 years of age at the time of utilization.

Comments and evidence
In Japan, various terms had been used to describe dementia depending on the time of onset, such as juvenile dementia,
presenile dementia, and senile dementia. However, in several diseases such as juvenile Parkinson’s disease, “juvenile” refers
to onset age younger than 40 years. It was pointed out that since the same term “juvenile” may refer to different age groups
depending on the disease, terms such as juvenile dementia and senile dementia perhaps should not be used to avoid confusion[Japan Society for Dementia Research (Ed.) Textbook of Dementia 2008]. Then, since launching of “Policies for early-onset
dementia” 1) in 2009 (http://www.mhlw.go.jp/topics/kaigo/dementia/e01.html), the term “early-onset dementia” was clearly
described in the 5-year Plan for Promotion of Measures Against Dementia (the Orange Plan) in 2013 and the Comprehensive
Strategy to Accelerate Dementia Measures (the New Orange Plan) in 2015. At present, the notation of early-onset dementia
as onset of dementia younger than 65 years of age is commonly used at the administrative level.
According to the “Study report on the status of early-onset dementia and infrastructure development as control measures”(2009, Asada et al. 2)), the number of persons with early-onset dementia per 100,000 population was 47.6 [95% confidence
interval (CI) 45.5 to 49.7) in the 18–64 year-old population, 57.8 in men, 36.7 in women, and the total number of persons
with early-onset dementia nationwide was estimated to be 37,800 (95% CI 36,100 to 39,500). The causative diseases were
vascular dementia (39.8%), Alzheimer’s disease dementia (25.4%), sequelae of head injury (7.7%), frontotemporal lobar
degeneration (3.7%), alcoholic dementia (3.5%), and dementia with Lewy bodies (3.0%).
In addition to being younger, persons with early-onset dementia have life issues that are different from older persons withdementia: they are the main providers of family finance and childcare; the family may have children still attending school,etc. Therefore interventions should take these into consideration 4). In an environment where services are not fully utilized,
active and comprehensive use of systems including informal services should be promoted 3).
Since 2016, early-onset dementia support coordinators have been deployed in each prefecture, who are available for
consultation. The purpose of this service is to provide support that meets the needs of each person. In addition to providing
consultation service, this office is expected to build a collaborating system with municipalities and related organizations, aswell as to disseminate correct knowledge and conduct education activities about early-onset dementia 5).

▪ References
1) Ministry of Health, Labour and Welfare. Summary of study results on the status of early-onset dementia and the Ministry of Health, Labour andWelfare policies for measures against early-onset dementia. 2009.
http://www.mhlw.go.jp/houdou/2009/03/h0319-2.html (In Japanese)
2) Asada T. Study report on the status of early-onset dementia and infrastructure development as control measures. 2009. (In Japanese)3) Dementia Care Research Training Obu Center. Handbook on early-onset dementia (revised edition). https: //www.dcnet.gr.jp/support/research/
center/list.html?center=2 (In Japanese)4) Dementia Care Research Training Obu Center. Handbook on support for early-onset dementia (revised edition). 
https: //www.dcnet.gr.jp/support/research/center/list.html?center=2 (In Japanese)5) Dementia Care Research Training Obu Center. Manual for placement of support coordinator for early-onset dementia (excerpt). 
https: //www.dcnet.gr.jp/support/research/center/list.html?center=2 (In Japanese)

Chapter 5125▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 “juvenile dementia” OR “early onset dementia” OR “young onset dementia” OR ((“Dementia” [Mesh] OR dementia [TI]) AND (juvenile OR“early onset” OR “young onset” OR “Age Factors” [Mesh])) AND (“economics” [subheading] OR “Economics” [Mesh] OR economic* [TI]) AND(“Social Support” [Mesh] OR “Health Planning” [Mesh] OR “Delivery of Health Care” [Mesh])
Ichushi search: June 27, 2015 (Saturday)#1 (Early-onset dementia/AL OR ((Dementia/TH OR Dementia/TI) AND Juvenile/AL)) AND (Economics/TH OR Economic/TI) AND (Social
support/TH OR Social resource/TI OR Support system/TI OR Health care plan/TH OR Health service provision/TH)

126

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CQ 5C-2

What are the support systems to help persons with early-onset dementia
with their economic challenges?
AnswerPublic supports including medical payment for services and supports for persons with disabilities under the Services
and Supports for Persons with Disabilities Act, accident and sickness benefits, and disability pension are available, butwhether the patient is eligible to receive these supports depends on the disease condition, disease stage, and householdincome.

Comments and evidence
If a person is diagnosed with early-onset dementia while still in employment, the first financial support available is the
reduction in copayment (portion paid by patient) of medical expenses under the System of Services and Supports for Persons
with Disabilities. If the person takes leave of absence, he/she will receive accident and sickness benefits for a period of 1 year
and 6 months. In addition, the person can apply for the Health and Welfare Certificate of Persons with Mental Disabilities
from 6 months after the date of the first hospital visit, which allows him/her to benefit from deductions of service fees andtaxes. After leaving employment, the person can apply for disability pension from 1 year and 6 months after the date of thefirst hospital visit. In addition, if the person continues to receive accident and sickness benefits after leaving employment,
once he/she applies for extension of the employment insurance benefit (unemployment benefit), he/she will be able to use thedisability welfare services. When the payment of accident and sickness benefits is stopped, those who have joined theemployment insurance can also receive unemployment insurance benefits for a certain period.
The System of Services and Supports for Persons with Disabilities offers the following benefits. When a person is diagnosed
with dementia and receives non-hospitalization-based medical care, by applying at the municipal office to utilize the above
System, the copayment portion of medical expenses is reduced to 10% in principle. Accident and sickness benefit is a social
security system for persons under medical treatment provided by the Health Insurance Law. When a person who is insured
with a health insurance society is under medical treatment and cannot work for more than 3 consecutive days, then from the
4th day at which he/she has not been paid a salary, he/she is entitled to receive a sum of two-thirds of the standard daily wage,
for a period of 1 year and 6 months.
Health and Welfare Certificate of Persons with Mental Disabilities under the Mental Health and Welfare Act allows aperson with a certain degree of mental disability to receive various assistances, aiming to promote the person’s independence
and social participation. The Certificate entitles a person to receive two types of services: services that can be received
nationwide, and services that can be received depending on region and employer. The former includes deductions in income
tax, resident tax, inheritance tax; reduction in automobile tax and automobile acquisition tax; reduction or exemption ofutility charges; and social welfare loan. The latter include discounts for railway, bus, taxi fares; discounts for mobile phone
fee and water and sewage charges; discount for public facility admission fee; increases of welfare benefit and public assistancefor persons with disabilities; and priority to be allocated public housing. The patient may apply for the Health and Welfare
Certificate of Persons with Mental Disabilities at the municipal office after 6 months from the date of the first hospital visit.
The Certificate is classified from grade 1 to grade 3 according to the degree of disability. Note that at this stage, it is also
possible to apply simultaneously for medical payment subsidy under the System of Services and Supports for Persons with
Disabilities.
Furthermore, persons who have joined the national or employee pension scheme can receive a disability pension after 1
year and 6 months from the date of the first hospital visit. An insured person of the national pension scheme receives a basic
disability pension. An insured person of the employee pension scheme can receive the disability employee pension on top of
the basic disability pension. If the disability grade is less than grade 3, the person cannot receive a disability pension, but canreceive disability benefit as a lump sum.
In addition, in some cases, some patients are eligible for life insurance and other insurances, reduction or waiver of diaper
charge, and childcare system (depending on the municipality).
Also, since July 1, 2015, frontotemporal dementia and semantic dementia have been designated as intractable diseases
based on the Intractable/Rare Disease Act. Certain medical assistance is provided if the requirements are met.

Chapter 5127▪ Further reading
1) Awata S. Use medical care services, living support services, long-term care insurance services. Japanese Journal of Geriatric Psychiatry (Ronen
Seishin Igaku Zasshi) 2015; 26(4): 398-405. (In Japanese)
2) Japan National Council of Social Welfare . Use of disability welfare services. April 2014 edition. http://www.shakyo.or.jp/business/pdf/pamphlet_
h2604.pdf (In Japanese)3) Nakanishi A, Tagawa R. Method of system utilization for diagnosing dementia: Method of using services of Health and Welfare Certificate of
Persons with Mental Disabilities and Services and Supports for Persons with Disabilities Act. Japan Medical Journal (Nihon Iji Shinpo) 2015;(4769): 38-43. (In Japanese)4) Ministry of Health, Labour and Welfare. Let’s start from knowing: General site on mental health for everyone.
http://www.mhlw.go.jp/kokoro/support/promotion_4.html (In Japanese)▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 “juvenile dementia” OR “early onset dementia” OR “young onset dementia” OR ((“Dementia” [Mesh] OR dementia [TI]) AND (juvenile OR“early onset” OR “young onset” OR “Age Factors” [Mesh])) AND (“Social Support” [Mesh] OR social support* [TI] OR life support* [TI] OR“Health Planning” [Mesh] OR “Delivery of Health Care” [Mesh])
Ichushi search: June 27, 2015 (Saturday)#1 (early-onset dementia/AL OR ((Dementia/TH OR Dementia/TI) AND Juvenile/AL)) AND (Social support/TH OR Social resource/TI OR
Support system/TI OR Health care plan/TH OR Health service provision/TH)

128

Clinical Practice Guideline for Dementia 2017

CQ 5C-3

What are the systems that can be used to support the living of persons
with early-onset dementia?
Answer
If a person is diagnosed with any of the 16 specified illnesses of early-onset dementia, he/she can utilize the long-termcare insurance system from the age of 40 years. If younger than 40 years, the long-term care insurance system cannot be
used. If the person is certified as a person with mental disorder, he/she can utilize facilities based on the Services andSupports for Persons with Disabilities Act.

Comments and evidence
If a person is diagnosed with any of the 16 specified illnesses* of early-onset dementia, he/she can utilize the long-termcare insurance system from the age of 40 years. However, these services are difficult to use because most long-term careservices are operated with the assumption that the users are older people. For persons of all ages having mental disorders, it
is possible to use facilities for mentally disabled persons based on the Services and Supports for Persons with Disabilities Act.
However, there is also a problem that these services may be difficult to use because they are not operated with the assumptionthat users have dementia.

<Specified diseases*>
The Ministry of Health, Labor and Welfare lists the specific diseases as described below, from the viewpoint of clarifying
the scope of the diseases and facilitating certification of the level of care/support needed in the long-term care insurance
system (Enforcement Order of Long-term Care Insurance Act, Article 2).
A specified disease is a disease that is considered to have a medical relationship with the psychosomatic pathological aging
phenomenon. The disease should meet all the requirements listed below. Upon comprehensive consideration, the disease isrecognized as one that causes psychosomatic changes with aging, leading to a state requiring long-term care.
1) The disease occurs frequently in older people aged 65 years and older, while it is also found in the age group from 40 toyounger than 65 years. In this disease, a relationship of its incidence/prevalence (including similar indicators) with aging
is observed, and the medical concept can be clearly defined.
2) A disease that is considered to have a high rate of needing care or support for 3 to 6 months or above .
1. Cancer (terminal stage of cancer)*
(limited to those judged by a doctor to have no prospect of recovery based on generally accepted medical knowledge.
2. Rheumatoid arthritis*
3. Amyotrophic lateral sclerosis
4. Ossification of the posterior longitudinal ligament
5. Osteoporosis with bone fracture
6. Dementia in early old age
7. Progressive supranuclear palsy, corticobasal degeneration, and Parkinson’s disease* (Parkinson’s disease-relateddiseases)
8. Spinocerebellar degeneration
9. Spinal canal stenosis
10. Progeria
11. Multiple system atrophy *12. Diabetic neuropathy, diabetic nephropathy, diabetic retinopathy
13. Cerebrovascular disease
14. Arteriosclerosis obliterans
15. Chronic obstructive pulmonary disease
16. Osteoarthritis with significant deformation in bilateral knee or hip joints (Asterisks denote diseases added in April 2006, after revision)

Chapter 5129▪ Further reading
1) Awata S. Use medical care services, living support services, long-term care insurance services. Japanese Journal of Geriatric Psychiatry (Ronen
Seishin Igaku Zasshi) 2015; 26(4): 398-405. (In Japanese)2) Ministry of Health, Labour and Welfare. Selection criteria for specified diseases. 
http://www.mhlw.go.jp/topics/kaigo/nintei/gaiyo3.html (In Japanese)3) Ministry of Health, Labour and Welfare. Let’s start from knowing: General site on mental health for everyone. 
http://www.mhlw.go.jp/kokoro/support/promotion_4.html (In Japanese)▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 (“juvenile dementia” OR “early onset dementia” OR “young onset dementia” OR ((“Dementia” [Mesh] OR dementia [TI]) AND (juvenile OR“early onset” OR “young onset” OR “Age Factors” [Mesh]))) AND (“Social Support” [Mesh] OR social support* [TI] life support* [TI] OR “Health
Planning” [Mesh] OR “Delivery of Health Care” [Mesh])
Ichushi search: June 27, 2015 (Saturday)#1 (early-onset dementia/AL OR ((Dementia/TH OR Dementia/TI) AND Juvenile/AL)) AND (Social support/TH OR Social resource/TI OR
Support system/TI OR Health care plan/TH OR Health service provision/TH)

130

Clinical Practice Guideline for Dementia 2017

CQ 5C-4

What kind of consultation support is available for persons with early-onset
dementia?
AnswerThere are family associations in various districts, counseling bodies commissioned by municipalities, and others.
However, the actual situation varies depending on the region, so it is necessary to contact the municipalities.

Comments and evidence
From the disease characteristics of dementia and also from the viewpoint of information exchange and peer counseling, it
is important to utilize the consultation counters, participate in family associations of caregiving families, use informal
services, and utilize dementia cafes that have been set up in various places in recent years.
In 2009, Ministry of Health, Labour and Welfare set up a call center at the Dementia Care Research Training Obu Center(http://www.mhlw.go.jp/houdou/2009/09/h0930-6.html) as a free consultation telephone service for persons with earlyonset dementia.
• Early-onset dementia call center
http://y-ninchisyotel.net/callcenter/new.html
Some municipalities also set up independent support centers.
• Tokyo early-onset dementia support center
http://www.fukushihoken.metro.tokyo.jp/zaishien/ninchishou_navi/kisochishiki/jakunensei/jakunen_center/▪ Further reading
1) Awata S. Use medical care services, living support services, long-term care insurance services. Japanese Journal of Geriatric Psychiatry (Ronen
Seishin Igaku Zasshi) 2015; 26(4): 398-405. (In Japanese)2) Ministry of Health, Labour and Welfare. Summary of the future policies for early-onset dementia. 
http://www.mhlw.go.jp/topics/kaigo/dementia/e01.html (In Japanese)▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 (“juvenile dementia” OR “early onset dementia” OR “young onset dementia” OR ((“Dementia” [Mesh] OR dementia [TI]) AND (juvenile OR“early onset” OR “young onset” OR “Age Factors” [Mesh]))) AND (“Referral and Consultation”[ Mesh] OR consult[ TI] OR consultation[ TI] OR
referral[ TI])
Ichushi search: June 27, 2015 (Saturday)#1 (early-onset dementia/AL OR ((Dementia/TH OR Dementia/TI) AND Juvenile/AL)) AND (Social support/TH OR Social resource/TI OR
Support system/TI OR Health care plan/TH OR Health care service provision/TH) AND (Referral and consultation/TH OR Consultation/TI
OR Consultant/TI OR Counseling/TH OR Counseling/TI)

Chapter 5131

D | Road Traffic Act
CQ 5D-1

What should be done if one finds that a person diagnosed with dementia
holds a driver license and is still driving?
AnswerSince 2002, driving is not permitted if a person is diagnosed with dementia in Japan. From 2014, a voluntary reporting
system has been started, and reporting to the Prefectural Public Safety Commission has been approved.
C

Comments and evidence
1. Comments

Various medical assessments of driving competency for people with dementia have been examined, but no testing methods
have been established for determining and predicting driving ability and competency, with consideration of dementia as theunderlying disease. No conclusions have been drawn regarding the conditions and the types of dementia that present danger
when persons with dementia continue to drive. The reasons are that dementia has diverse underlying diseases, and thatdriving ability may be influenced by the severity of dementia. On the other hand, in Japan, the 2002 revision of the Road
Traffic Act restricts driving related to dementia.
Currently, if a person aged 75 years or above applying for renewal of the driver license is suspected of dementia after taking
the Cognitive Impairment Screening Test for Senior Drivers, and if that person has caused specific traffic violation called“standard actions” within one year, the Public Safety Commission will order the person to undergo a Special Driving
Competency Test or to be examined by a family doctor for assessment of dementia. If the result determines that the person
has dementia as provided by the Article 5-2 of Long-term Care Insurance Act, the driver license will be revoked.
Under the Revised Road Traffic Act enacted in March 2017, a special screening test is introduced for persons aged 75 years
or above who have committed traffic violation of one or more of 18 items, and they are obliged to take the Cognitive
Impairment Screening Test for Senior Drivers without waiting for the time of license renewal. And, if the person is assessed
as category 1, he/she has to see a doctor for assessment for the presence or absence of dementia. The “Guide for family doctors
on writing medical certificate related to renewal of driver’s license for older people with dementia” produced by Japan
Medical Association was released on March 8, 2017 (http://www.med.or.jp/doctor/report/004984.html). Doctors may referto this guide when writing a medical certificate.
Furthermore, the voluntary reporting system was started in June 2014. Doctors who are engaged in medical care fordementia can report to the Public Safety Commission when dementia is suspected or when dementia is diagnosed, but theyshould first of all diagnose appropriately regarding whether or not the person has dementia. When dementia is diagnosed
based on evidence, after disclosing the diagnosis of dementia to the patient and the family, the doctor should explain
carefully all the details about the patient’s need to give up driving, and record in the medical record the patient’s and thefamily’s reactions to the explanations. In addition, the doctor should keep in mind to provide guidance to the patient andfamily on daily living, including the effect of giving up driving on the patient’s treatment and daily life, not only just once
after notifying the patient to give up driving but to repeat thereafter. Five medical societies related to dementia have jointly
released a guideline for using the voluntary reporting system. Doctors may refer to these guidelines (http://dementia.umin.
jp/GL_2014.pdf).

▪ Further reading
1) Martin AJ, Marottoli R, O’Neill D. Driving assessment for maintaining mobility and safety in drivers with dementia. Cochrane Database Syst Rev.
2013; (5): CD006222.
2) Martin AJ, Marottoli R, O’Neill D. Driving assessment for maintaining mobility and safety in drivers with dementia. Cochrane Database Syst Rev.
2009; (1): CD006222.
3) Dawson JD, Anderson SW, Uc EY, et al. Predictors of driving safety in early Alzheimer disease. Neurology. 2009; 72(6): 521-527.

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▪ Search formula
PubMed search: July 14, 2015 (Tuesday)#1 (“Dementia” [Mesh] OR dementia [TI] OR “Cognition Disorders” [Mesh] OR cognition disorder* [TI] OR cognitive disorder* [TI]) AND“Automobile Driving” [Mesh] AND (“Decision Support Techniques” [Mesh] OR decision support* [TI] OR “Health Education” [Mesh] OR
education [TI] OR “Law Enforcement” [Mesh] OR law enforcement* [TI] OR “Safety Management” [Mesh] OR safety [TI] OR “Physician’s Role”[Mesh] OR physician’s role* [TI] OR ((“Accidents, Trac” [Mesh] OR trac accident* [TI]) AND (risk [Mesh] OR risk [TI])) OR “Dangerous
Behavior” [Mesh] OR dangerous behavior* [TI] OR dangerous action* [TI])
Ichushi search: July 14, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND (Automobile driving/TH OR
Automobile driving/TI OR Driver license/TI) AND (Patient education/TH OR Education/TI OR Law enforcement/TH OR Road Traffic Act/TI
OR Safety management/TH OR Safety management/TI OR Doctor’s role/TH OR Doctor’s role/TI OR ((Traffic accident/TH OR Traffic accident/
TI OR Traffic violation/TI) AND (Risk/TH OR Risk/TI)) OR Risky actions/TH OR Risky actions/TI OR Risky behavior/TI)

Chapter 5133

Chapter 6
Alzheimer’s Disease Dementia

Objective
To review recent reports on the diagnosis, treatment, care, and social response for Alzheimer’s disease dementia, and toclarify the level of evidence and grading of recommendation.

Concept
Alzheimer’s disease is characterized by two pathological changes; neurofibrillary tangles (tauopathy) and amyloid
deposition (Aβ amyloidosis; cerebral cortex, cerebral blood vessels), which cause neuronal death, synapse depletion anddecreased acetylcholine in the cerebral cortex, hippocampus, and frontobasal region, leading to development of dementia.
Typically, the major symptoms are learning and memory impairments starting from slowly progressive episodic memory
impairment, progressing to aphasia, executive function impairment, visuospatial function impairment, and social cognitive
impairment including personality change. There are also atypical cases with onset symptoms including posterior cortical
atrophy, logopenic aphasia, frontal variant with visual construction deficits, aphasia, and frontal lobe function impairment.

Pathology
In autosomal dominant Alzheimer’s disease, many mutations have been identified in APP, PSEN1 and PSEN2, all ofwhich have been shown to increase Aβ42 production. Increased production together with reduced transport and metabolismof Aβ leads to formation of Aβ42 aggregates (oligomer) that damage synapses, induce neurofibrillary tangles and neuronal
death. This process has been suggested to be the mechanism for the development of mild cognitive impairment and dementia(the amyloid β‒tauopathy cascade hypothesis).

Progression and course of symptoms
Characteristic symptoms include forgetfulness and memory impairment due to damage of the hippocampus and medialsurface of the temporal lobe; verbal amnesia due to damage of the temporal, parietal and occipital regions; visuospatial
deficit; apraxia; semantic memory impairment due to damage of the lateral surface of the temporal lobe; as well as reduced
disease awareness and spontaneity due to damage of the frontal lobe. Impairment of episodic memory is also a characteristic,
and “saving appearance response” and repetition behavior are often observed. In moderate cases, impairment of immediate
memory and impairment of long-term memory (starting from recent events) progress, and the number of words that can beused decreases due to semantic memory impairment and aphasia. In severe cases, almost all memories are impaired.
Constitutional impairment is commonly found. Initially, drawing and copying of complex pictures such as clocks andcubes are impaired. Then other symptoms begin to appear including inability of using everyday tools and inability of using
multiple objects due to ideational apraxia, inability of imitating oral and visual commands due to ideomotor apraxia, andcortical symptoms such as limb-kinetic apraxia. Dressing apraxia is also a symptom commonly seen in moderate Alzheimer’s
disease dementia, and these apraxias progress in conjunction with impairment of procedural memory for learned movements.
Early stage dementia is recognized by memory decline and reduced ability to execute work and housework. As the diseaseprogresses, lowered initiation of actions, persistence and stubbornness, as well as impulsiveness and disinhibition appear, andself-correction becomes difficult. Many patients have no awareness of the disease, and appear cheerful. Eventually, thepatient becomes incapable of self-care such as grooming, dressing, taking meals, toileting, and bathing; and incapable ofunderstanding words and speaking. This progresses to loss of basic motor abilities such as standing, sitting and walking, andthe average survival is around 10 years.
In approximately 80% of the patients, behavioral and psychological symptoms of dementia (BPSD) appear as the diseaseprogresses, and these pose a burden on families and caregivers. Depression and apathy in the early stage progress to irritability,
abusive language and violence, frustration and agitation, rejection, hallucination, delirium, insomnia, and wandering
behaviors. In severe cases, inability to walk, incontinence, myoclonus, parkinsonism, and convulsions are seen. In the UnitedStates Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, which observed subjects from mild cognitive impairment
to the onset of dementia, the time from mild cognitive impairment with impaired memory (amnestic MCI) to onset ofdementia was 1 year in 16% of the subjects, 2 years in 24%, and 3 years in 49%.

136

Clinical Practice Guideline for Dementia 2017

CQ 6-1

What are the features and key points of diagnosis for neuropsychiatric
symptoms in Alzheimer’s disease dementia?
AnswerAlzheimer’s disease dementia (1) has insidious onset and slow progression; (2) often presents initially as decline in recent
memory; (3) as the disease progresses, additional symptoms of disorientation, impaired executive function, and visuospatial
impairment appear; (4) followed by apathy, psychiatric symptoms such as depressive symptoms, disease unawareness, andcharacteristic interpersonal behaviors such as saving appearance response; (5) in presenile-onset dementia cases, cognitive
impairment other than memory decline, such as aphasic symptoms, visuospatial impairment, and executive function
impairment are often observed in the foreground; (6) marked focal neurological signs are rarely seen from the early stageof disease.

Comments and evidence
1. Cognitive impairment

The core symptom is memory impairment. Specifically, the characteristic memory loss is recent memory impairment
when classified by the retention time, and episodic memory decline when classified based on content. The patient forgets
appointments, cannot recall where things are kept, forget what he/she has said and repeats the same narration. The delayedrecall task is the most sensitive tool to detect memory impairment in Alzheimer’s disease dementia; characteristically thepatient cannot give a correct answer even when given cues 1, 2). In contrast to recent memory, remote memory is relatively
preserved.
In many patients, memory impairment is followed by disorientation, impaired executive function, visuospatial impairment,
and language impairment. Disorientation often progresses in the order of time → place → person. Impaired executivefunction is often recognized from a relatively early stage and interferes with day-to-day operations such as work andhousework. The patient has difficulties copying figures due to visuospatial disturbance, and begins to get lost even in theneighborhood. As the disease progresses, apraxia (cannot use objects) also becomes noticeable. With respect to language, in
addition to amnesic aphasia causing difficulties in understanding the names of objects, verbal paraphasia is conspicuous andlanguage understanding becomes poor. Fluency and repetition are preserved until the terminal stage, presenting a clinicalpicture of transcortical sensory aphasia. Although social cognitive impairment is also observed, it is less severe compared tofrontotemporal dementia 3). Regarding daily life functioning, instrumental activities of daily living (IADL) are impaired
from a relatively early stage, while impairment of activities of daily activity (ADL) appears after the disease has advanced 4).

2. Behavioral and psychological symptoms of dementia
According to studies using the Neuropsychiatric Inventory (NPI) for evaluation, apathy is the most common symptom
observed in 30 to 80% of the patients 5-7), and reduced spontaneity and indifference cause problems in daily life. The
prevalence of depressive state is also high; major depression according to the DSM criteria is present in 12.7%, and a
depressive state based on specific criteria for dementia in 42% 8). The prevalence is higher in studies of patients visiting
hospitals or clinics compared to population-based studies 8). The frequency of delusion is 36%, and delusion of theft is mostfrequent (50.9%). Hallucinations are found in 18% of the patients, and visual hallucinations is more common than auditory
hallucinations 9). When the severity of dementia progresses to moderate or above, wandering, agitation, and irritability
become conspicuous.

3. Focal neurological signs
Except for some cases of familial Alzheimer’s disease, definite neurological signs such as extrapyramidal symptoms,
myoclonus, and seizures are rarely found from the early stage of Alzheimer’s disease dementia. When significant neurologicalfindings are observed from the early stage of the disease, diseases other than Alzheimer’s disease dementia should besuspected.

Chapter 6137

4. Atypical cases
Alzheimer’s disease dementia that causes atypical symptoms accounts for 6-17% of the total 10-12). They include a type withvisual cognitive impairment in the foreground due to localized atrophy in parietal and occipital lobes, a type with conspicuous
behavioral abnormalities and executive function impairment due to severe frontal lobe degeneration, and a type with only
prominent language impairment. Among patients with progressive aphasia, those showing logopenic aphasia often have thepathology of Alzheimer’s disease 13).

5. Key points for diagnosis
When disease is in the early stage, paying attention to the characteristics of memory impairment and other symptoms isimportant to distinguish dementia from forgetfulness due to normal aging, depression, and delirium. Patients with
forgetfulness due to normal aging are fully aware of the symptom (disease awareness), and the impairment is mild or
appropriate to age. Patients with depression often exaggerate their forgetfulness. Patients with senile depression often havephysical complaints such as general malaise, headache, stiff shoulders, and constipation in the foreground, while depression
may not be remarkable.
Even when cognitive impairment such as memory decline is recognized, delirium should be considered if the onset is sudden,
the symptoms change, and impaired consciousness is strongly suspected. Check for environmental changes, physical factors
such as electrolyte abnormalities, and drugs that may cause delirium (including anxiolytics, anti-parkinsonian drugs, drugs
with anticholinergic effects). Alzheimer’s disease dementia has insidious onset and slow progression. If symptoms develop withina short time span of days or hours, vascular disorders and delirium are suspected. Confirm whether or not there are major signsof other diseases [dementia with Lewy bodies (DLB), frontotemporal dementia (FTD)], and make an exclusion diagnosis. A lackof disease awareness, and presence of saving appearance reaction and repetition signs may also help with the diagnosis.

▪ References
1) Mathias JL, Burke J. Cognitive functioning in Alzheimer’s and vascular dementia: a meta-analysis. Neuropsychology. 2009; 23(4): 411-423.
2) Dubois B, Feldman HH, Jacova C, Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014; 13(6):614-629.
3) Bora E, Walterfang M, Velakoulis D. Theory of mind in behavioural-variant frontotemporal dementia and Alzheimer’s disease: a meta-analysis. J
Neurol Neurosurg Psychiatry. 2015; 86(7): 714-719.
4) Delva F, Auriacombe S, Letenneur L, et al. Natural history of functional decline in Alzheimer’s disease: a systematic review. J Alzheimers Dis. 2014;40(1): 57-67.
5) Lyketsos CG, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memoryin Aging. Am J Psychiatry. 2000; 157(5): 708-714.
6) Lyketsos CG, Lopez O, Jones B, et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from thecardiovascular health study. JAMA. 2002; 288(12): 1475-1483.
7) Hirono N, Mori E, Tanimukai S, et al. Distinctive neurobehavioral features among neurodegenerative dementias. J Neuro-psychiatry Clin Neurosci.
1999; 11(4): 498-503.
8) Chi S, Wang C, Jiang T, et al. The prevalence of depression in Alzheimer’s disease: a systematic review and meta-analysis. Curr Alzheimer Res. 2015;12(2): 189-198.
9) Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003.
Am J Psychiatry. 2005; 162(11): 2022-2030.
10) Lopez OL, Becker JT, Klunk W, et al. Research evaluation and diagnosis of probable Alzheimer’s disease over the last two decades: I. Neurology.
2000; 55(12): 1854-1862.
11) Galton CJ, Patterson K, Xuereb JH, et al. Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging andpathological study of 13 cases. Brain. 2000; 123(Pt 3): 484-498.
12) Snowden JS, Stopford CL, Julien CL, et al. Cognitive phenotypes in Alzheimer’s disease and genetic risk. Cortex. 2007; 43(7): 835-845.
13) Teichmann M, Kas A, Boutet C, et al. Deciphering logopenic primary progressive aphasia: a clinical, imaging and biomarker investigation. Brain.
2013; 136(Pt 11): 3474-3488.

▪ Search formula
PubMed search: July 2, 2015 (Thursday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer [TI] AND (diagnosis [TI] OR diagnostic [TI]))) AND (sign [TI] OR signs [TI] OR
symptom [TI] OR symptoms [TI] OR symptomatology [TI])
Ichushi search: July 2, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND (Characteristics/TI
OR Signs/TI OR Symptoms/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasounddiagnosis) OR Diagnosis/TH OR Diagnosis/TI)

138

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CQ 6-2

What are the diagnostic criteria for Alzheimer’s disease dementia?
Answer
The Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American
Psychiatric Association or the diagnostic criteria of the National Institute on Aging–Alzheimer’s Association (NIA-AA) is
recommended for clinical diagnosis of Alzheimer’s disease dementia. For the purpose of strict diagnosis and research, theIWG-2AD advanced research diagnostic criteria for dementia developed by the International Working Group (IWG) isavailable.
A

Comments and evidence

In the Diagnosis and Statistical Manual of Mental Disorders Fifth Edition published by American Psychiatric Associationin 2013, the diagnostic criteria for dementia and Alzheimer’s disease dementia were completely revised. The term dementia
was abolished and was changed to “major neurocognitive disorder”. The diagnosis of Alzheimer’s disease dementia is basedon meeting the criteria for dementia (A), insidious onset and gradual progression of impairment (B), and exclusion of otherdiseases (D), and is classified as either probable or possible (C). While amyloid PET and cerebrospinal fluid Aβ42 level aredescribed as significant for diagnosis, other tests including genetic analyses (APP, PSEN1/2, and APOE ε4), cerebrospinal
fluid total tau and phosphorylated tau levels, cortical atrophy in hippocampus and temporal lobe on MRI, and decreased
glucose metabolism in bilateral parietal lobes on FDG-PET are described as tests for future clinical application 1).
In 2011, diagnostic criteria for dementia and Alzheimer’s disease dementia were proposed by the Workgroup of the National
Institute on Aging (NIA) and the Alzheimer’s Association (AA) in the United States. In these diagnostic criteria, Alzheimer’s
disease is a term that reflects brain pathology. Based on the stage and clinical symptoms, Alzheimer’s disease is subdivided into
preclinical Alzheimer’s disease, mild cognitive impairment (MCI) due to Alzheimer’s disease, and Alzheimer’s disease dementia.
The proposed major clinical criterion is the presence of slowly progressive, objective cognitive impairment in the memory or
non-memory domain. To ensure that the diagnostic criteria can also be used in research, the Workgroup also describes recent
advances in amyloid deposition biomarkers including decreased cerebrospinal fluid Aβ42 level and Aβ deposits on PiB amyloid
PET, neurodegeneration biomarkers including increased cerebrospinal fluid total tau and phosphorylated tau levels, decreased
glucose metabolism on FDG-PET, progressive brain atrophy on MRI, and genetic testing 2).
In 2014, the International Working Group (IWG) and NIA–AA more clearly classified the clinical symptoms of
Alzheimer’s disease dementia, and proposed the advancing research diagnostic criteria (IWG-2 diagnostic criteria) for
Alzheimer’s disease adopting biomarker findings 3). Clinical phenotypes are broadly classified into typical Alzheimer’s disease
dementia with onset symptom of episodic memory impairment progressing to cerebral cortex symptoms involving otherdomains, and atypical Alzheimer’s disease dementia with atypical onset symptoms including posterior cortical atrophy,logopenic aphasia, and frontal variant. Tests necessary for diagnosis include brain amyloid PET, decreased cerebral spinal
fluid Aβ42 level together with increased total tau and phosphorylated tau levels, and genetic testing.

▪ References

1) American Psychiatric Association. Diagnostic and statistical manual of mental disorders Fifth Edition: DSM-5. Arlington, VA: American Psychiatric
Association; 2013.
2) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
3) Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6): 614-629. Erratum in: Lancet Neurol. 2014 Aug; 13(8): 757.

▪ Search formula

PubMed search: July 22, 2015 (Wednesday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer* [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND ((criteria [TI]
AND diagnosis* [TI]) OR “Diagnosis, Differential” [Mesh] OR “Diagnostic Errors” [Mesh] OR “Sensitivity and Specificity” [Mesh] OR“differential diagnosis” [TI] OR sensitivity [TI] OR specificity [TI] OR diagnostic error* [TI]
Ichushi search: July 22, 2015 (Wednesday)#1 Alzheimer’s disease/TH OR Alzheimer’s disease/TI) AND ((Criteria/TI AND Diagnosis/TI) OR ((SH = Diagnostic use, diagnosis, diagnostic
imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND (Differential diagnosis/TH
OR Differential diagnosis/TI OR Misdiagnosis/TH OR Misdiagnosis/TI OR Sensitivity and specificity/TH OR Sensitivity/TI OR Specificity/TI))

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CQ 6-3What are the characteristic image findings of Alzheimer’s disease dementia?
AnswerThe characteristic image findings of Alzheimer’s disease dementia are as follows: (1) CT and MRI depicting atrophy inmedial temporal lobe, especially the hippocampus; (2) SPECT and FDG-PET showing decreased blood flow and glucose
metabolism in bilateral temporal/parietal lobes and posterior cingulate gyrus, (3) amyloid PET indicating amyloid
deposition in frontal lobe, posterior cingulate gyrus, and anterior wedge.
A

Comments and evidence
In 20 studies that evaluated the diagnostic accuracy of diagnostic imaging by CT, MRI, SPECT, and PET for Alzheimer’s
disease dementia, histopathologically diagnosed Alzheimer’s disease dementia was differentiated from healthy individuals
and non-Alzheimer’s disease dementia with a sensitivity of 86.8% [95% confidence interval (CI) 81.9 to 91.7%] and specificityof 78.7% (95% CI 70.3- to 87.1%) 1). In 12 studies using MRI, Alzheimer’s disease dementia due to atrophy of medial
temporal lobe was differentiated from healthy subjects with a sensitivity of 85% and specificity of 88% 2). Moreover,hippocampal atrophy correlated with Braak stage and MMSE score, and was associated with the carrier status of APOE ε4 3).
In a meta-analysis of 49 of 775 studies using cerebral blood flow SPECT, 99mTc-HMPAO SPECT differentiated Alzheimer’s
disease dementia from frontotemporal dementia with 79.7% sensitivity and 79.9% specificity, Alzheimer’s disease dementia
from vascular dementia with 74.5% sensitivity and 72.4% specificity, Alzheimer’s disease dementia from dementia with
Lewy body with 70.2% sensitivity and 76.2% specificity, and Alzheimer’s disease dementia from healthy subjects with 76.1%
sensitivity and 85.4% specificity 4). In 119 studies on the diagnostic accuracy of FDG-PET for Alzheimer’s disease dementia,
Alzheimer’s disease dementia was differentiated from healthy subjects with a sensitivity of 90% (95% CI 84% to 94%) andspecificity of 89% (95% CI 81% to 96%), and Alzheimer’s disease dementia was differentiated from non-Alzheimer’s disease
dementia (including mild cognitive impairment) with a sensitivity of 92% (95% CI 84% to 96%) and specificity of 78%(95% CI 69% to 85%) 5). The Dominantly Inherited Alzheimer Network (DIAN) study reported that amyloid deposition
depicted by PIB-PET was observed 15 years before the onset age 6). In a meta-analysis of amyloid PET positivity in Alzheimer’s
disease dementia and non-Alzheimer’s disease dementia, the positive rates were 88% (95% CI 85% to 90%) for Alzheimer’s
disease dementia, 51% (95% CI 33% to 69%) for dementia with Lewy body, 30% (95% CI 21% to 42%) for vasculardementia, and 12% (95% CI 8% to 18%) for frontotemporal dementia 7). In a study examining the predictive accuracy ofamyloid PET for progression from mild cognitive impairment to Alzheimer’s disease dementia, the sensitivity was 94.7%(95% CI 89.8 to 97.7%) and specificity was 57.2% (95% CI 50.1 to 64.2%), and both sensitivity and specificity increased bylong-term follow-up 8).
For proper use of amyloid PET, see CQ6-6.
Amyloid PET and FDG-PET are not covered by health insurance in Japan.

▪ References
1) Cure S, Abrams K, Belger M, et al. Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer’s disease and otherdementia using autopsy as standard of truth. J Alzheimers Dis. 2014; 42(1): 169-182.
2) Scheltens P, Fox N, Barkhof F, et al. Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet
Neurol. 2002; 1(1): 13-21.
3) Liu Y, Yu JT, Wang HF, et al. APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis. J Neurol
Neurosurg Psychiatry. 2015; 86(2): 127-134.
4) Yeo JM, Lim X, Khan Z, et al. Systematic review of the diagnostic utility of SPECT imaging in dementia. Eur Arch Psychiatry Clin Neurosci. 2013;
263(7): 539-552.
5) Bloudek LM, Spackman DE, Blankenburg M, et al. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer’s disease. J
Alzheimers Dis. 2011; 26(4): 627-645.
6) Benzinger TL, Blazey T, Jack CR Jr, et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc Natl Acad
Sci U S A. 2013; 110(47): E4502-E4509.
7) Ossenkoppele R, Jansen WJ, Rabinovici GD, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015;
313(19): 1939-1949.
8) Ma Y, Zhang S, Li J, et al. Predictive accuracy of amyloid imaging for progression from mild cognitive impairment to Alzheimer disease withdifferent lengths of follow-up: a meta-analysis. Medicine. 2014; 93(27): e150.

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▪ Search formula
PubMed search: July 22, 2015 (Wednesday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer* [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND (“Diagnostic
Imaging” [Mesh] OR “magnetic resonance imaging” OR “single-photon emission computed tomography” OR “positron emission tomography” OR“amyloid imaging” OR “tau imaging” OR MRI OR SPECT OR PET)
Ichushi search: July 22, 2015 (Wednesday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH = Diagnostic use,
diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND(Diagnostic imaging/TH OR MRI/TI OR Magnetic resonance imaging OR Magnetic resonance tomography OR Magnetic resonance imaging OR
Nuclear magnetic resonance imaging OR PET/TI OR Positron emission tomography OR Positron emission tomography OR SPECT/TI OR Single
photon emission computed tomography OR Single photon emission computed tomography OR Single photon computed tomography OR Single
photon emission computed tomography OR Single photon emission computed tomography)

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CQ 6-4

Is APOE genetic testing useful for the diagnosis of Alzheimer’s disease dementia?
Answer

The APOE gene ε4 allele is a powerful genetic risk factor for the onset of Alzheimer’s disease dementia in Japanese.
Homozygous carriers of ε4 allele are known to have a higher risk of onset than heterozygous carriers this allele. Currently,
routine testing APOE gene polymorphism is not recommended. In accordance with the Ethical Guidelines for Human
Genome/Gene Analysis Research, explanations to patients and obtaining consent, support by genetic counseling, andconducting genetic testing at specialized facilities are recommended for genetic testing.
C

Comments and evidence

The ε4 allele of apolipoprotein E (APOE) gene polymorphism is a risk factor for the development of Alzheimer’s disease
dementia 1), and the onset rate increases as the number of ε4 alleles increases 2). However, there are also cases where ε4/ε4carriers do not develop Alzheimer’s disease. Therefore, APOE ε4 allele should be understood as a genetic risk factor, not acausative gene. Routine testing for APOE gene polymorphisms is not recommended in the guidelines of the American
Academy of Neurology and the European Federation of Neurological Societies 3, 4). Furthermore, DSM-5 published by theAmerican Psychiatric Association has not clarified the significance of APOE genetic analysis 5). The NIA‒AA diagnostic
criteria for Alzheimer’s disease dementia revised in 2011 state that carrier state of APOE ε4 allele does not have sufficient
specificity for the diagnosis of Alzheimer’s disease dementia 6). Regarding disclosure of APOE genotyping result, althoughtest-related stress is reduced in adults who were informed that their APOE gene ε4 testing result was negative, adults withstrong psychological stress before undergoing genetic testing tended to have strong psychological stress also after disclosure.
Disclosure of APOE genotyping result did not pose a significant psychological risk in the short term 7).
Regarding genetic testing, the Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health,
Labor and Welfare; and the Ministry of Economy, Trade and Industry published the “Ethical Guidelines for Human
Genome/Gene Analysis Research” (partially revised on November 25, 2014). See also “Guidelines on Genetic Diagnosis of
Neurological Diseases, 2009” developed by the Japanese Society of Neurology 8).

▪ References
1) Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele
in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90(5): 1977-1981.
2) Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s
disease. Neurology. 1993; 43(8): 1467-1472.
3) Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia(an evidence-based review). Report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56(9): 1143-1153.
4) Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associatedwith dementia: EFNS guideline. Eur J Neurol. 2007; 14(1): e1-26.
5) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. Arlington, VA: American
Psychiatric Association; 2013.
6) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
7) Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009; 361(3): 245-254.
8) “Guidelines on Genetic Diagnosis of Neurological Diseases” Preparation Committee (Ed.). Japanese Society of Neurology (Supervision). Guidelines
on Genetic Diagnosis of Neurological Diseases, 2009. Tokyo: Igaku Shoin; 2009. (In Japanese)▪ Search formula
PubMed search: July 23, 2015 (Thursday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer* [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND(“Apolipoproteins E” [Mesh] OR “Apolipoproteins E” [TI])
Ichushi search: July 22, 2015 (Wednesday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH = Diagnostic
use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND(“Apolipoproteins E”/TH OR “Apolipoproteins E”/TI OR “Apolipoprotein E”/TI OR ApoE [TI])142

Clinical Practice Guideline for Dementia 2017

CQ 6-5

What are the useful biomarkers for the diagnosis of Alzheimer’s disease dementia?
AnswerMany large-scale prospective studies have provided evidence for decreased Aβ42 level and increased total tau or
phosphorylated tau level in cerebrospinal fluid (CSF) as biomarkers for the diagnosis and prediction of onset of Alzheimer’s
disease dementia. The Dominantly Inherited Alzheimer Network (DIAN) study, an observational study of autosomal
dominant Alzheimer’s disease, reports that Aβ42 decreases from 25 years and total tau increases from 15 years before theestimated onset age. The NIA-AA criteria recommend use of these biomarkers for research in Alzheimer’s disease dementia
and mild cognitive impairment, while the IWG-2 advancing research diagnostic criteria for Alzheimer’s disease dementia
include these markers as tests required for diagnosis.
A

Comments and evidence
Decrease in cerebrospinal fluid (CSF) Aβ42 level correlates with the amount of Aβ deposition in brain. Increases in CSF
total tau and phosphorylated tau levels reflect neurofibrillary tangles and neuronal death. The evidence of these biomarkers
has been confirmed by many large-scale multicenter prospective studies. When used alone, Aβ42 has the best accuracy(sensitivity 81-96%, specificity 77-89%), and a combination of Aβ42 and total tau or phosphorylated tau may further
improve the accuracy of diagnosis (sensitivity 60-92%, specificity 47-93%). Moreover, these markers have been reported to
be predictive markers for the development of Alzheimer’s disease dementia from a healthy state or from mild cognitive
impairment (MCI) (combination of Aβ42 with total tau or phosphorylated tau; sensitivity 83-98%, specificity 38-90%).
The Alzheimer’s Disease Neuroimaging Initiative (ADNI), which was started in 2004 in the United States aiming toelucidate the factors associated with early diagnosis and onset of Alzheimer’s disease dementia, has generated a large volume
of evidence in biomarker research 1). The Dominantly Inherited Alzheimer Network (DIAN) study has revealed that CSF
Aβ42 level decreases in autosomal dominant Alzheimer’s disease from 25 years before the estimated age of dementia onset,
thus establishing CSF Aβ42 as the biomarker showing the earliest change. An increase in CSF tau level is detected 15 years
before dementia onset and is considered to be a secondary marker for neuronal injury 2). In 2011, NIA‒AA incorporated
elevated CSF tau level as a biomarker for “probable AD dementia with evidence of the AD pathophysiological process” in the
new diagnostic criteria for Alzheimer’s disease dementia 3). Furthermore, in 2014, in the advancing research diagnostic
criteria for Alzheimer’s disease (IWG-2 criteria), a combination of decreased Aβ42 with increased total tau or phosphorylated
tau has been included as a marker that reflects Alzheimer’s disease pathological findings required for the diagnosis of
Alzheimer’s disease dementia 4). While a clinical diagnosis can be made using major clinical diagnostic criteria alone,biomarker measurements are recommended for clinical research and interventional studies.
The issues of using CSF biomarkers for clinical diagnosis include variability of measured values among facilities, andfluctuation of values depending on sampling methods and storage conditions. Therefore, standardization of CSF handling,measurement methods and cut-off points is considered necessary, and standard measurement methods have been proposed 5).
Although the differentiation of Alzheimer’s disease dementia from normal controls has high diagnostic sensitivity and specificity,
overlap occurs with other dementia subtypes. Especially since CSF Aβ42 level also decreases in dementia with Lewy bodies,differentiation is difficult using CSF Aβ42 alone 6). In Japan, total tau measurement in CSF is covered by health insurance forthe diagnosis of Creutzfeldt-Jakob disease, and phosphorylated tau measurement in CSF is covered by insurance for differential
diagnosis of dementia.

▪ References
1) Weiner MW, Veitch DP, Aisen PS, et al. 2014 Update of the Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its
inception. Alzheimers Dement. 2015; 11(6): e1-e120.
2) Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;
367(9): 795-804.
3) McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263-269.
4) Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6): 614-629.
5) Molinuevo JL, Blennow K, Dubois B, et al. e clinical use of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper

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from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement. 2014; 10(6): 808-817.
6) Ewers M, Mattsson N, Minthon L, et al. CSF biomarkers for the differential diagnosis of Alzheimer’s disease. A large-scale international multicenter
study. Alzheimers Dement. 2015; 11(11): 1306-1315.

▪ Search formula
PubMed search: July 23, 2015 (Thursday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer* [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND (“BiologicalMarkers” [Majr] OR biological marker* [TI] OR biomarker* [TI] OR “Hematologic Tests” [Mesh] OR hematologic test* [TI] OR blood test* [TI]
OR “Cerebrospinal Fluid” [Mesh] OR “cerebrospinal fluid” [TI] OR CSF [TI] OR “cerebrospinal fluid” [subheading])
Ichushi search: July 23, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH = Diagnostic
use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND(Biological marker/MTH OR Biological marker/TI OR Biomarker/TI OR Blood test/TH OR Hematological test/TI OR Blood test/TI OR
Cerebrospinal fluid test/TH or Cerebrospinal fluid test/TI)

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CQ 6-6

Is amyloid PET examination useful for the diagnosis of Alzheimer’s disease
dementia?
Answer
The positive rates of amyloid PET examination are approximately 98% for Alzheimer’s disease dementia, approximately
68% for mild cognitive impairment (MCI), and 33% in healthy older persons. Amyloid PET negativity is useful fordifferentiating non-Alzheimer’s disease dementia. In the NIA-AA criteria and IWG-2 advancing research diagnostic
criteria for Alzheimer’s disease, amyloid PET examination is required as a biomarker of brain amyloid deposition.
Participation in clinical studies requires consent, and general clinical use should conform to appropriate guidelines.
Amyloid PET examination is not covered by health insurance in Japan.
A

Comments and evidence

Many studies have demonstrated the disposition of amyloid β (Aβ) before onset of Alzheimer’s disease dementia. Aβ depositionis one of the required items in NIA-AA diagnostic criteria and IWG-2 AD advancing research criteria. However, amyloid
deposition is observed in 10.4% of people aged 50 years and in 43.8% of healthy older people at age 90. Moreover, Aβ depositionis also observed in dementia-related diseases other than Alzheimer’s disease dementia, such as dementia with Lewy bodies.
Therefore, although amyloid PET is useful for differentiating Alzheimer’s disease dementia from non-Alzheimer’s disease
dementia, when amyloid PET is used in clinical diagnosis, attention is required in patient selection and interpretation of results.
Furthermore, the needs for consent, disclosure, counseling, education, and psychological support are emphasized.
In 2013, the Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association jointly developed theworld’s first appropriate use criteria for amyloid PET that can be used in clinical practice 1). Experts concluded that use of
amyloid PET requires the following: (1) a cognitive complaint with objectively confirmed cognitive impairment; (2)Alzheimer’s disease as a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by adementia expert; and (3) when knowledge of the presence or absence of amyloid-beta pathology is expected to increase
diagnostic certainty and alter management. The document also provides examples of appropriate and inappropriate use.
Furthermore, an update of the criteria expands the following topics: (1) defining dementia experts and their use of proper
documentation to demonstrate the medical necessity of an amyloid PET scan; (2) identifying a specific subset of individuals
with mild cognitive impairment for whom an amyloid PET scan is appropriate; and (3) developing educational programs forappropriate use of amyloid PET 2).
Recommendation from the Italian Interdisciplinary Working Group for the clinical use of amyloid imaging limits the use
to patients with objective cognitive impairment of unknown cause, in whom amyloid PET results are expected to be usefulfor diagnostic accuracy and treatment 3). In Japan, use of amyloid PET should comply with the Guidelines for Proper Use of
Amyloid PET Imaging Agent Synthesis Device (released in April 2015) developed by the Joint Working Group of theJapanese Society of Nuclear Medicine, Japan Society for Dementia Research, and Japanese Society of Neurology 4). According
to the guidelines, proper use is defined as follows: (1) dementia patients with atypical clinical symptoms, in whom a definitive
diagnosis is required for appropriate treatment; and (2) patients with atypical onset age (onset age younger than 65 years), in
whom a definitive diagnosis is required for appropriate treatment. Use for mild cognitive impairment is not recommended.

▪ References
1) Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of
Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013; 9(1): e1-e16.
2) Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive
impairment, and education. Amyloid Imaging Task Force of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging.
Alzheimers Dement. 2013; 9(4): e106-e109.
3) Guerra UP, Nobili FM, Padovani A, et al. Recommendations from the Italian Interdisciplinary Working Group (AIMN, AIP, SINDEM) for theutilization of amyloid imaging in clinical practice. Neurol Sci. 2015; 36(6): 1075-1081.
4) Ministry of Health, Labour and Welfare Study Group “Multicenter clinical study on the clinical use of amyloid imaging as a method of risk
prediction of Alzheimer’s disease onset”. Guidelines for Proper Use of Amyloid PET Imaging Agent Synthesis Device, first edition, 2015. (inJapanese)

Chapter 6145▪ Search formula
PubMed search: July 23, 2015 (Thursday)#1 (“Alzheimer Disease/diagnosis” [Majr] OR (Alzheimer* [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND (“PositronEmission Tomography” [Mesh] OR “positron emission tomography” OR PET [TI]) AND (Amyloid [Mesh] OR amyloid* [TI])
Ichushi search: July 23, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH = Diagnostic
use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI) AND(“amyloid pet”/TI OR Amyloid PET/TI OR ((Positron emission tomography/TH OR PET/TI OR Positron emission tomography OR Positronemission tomography) AND (Amyloid/TH OR Amyloid/TI)))

146

Clinical Practice Guideline for Dementia 2017

CQ 6-7

What are the pharmacotherapy and treatment algorithms for Alzheimer’s
disease dementia?
Recommendation
The currently available drugs for improving cognitive function in Alzheimer’s disease dementia are the threecholinesterase inhibitors (ChEIs); donepezil, galantamine, and rivastigmine, as well as the NMDA receptor antagonist
memantine. Scientific evidence of efficacy has been demonstrated for both classes of drugs, and their use is recommended.

1A

Comments and evidence

1. Cholinesterase inhibitors (ChEIs)
Currently, three ChEIs are available; namely, donepezil, galantamine, and rivastigmine. A Cochrane Systematic Review
analyzed 10 randomized controlled trials (RCTs) in patients with mild to severe Alzheimer’s disease dementia. Treatment
with ChEIs improves the cognitive part of the Alzheimer’s Disease Assessment Scale (ADAS-cog) by 2.37 points on averagewith good clinician-rated global clinical state, and efficacy for activities of daily living (ADL) and behaviors was also
observed. Similar effects were observed in patients with severe Alzheimer’s disease dementia, although evidence wasinadequate because there were only two RCTs. Adverse events such as nausea, vomiting, and diarrhea were significantly more
frequent compared to the placebo group. In conclusion, although there are some differences in mechanism of action among
the three drugs, there are no remarkable differences in effectiveness, and ChEIs are recommended for mild to moderate
Alzheimer’s disease dementia 1).
In a systematic review of 96 publications on 59 clinical trials of ChEIs and memantine, treatment of dementia with ChEIs
and memantine was significantly effective, but clinical improvements in cognitive function and global assessment were mild 2).
The systematic review and meta-analysis reported by Hansen et al. 3) showed no difference in efficacy between the three ChEIs
on cognitive function, but found slight differences in the effects on global function and behavioral disorder as well as thefrequency of adverse events. In a systematic review and meta-analysis of global reports on the three ChEIs and memantine, allfour drugs, including galantamine capsule 32 mg/day, were efficacious for cognitive function. Only donepezil 10 mg/day andgalantamine 24 mg/day were effective for behavioral disorders. Donepezil 5 mg/day had no effect on functional outcome. There
were significantly more dropouts from clinical trials and more adverse events in the ChEIs group than in the placebo group 4).
A systematic review of seven RCTs on rivastigmine capsule (6-12 mg/day) and patch (9.5 mg/day) showed that bothformulations reduced the rates of cognitive decline and ADL decline in mild to moderate Alzheimer’s disease dementia, withgood clinician-rated global clinical state. There were fewer side effects using the patch than using the capsule 5). A 24-week
RCT of rivastigmine patch conducted in Japan reported improvement in ADAS-J cog at a dose of 18 mg/day with rare
serious adverse events 6).
Although treatment with donepezil for very mild Alzheimer’s disease dementia does not prevent the progression ofhippocampus atrophy 7), administration of donepezil to patients with mild cognitive impairment for one year has beenreported to decrease the progression of hippocampal atrophy by 45% 8).

2. NMDA receptor antagonist: memantine
In a RCT conducted by the Memantine Study Group in which 252 patients with moderate to severe Alzheimer’s disease
dementia were treated with memantine 20 mg/day for 28 weeks, global function was assessed by Clinician’s Interview-Based
Impression of Change Plus Caregiver Input (CIBIC-Plus), ADL was assessed by Alzheimer’s Disease Cooperative Study
Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev), and cognitive function was assessed by
Severe Impairment Battery (SIB). Significant improvements were observed in all the scales, and memantine was considered
to be effective 9). In a Cochrane Systematic Review of two RCTs on memantine for moderate to severe Alzheimer’s disease
dementia, mild improvements were found in assessments by SIB, ADCS-ADLsev, Neuropsychiatric Inventory (NPI), and
CIBIC-Plus. Patients with severe Alzheimer’s disease dementia were less likely to develop irritability, and the drug was welltolerated 10).
Doody et al. 11) conducted a meta-analysis of six RCTs, and reported that memantine was effective for Alzheimer’s disease

Chapter 6147dementia of all stages. Especially, efficacy was observed for behavioral disorders in moderate to severe dementia, and forcognitive function in mild to moderate dementia. In a meta-analysis of nine RCTs for moderate to severe Alzheimer’s disease
dementia conducted by Wilkinson et al. 12), memantine 20 mg/day was effective for cognitive function, ADL, and global
assessment scale, and ameliorated clinical worsening 12). A meta-analysis of 13 RCTs for mild to severe Alzheimer’s disease
dementia conducted by Jiang et al. 13) confirmed that memantine was beneficial for cognitive function, mental status, ADL,
and clinical global impression, and while the drug did not increase the number of all adverse events, serious adverse eventsor death, the risk of somnolence was elevated. Similarly, phase II and phase III clinical trials in Japanese patients have shown
memantine to be effective for moderate to severe Alzheimer’s disease dementia 14).
In a meta-analysis of three RCTs on memantine for mild to moderate Alzheimer’s disease dementia, no improvements in
ADAS-cog, CIBIC-Plus, ADCS-ADLsev, and NPI were found in patients with mild Alzheimer’s disease dementia, andefficacy was not proven 15).

3. Severe Alzheimer’s disease dementia
Four RCTs on donepezil, one RCT on galantamine, and one meta-analysis were identified. The RCT reported by Winblad
et al. 16) showed improvements in SIB and ADCS-ADLsev after 6-month treatment with 5-10 mg of donepezil. In thedonepezil group, although there were many cases of discontinuation due to adverse events, the drug was effective inmaintaining cognitive function and ADL even in patients with severe Alzheimer’s disease dementia 16). In the RCT reported
by Black et al. 17), donepezil was effective when assessed by SIB, CIBIC-Plus and Mini-Mental State Examination (MMSE),
but no effect was observed when evaluated by ADCS-ADLsev, NPI, Caregiver Burden Questionnaire (CBQ) and Resource
Utilization for Severe Alzheimer Disease Patients (RUSP). In a Japanese multicenter trial consisting of a 6-month RCT
followed by a 52-week open-label study reported by Homma et al. 18), efficacy and safety were maintained for at least 1 year,
and the effect was sustained in the group that continued taking donepezil 10 mg/day without interruption. In a Japanese
RCT in patients with severe Alzheimer’s disease dementia, there were no significant differences in SIB and CIBIC-Plus
scores between doses of 23 mg/day and 10 mg/day, indicating that the appropriate dose in Japan is 10 mg/day 19 ).
In one RCT for severe Alzheimer’s disease dementia, galantamine 24 mg/day improved cognitive function (SIB) but did
not improve ADL 20). In a meta-analysis on the efficacy of ChEIs and memantine in relation to severity of Alzheimer’s disease
dementia, all the drugs tested slightly improved cognitive function, ADL, and BPSD regardless of disease severity, and theimprovement of ADL by memantine was more marked in severe patients 21).

4. Combination of ChEIs with memantine
In a RCT in which patients with moderate to severe Alzheimer’s disease dementia already receiving oral donepezil were
given memantine 20 mg in combination for 24 weeks, significant improvements in SBT, ADCS-ADL19, and CIBIC-Plus
scores were observed 22). In the same RCT, when abnormal behaviors were evaluated using NPI, using memantine in
combination significantly decreased NPI scores compared to donepezil alone. Among 12 items in NPI, significant
improvements were seen in agitation/aggression, appetite, and irritability/lability 23). The DOMINO-AD study enrolled 295
patients with moderate to severe Alzheimer’s disease dementia who were treated with donepezil 10 mg for 3 months, followedby random allocation to with or without memantine in combination for 52 weeks. Differences in MMSE and Bristol Activityof Daily Living Scale (BADLS) scores were observed between the continued donepezil group and discontinued donepezil
group, and between the donepezil-with-memantine group and donepezil-with-placebo group, but the differences did notreach statistical significance. Therefore, the beneficial effect of using a combination of donepezil with memantine was notproven 24). In a sub-analysis of a follow-up study for 3 years after completion of the DOMINO-AD study, the risk ofadmission to nursing homes increased in the group that discontinued donepezil during the first year 25). Therefore, caution
should be exercised in discontinuing drug treatment.
In a RCT in which patients with moderate to severe Alzheimer’s disease dementia already treated with ChEIs were given
memantine 28 mg in combination for 24 weeks, combination with memantine significantly improved SIB, CIBIC-Plus,
NPI, and verbal frequency test scores, but there was no significant difference in ADCS-ADL19 score 26). There are few
systematic reviews of combination therapies 27, 28). Farrimond et al. 27) reported a systematic review and meta-analysis of three
RCTs that evaluated combined memantine and ChEIs therapy for moderate to severe Alzheimer’s disease dementia, whichshowed minor improvements in global score, cognitive function, behavior, and mood.
No benefits of combined ChEIs and memantine therapy were found in patients with mild to moderate Alzheimer’s disease
dementia 29).
It has been pointed out that in addition to RCT, long-term observational studies are important for determining the effects
of anti-dementia drugs in delaying the progression of Alzheimer’s disease dementia 30). A longitudinal observational study

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that followed 201 patients with Alzheimer’s disease dementia for 6 years reported that use of ChEIs prolonged the time tofunctional impairment and death, while memantine prolonged the time to death 31).

5. Methods of using various drugs
For insurance-covered medical care in Japan, all drugs are gradually up-titrated while paying attention to adverse effects.
Titration up to 10 mg of donepezil is approved for severe Alzheimer’s disease dementia. Memantine is indicated for moderate
to severe Alzheimer’s disease dementia and can be used in combination with ChEIs. Regarding the rivastigmine patch, in
addition to the conventional three-step titration method, a one-step titration method from 9 mg/day to 18 mg/day for welltolerated cases can also be used. For details of adverse effects, refer to the package insert of each drug and CQ3A-6.

6. Treatment algorithm(1) Mild: Select and administer one of the ChEIs considering the characteristics of each drug. Consider changing to another
ChEIs when there is no or inadequate response to the drug being used, when the effect is attenuated, or when the drug
has to be discontinued due to adverse effects.
(2) Moderate: Select and administer one ChEIs or memantine considering the characteristics of each drug. Change toanother ChEIs or to memantine, or consider using ChEIs and memantine in combination (if combination is not used),
when there is no or inadequate response to the drug being used, when the effect is attenuated, or when the drug has tobe discontinued due to adverse effects.
(3) Severe: Consider using donepezil 5-10 mg, or memantine, or a combination of both. Consider also discontinuation if
both drugs are ineffective or the drugs cannot be continued due to adverse effects. However, there are cases in which
cognitive impairment progresses rapidly after drug withdrawal. Treatment discontinuation has to be judged withcaution.

▪ References
1) Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006; (1): CD005593.
2) Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinicalpractice guideline. Ann Intern Med. 2008; 148(5): 379-397.
3) Hansen RA, Gartlehner G, Webb AP, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease:a systematic review and meta-analysis. Clin Interv Aging. 2008; 3(2): 211-225.
4) Tan CC, Yu JT, Wang HF, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s
disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014; 41(2): 615-631.
5) Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2015; 9: CD001191. [Epub ahead of print]
6) Nakamura Y, Imai Y, Shigeta M, et al. A 24-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety and tolerabilityof the rivastigmine patch in Japanese patients with Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2011; 1(1): 163-179.
7) Wang L, Harms MP, Staggs JM, et al. Donepezil treatment and changes in hippocampal structure in very mild Alzheimer disease. Arch Neurol.
2010; 67(1): 99-106.
8) Dubois B, Chupin M, Hampel H, et al. Hippocampus Study Group. Donepezil decreases annual rate of hippocampal atrophy in suspected
prodromal Alzheimer’s disease. Alzheimers Dement. 2015; 11(9): 1041-1049.
9) Reisberg B, Doody R, Stoer A, et al; Memantine Study Group. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003; 348(14):1333-1341.
10) McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006; (2): CD003154.
11) Doody RS, Tariot PN, Pfeiffer E, et al. Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimers Dement. 2007; 3(1): 7-17.
12) Wilkinson D, Wirth Y, Goebel C. Memantine in patients with moderate to severe Alzheimer’s disease: meta-analyses using realistic definitions ofresponse. Dement Geriatr Cogn Disord. 2014; 37(1-2): 71-85.
13) Jiang J, Jiang H. Efficacy and adverse effects of memantine treatment for Alzheimer’s disease from randomized controlled trials. Neurol Sci. 2015;
36(9): 1633-1641.
14) Nakamura Y, Kitamura S, Homma A, et al. Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer’s disease: results of apooled analysis of two randomized, double-blind, placebo-controlled trials in Japan. Expert Opin Pharmacother. 2014; 15(7): 913-925.
15) Schneider LS, Dagerman KS, Higgins JP, et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011 Aug;68(8): 991-998.
16) Winblad B, Kilander L, Eriksson S, et al; Severe Alzheimer’s Disease Study Group. Donepezil in patients with severe Alzheimer’s disease: doubleblind, parallel-group, placebo-controlled study. Lancet. 2006 Apr 1; 367(9516): 10571065. Erratum in: Lancet. 2006; 368(9548): 1650. Lancet.
2006; 367(9527): 1980.
17) Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology. 2007;
69(5): 459-469.
18) Homma A, Imai Y, Tago H, et al. Long-term safety and efficacy of donepezil in patients with severe Alzheimer’s disease: results from a 52-week,
open-label, multicenter, extension study in Japan. Dement Geriatr Cogn Disord. 2009; 27(3): 232-239.
19) Homma A, Atarashi H, Kubota N, et al. Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil

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Standard Dose in Japanese Patients with Severe Alzheimer’s Disease: A Randomized, Double-Blind Trial. J Alzheimers Dis. 2016; 52(1): 345-357.
20) Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease(the SERAD study): a randomised,
placebo-controlled, double-blind trial. Lancet Neurol. 2009; 8(1): 39-47.
21) Di Santo SG, Prinelli F, Adorni F, et al. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation toseverity of Alzheimer’s disease. J Alzheimers Dis. 2013; 35(2): 349-361.
22) Tariot PN, Farlow MR, Grossberg GT, et al; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease
already receiving donepezil: a randomized controlled trial. JAMA. 2004; 291(3): 317-324.
23) Cummings JL, Schneider E, Tariot PN, et al; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease
patients receiving donepezil treatment. Neurology. 2006; 67(1): 57-63.
24) Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012; 366(10):893-903.
25) Howard R, McShane R, Lindesay J, et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease(DOMINO-AD)trial: secondary and post-hoc analyses. Lancet Neurol. 2015; 14(12): 1171-1181.
26) Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized,
double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs. 2013;27(6): 469-478.
27) Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: a systematic review.
BMJ Open. 2012; 2(3). pii: e000917.
28) Matsunaga S, Kishi T, Iwata M. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: A systematic review
and meta-analysis. Int J Neuropsychopharmacol. 2015; 1-11.
29) Porsteinsson AP, Grossberg GT, Mintzer J, et al; Memantine MEM-MD-12 Study Group. Memantine treatment in patients with mild to moderate
Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008;
5(1): 83-89.
30) Rountree SD, Atri A, Lopez OL, et al. Effectiveness of antidementia drugs in delaying Alzheimer’s disease progression. Alzheimers Dement. 2013;
9(3): 338-345.
31) Zhu CW, Livote EE, Scarmeas N, et al. Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among
patients with Alzheimer’s disease. Alzheimers Dement. 2013; 9(6): 733-740.

▪ Search formula
PubMed search: July 23, 2015 (Thursday)#1 (“Alzheimer Disease/drug therapy” [Majr] OR (Alzheimer* [TI] AND (“drug therapy” [TI] OR chemotherapy [TI] OR pharmacotherapy [TI]
OR “pharmacological therapy” [TI]))) AND (Algorithms [Mesh] OR algorithm* [TI] OR NMDA antagonist* [TI] OR “Receptors, N-Methyl-DAspartate/antagonists and inhibitors” [Mesh] OR “N-Methylaspartate/antagonists and inhibitors” [Mesh] OR “Cholinesterase Inhibitors” [Mesh]
OR cholinesterase inhibitor* [TI])
Ichushi search: July 22, 2015 (Wednesday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH =Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI OR Antipsychotics/TH OR Therapeutic drug/TI)
AND (Algorithm/TH OR Algorithm/TI OR Algorithm/TI OR “NMDA Receptor Antagonists”/TH OR “NMDA Receptor Antagonist”/TI OR
NMDA receptor antagonist/TI OR NMDA antagonist/TI OR NMDA receptor blocker/TI OR NMDA receptor inhibitor/TI OR ((“NMDA
Receptors”/TH) AND (SH = Antagonist·Inhibitor)) OR (“NMDA Receptor”/TI AND (Antagonize/TI OR Inhibit/TI)) OR ((N-Methylaspartate/TH) AND (SH = Antagonist·Inhibitor)) OR ((N-Methylaspartate/TI) AND (Antagonize/TI OR Inhibit/TI)) OR “Cholinesterase Inhibitors”/TH
OR “Cholinesterase Inhibitors”/TI)

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CQ 6-8What are the effects of non-pharmacological therapies for Alzheimer’s disease
dementia?
Answer
The therapeutic effects of non-pharmacological therapies depend largely on the patient’s preference and the capabilityof the practitioner. Therefore, it is not meaningful to decide whether a therapy is superior or inferior. It is important thatthe patient participate willingly in therapy, and it is desirable to use multiple therapies as needed.
C

Comments and evidence
Non-pharmacological therapies should be given priority over pharmacotherapy in the treatment of behavioral andpsychological symptoms of dementia (BPSD). However, it should be noted that even non-pharmacological therapies may
have negative effects. See CQ3A-7-1, 2 and CQ4C-1 for non-pharmacological therapies for dementia in general, and CQ3B1-7 for the effects of non-pharmacological therapies for BPSD.

1. Approach focusing on cognition
Cognitive stimulation (therapy) was originally developed from reality orientation, but now includes various miscellaneous
elements. Although certain effects on cognitive function can be expected in patients with Alzheimer’s disease dementia, theevidence level is low 1).
A meta-analysis has reported that cognitive training is beneficial for improving overall cognitive function in Alzheimer’s
disease dementia 2). However, the validity of this analysis remains questionable due to the issues of quality of the trials andheterogeneity among studies 3).

2. Approaches focusing on aspects other than cognition
There are few RCTs on reminiscence therapy for Alzheimer’s disease dementia, and it is difficult to confirm whether thistherapy is effective 4, 5).
Exercise therapy attenuates worsening of physical function and activities of daily living (ADL) in Alzheimer’s disease
dementia 6, 7). In addition, although the possibility that exercise therapy may slow the decline in cognitive function has beensuggested 8), heterogeneity between studies is high 7).
Music therapy is considered to be effective to some extent in improving BPSD, including anxiety, but the level of evidence
is low because of the issues of quality of research and heterogeneity among studies 9, 10).

▪ References
1) Woods B, Aguirre E, Spector AE, et al. Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database Syst
Rev. 2012; 2: CD005562.
2) Bahar-Fuchs A, Clare L, Woods B. Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer’s disease and vascular dementia.
Cochrane Database Syst Rev. 2013; (6): CD003260.
3) Alves J, Magalhaes R, Thomas RE, et al. Is there evidence for cognitive intervention in Alzheimer disease? A systematic review of efficacy, feasibility,
and cost-effectiveness. Alzheimer Dis Assoc Disord. 2013; 27(3): 195-203.
4) Woods B, Spector AE, Jones CA, et al. Reminiscence therapy for dementia. Cochrane Database Syst Rev. 2005; (2): CD001120.(Woods B, Spector
A, Jones C, Orrell M, Davies S. Reminiscence therapy for dementia. Cochrane Dementia and Cognitive Improvement Group, Cochrane Database
Syst. Rev. 2009; 1)
5) Huang HC, Chen YT, Chen PY, et al. Reminiscence therapy improves cognitive functions and reduces depressive symptoms in elderly people withdementia: A meta-analysis of randomized controlled trials. J Am Med Dir Assoc. 2015; 16(12): 1087-1094.
6) Pitkala K, Savikko N, Poysti M, et al. Efficacy of physical exercise intervention on mobility and physical functioning in older people with dementia:
a systematic review. Exp Gerontol. 2013; 48(1): 85-93.
7) Forbes D, Forbes SC, Blake CM, et al. Exercise programs for people with dementia. Cochrane Database Syst. Rev. 2015; (4): CD006489.
8) Farina N, Rusted J, Tabet N. The effect of exercise interventions on cognitive outcome in Alzheimer’s disease: a systematic review. Int Psychogeriatr.
2014; 26(1): 9-18.
9) Vink AC, Bruinsma MS, Scholten RJPM. Music therapy for people with dementia. Cochrane Database Syst Rev. 2004; (3): CD003477.(Vink AC,
Bruinsma MS, Scholten RJPM. Music therapy for people with dementia. Cochrane Database Syst. Rev. 2013; 9)10) Ueda T, Suzukamo Y, Sato M, et al. Effects of music therapy on behavioral and psychological symptoms of dementia: a systematic review and meta-

Chapter 6151

analysis. Ageing Res Rev. 2013; 12(2): 628-641.
(References 1, 4-7, 9 and 10 were identified through manual search)▪ Search formula
PubMed search: July 2, 2015 (Thursday)#1 (“Alzheimer Disease/therapy” [Majr] OR (Alzheimer [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) NOT (“Alzheimer
Disease/drug therapy” [Mesh] OR (Alzheimer [TI] AND (“drug therapy” [TI] OR chemotherapy [TI] OR “endocrine therapy” [TI])))
Ichushi search: July 2, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND Dementia/TH OR Dementia TI)) AND ((SH = Therapeuticuse, Treatment, Surgical treatment, Transplantation, Dietary therapy, Psychological therapy, Radiation therapy) OR Treatment/TI OR Therapy/TI)) NOT ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI OR ((Alzheimer/TI) AND (Dementia/TH OR Dementia/TI))) AND ((SH =Pharmacotherapy) OR Pharmacotherapy/TH OR Pharmacological action/TH OR Pharmacotherapy/TI OR Drug treatment/TI OR Chemotherapy/
TI))

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CQ 6-9What are the key points in care for Alzheimer’s disease dementia?
Answer
It is important to respect the patient’s intentions and respond with respect and empathy. Since there is no establishedcare method specially for Alzheimer’s disease dementia, care for dementia in general can be applied to Alzheimer’s disease
dementia. The concept of person-centered care and techniques such as validation have been proposed.

Comments and evidence
Obtaining medical evidence in the field of care is a difficult task, and a low level of evidence does not mean that care isineffective. Respecting the intentions of a patient with dementia and responding with respect and empathy are related to thepatient’s dignity as a person, and is a principle that should be observed regardless of the existence of evidence. Refer to
CQ3A-7-1 and CQ4C-1-5 for care and guidance support for dementia in general.
Regarding caregivers’ attitudes to patients with dementia, the general principles recommended by the American Psychiatric
Association (APA) treatment guidelines are as follows 1):• recognize patient’s decline in capacity, avoid over-expectation• pay attention to rapid progression and emergence of new symptoms• keep requests and demands simple,• change requests if the patient becomes overly upset or angered• avoid difficult tasks that may lead to frustration• do not confront patients to face their impairment• remain calm, firm, and supportive• avoid unnecessary changes• explain in detail and provide cues to maintain patient’s orientation
Explain interventions also to caregivers. RCTs focusing on Alzheimer’s disease dementia have reported that providing
education/support and stress management to caregivers reduce patients’ behavioral and psychological symptoms of dementia(BPSD), care burden, and caregivers’ depression, subsequently delaying admission to care facilities 2-5). However, heterogeneity
among studies is high due to factors such as diversity of intervention methods. Currently, the evidence level is low.

▪ References
1) APA Work Group on Alzheimer’s Disease and other Dementias, Rabins PV, Blacker D, et al. American Psychiatric Association practice guideline
for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry. 2007; 164(12 Suppl): 5-56.
2) Livingston G, Johnston K, Katona C, et al. Systematic review of psychological approaches to the management of neuropsychiatric symptoms ofdementia. Am J Psychiatry. 2005; 162(11): 1996-2021.
3) Olazaran J, Reisberg B, Clare L, et al. Nonpharmacological therapies in Alzheimer’s disease: a systematic review of efficacy. Dement Geriatr Cogn
Disord. 2010; 30(2): 161-178.
4) Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;
169(9): 946-953.
5) Jensen M, Agbata IN, Canavan M, et al. Effectiveness of educational interventions for informal caregivers of individuals with dementia residing in
the community: systematic review and meta-analysis of randomised controlled trials. Int J Geriatr Psychiatry. 2015; 30(2): 130-143.
(References 2-5 were identified through manual search)▪ Search formula
PubMed search: July 2, 2015 (Thursday)#1 (“Alzheimer Disease/therapy” [Majr] OR (Alzheimer [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) AND (“Counseling”[Mesh] OR counsel* [TI] OR “Patient Care” [Majr] OR care [TI] OR intervention [TI])
Ichushi search: July 2, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND (Dementia/TH OR Dementia/TI)) AND (Patient management/
TH OR Counseling/TH OR Care/TI OR Counseling/TI)

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CQ 6-10

What kind of social support is available for Alzheimer’s disease dementia?
AnswerIn order to reduce the care burden, active utilization of social support is necessary from the early stage of disease.
It is desirable to have some knowledge about the available systems and social support.

Comments and evidence
Refer to CQ5C-1 to 4 for details of financial support and daily living support for early-onset dementia.

1. Public long-term care
Persons aged 40 years and above who have dementia-related diseases are eligible to use long-term care insurance services 1).
In-home long-term care support (home services) including visiting services (such as home-visit long-term care and homevisit nursing), day services/daycare (day rehabilitation), and short stay services are important 1, 2). For home-visit long-termcare, home helpers visit the homes of persons with dementia to provide care for daily living. For day services/daycare, persons
with dementia visit facilities during the day and receive care or rehabilitation. For short stay services, persons with dementia
are admitted to facilities that provide facility care support for a short period of time. Group home (communal long-term carefor dementia) belongs to in-home long-term care support within the long-term care insurance system 1). Other in-home care
support includes home-visit rehabilitation and home-visit bathing service 3).
There are three types of facility care support: long-term care welfare facilities for older people (special nursing homes forolder people), long-term care health facilities for older people (health facilities for older people), and long-term caresanatorium-type medical facility (medical care facilities) 1). In addition, as one of the community-based services,multifunctional long-term care in small group home allows the provision of day service, home-visit services and overnight
stay services in one facility 1).

2. Medical care
Daycare provided by medical care insurance includes daycare for persons with severe dementia. In-patient facilities include
dementia treatment wards 1).

3. Organization for persons affected by dementia
As an organization for persons affected by dementia, the “Alzheimer’s Association Japan” is a private organization for
persons with dementia and their families, and is an active organization with branches in all the prefectures. Activities include“telephone helpline service for dementia” 1).

▪ References
1) Miyake Y. Social resources (Chapter 4: Treatment and Care). Tahira T (Ed.) Latest Medical Supplement, Alzheimer’s Disease Dementia, 2ndrevision. Osaka: Saishin Igakusha; 2014: 184-193. (In Japanese)
2) Awata S. Mechanism in the community to support persons with dementia. Bio Clin. 2014; 29(7): 635-639. (In Japanese)3) Endo H. Integrated medical care, collaboration (Chapter 4: Treatment and Care). Tahira T (Ed.) Latest Medical Supplement, Alzheimer’s Disease
Dementia, 2nd revision. Osaka: Saishin Igakusha; 2014: 184-193. (In Japanese)▪ Search formula
PubMed search: July 2, 2015 (Thursday)#1 (“Alzheimer Disease” [Majr] OR Alzheimer [TI]) AND (“Social Support” [Mesh] OR social support* [TI] OR “Health Resources” [Mesh] OR
health resource* [TI] OR social resource* [TI] OR health care system* [TI] OR healthcare system* [TI] OR “Social Welfare” [Mesh] OR “social
welfare” [TI] OR “welfare system” [TI])
Ichushi search: July 2, 2015 (Thursday)#1 ((Alzheimer’s disease/TH OR Alzheimer’s disease/TI) OR (Alzheimer/TI) AND (Dementia/TH OR Dementia/TI)) AND (Social response/TI
OR Social support/TH OR Social support/TI OR Health care resource /TH OR Health care resource /TI OR Social resource/TI OR Health careservice/TI OR Health service/TI OR Social welfare/TH OR Social welfare/TI OR Welfare system/TI)

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Chapter 7
Dementia with Lewy bodies

CQ 7-1

What are the diagnostic criteria and key points for early diagnosis of dementia
with Lewy bodies (DLB)?
AnswerFor clinical diagnosis of DLB, the revised diagnostic criteria of the DLB International Workshop are used. The
diagnostic criteria for DLB are also provided in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-5). Memory impairment may not be noticeable in the early stage of the disease. The key point for early diagnosis is
to look for the presence or absence of decline of cognitive functions other than memory (such as attention, executivefunction, and visuospatial cognition), REM sleep behavior disorder, parkinsonism, autonomic symptoms, olfactory
disturbance, depressive symptoms, and other symptoms.
In June 2017, new DLB diagnostic criteria were published.
C

Comments and evidence
In 1995, the first DLB International Workshop proposed the term “dementia with Lewy bodies” (DLB) and its clinicaldiagnostic criteria 1). The diagnostic criteria were revised at the third workshop, and further revised in 2017 2). Probable DLB(almost definite) can be diagnosed if two or more of the core features are present. In the presence of only one core clinicalfeature, probable DLB can also be diagnosed if one or more of the indicative biomarkers are present. The DSM-5 publishedin 2013 shows the diagnostic criteria for major neurocognitive disorder (dementia) with Lewy bodies and mild neurocognitive
disorder (mild cognitive impairment) with Lewy bodies 3).
In DLB, since memory impairment is often unremarkable in the early stage of the disease, it is important to examine whether
there are disorders other than memory impairment, such as attention disorder, impaired executive function, and visuospatial
impairment. Moreover, diverse clinical symptoms may manifest in addition to cognitive impairment. Paying attention to theseclinical symptoms provides important clues for early diagnosis of DLB. REM sleep behavior disorder is often seen from the
prodromal stage 4). Furthermore, studies that compared early and prodromal stages of DLB with those of Alzheimer’s disease
have reported that parkinsonism 4-6), gait disorder 6), autonomic symptoms 4, 7), olfactory dysfunction 4, 7), hallucinations 4-6),
delirium 5, 6), sleep disturbance and psychiatric symptoms 7) occur more frequently in DLB. Since many factors such as
hypersensitivity to antipsychotic drugs, syncope, and falls are directly related to poor prognosis in DLB, an accurate diagnosis
from the early stage is important for appropriate disease management.

▪ References

1) McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB):
report of the consortium on DLB international workshop. Neurology. 1996; 47: 1113-1124.
2) McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB
Consortium. Neurology. 2017; 89: 1-13.
3) American Psychiatric Association: Diagnostic and Statistical manual of Mental Disorders, Fifth edition (DSM-5). American psychiatric Publishing, 2013.
4) Boeve BF. Mild cognitive impairment associated with underlying Alzheimer’s disease versus Lewy body disease. parkinsonism and related disorders
2012; 18S1: S41-S44.
5) Jicha GA, Schmitt FA, Abner E, et al. Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiology ofAging. 2010; 31: 1805-1813.
6) Auning E, Rongve A, Fladby T, et al. Early and Presenting symptoms of dementia with Lewy bodies. Dement Geriatr Cogn Disord. 2011; 32: 202-208.
7) Chiba Y, Fujishiro H Iseki E, et al, Retrospective survey of prodromal symptoms in dementia with Lewy bodies: comparison with Alzheimer’s
Disease. Dement Geriatr Cogn Disord. 2012; 33: 273-281.

▪ Search formula

PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 “Lewy Body Disease/diagnosis” [Mesh] OR ((Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (diagnosis[TI] OR diagnoses [TI] OR diagnostic [TI])) AND (“Early Diagnosis” [Mesh] OR early OR “diagnostic criteria” OR “diagnostic accuracy” OR“diagnostic classification” [TI] OR “Diagnosis, Differential” [Mesh] OR “differential diagnosis”)
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI OR Lewy body disease/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X
ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR Diagnosis/TI) AND (Early diagnosis/TH OR Early/TI OR
Diagnostic criteria/AL)

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CQ 7-2

What are the clinical and pathological differences between dementia
with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD)?
Answer(1) Lewy body disease (LBD) is a disease concept that includes all the diseases containing Lewy bodies from thepathological aspects. (2) There is no evidence that there is fundamental difference between DLB and PDD. DLB and
PDD can be viewed as a disease spectrum called LBD. (3) As an operational criterion used in research, it has been
proposed to diagnose DLB when dementia precedes parkinsonism, and PDD when parkinsonism precedes dementia for
one year or longer.

Comments and evidence

1. Terminology issue of DLB and PDD
At the first DLB International Workshop in 1995, the term DLB was proposed for dementia characterized by theneuropathological feature of the appearance of Lewy bodies with α-synuclein as the main component 1). On the other hand,
if dementia occurs after the onset of motor symptoms of Parkinson’s disease (PD), this condition has been called “Parkinson’s
disease with dementia (PDD)”. In the International Workshop, PDD is defined as cases in which parkinsonism has beenpresent for one year or longer before the onset of dementia, and DLB as cases in which the onset of dementia is before theonset of parkinsonism or within one year after onset of parkinsonism (1 year rule) 1). This one-year rule continues to be
adopted subsequently in the third workshop 2). However, note that this rule is only an operational criterion used in research.

2. Similarities and differences between DLB and PDD
A conference held in 2006 which examined the boundary issues between PDD and DLB concluded that “the differing
temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, asingle Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal
α-synuclein inclusions are the defining pathologic process common to both PDD and DLB” 3). The diagnostic criteria for
PDD have also been proposed 4).
Lewy bodies containing α-synuclein as the major component are frequently found in neurons of the brain and in autonomic
nervous system. According to the distribution pattern, Lewy body disorder is classified into the diffuse type (neocorticaltype), limbic type, brainstem type, and cerebral type (Lewy bodies are scarcely seen in the brainstem). Many patients with
LBD also have concomitant pathology of Alzheimer’s disease, and are classified into Alzheimer type, usual type, and puretype (in decremental order of concomitant Alzheimer’s pathology). Lewy body pathology spreads in different patterns,
including spread from the medulla oblongata ascending to the cerebral cortex, progression from the amygdala to cerebral
cortex or brainstem, and descending spread from the cerebral cortex to brainstem. Such pathological diversity probably
accounts for the broad spectrum of LBD phenotypes.

▪ References
1) McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB):
report of the consortium on DLB international workshop. Neurology. 1996; 47(5): 1113-1124.
2) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.
3) Lippa CF, Duda JE, Grossman M, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology.
2007; 68(11): 812-819.
4) Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson disease. Mov Discord. 2007; 22(12): 16891707.

Chapter 7157▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease/diagnosis” [Mesh] OR ((Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (diagnosis[TI] OR diagnoses [TI] OR diagnostic[TI]))) AND ((“Parkinson Disease” [Mesh] AND (Dementia [Mesh] OR “Cognition Disorders” [Mesh]))OR “Parkinson’s disease dementia” OR “Parkinson disease dementia” OR PDD) OR ((“Lewy Body Disease/diagnosis” [Mesh] OR ((“Lewy body”
OR “Lewy bodies”) AND “Dementia/diagnosis”[Majr])) AND (“Parkinson Disease/diagnosis” [Mesh] OR (“Parkinson disease” AND diagnosis[TI])) AND (criteria OR “Diagnosis, Differential” [Mesh] OR “Incidence” [Mesh] OR “differential diagnosis” [TI] OR “pathologic diagnosis”))
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND (Parkinson disease/TH OR Parkinson disease/TI OR Parkinson disease/TI) AND(Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI )158

Clinical Practice Guideline for Dementia 2017

CQ 7-3What are the characteristic laboratory and imaging biomarker of dementia
with Lewy bodies (DLB)?
AnswerDLB is characterized by reduced uptake on dopamine transporter scintigraphy and metaiodobenzylguanidine (MIBG)
myocardial scintigraphy. On CT/MRI, the medial temporal lobe is relatively preserved. Cerebral SPECT and FDG-PET
show decreased blood flow and glucose metabolism in the occipital lobe.
A

Comments and evidence
In DLB, decreased uptake is observed on 123I-MIBG myocardial scintigraphy and dopamine transporter scintigraphy. In
particular, 123I-MIBG myocardial scintigraphy is useful for differentiation from other parkinsonism-related diseases (such as
multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration) 1), while dopamine transporter
scintigraphy is highly useful for differentiation from Alzheimer’s disease 2). A report shows that a combination of 123I-MIBG
myocardial scintigraphy and dopamine transporter scintigraphy can differentiate DLB from Alzheimer’s disease dementia
with 96.1% sensitivity and 90.7% specificity 3).
When using dopamine transporter (DAT) scintigraphy in diagnosis, careful attention has to be given to the following.
(1) Differentiation between DLB and other parkinsonism-related diseases (including progressive supranuclear palsy,
multiple system atrophy, and corticobasal degeneration) is difficult because both are presynaptic disorders of nigrostriatal dopaminergic neurons.
(2) Vascular parkinsonism shows normal to mild loss in DAT uptake in the striatum. Drug-induced parkinsonism shows
normal findings, but it is necessary to confirm the history of the causative drugs use such as anti-dopaminergic agents.
(3) Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors(SNRI), and other drugs (drugs with stimulant effect such as cocaine, amphetamine, methylphenidate, and modafinil)
affect the imaging result because of interaction of the ligand with drugs that have mechanisms of action on dopaminetransporters and serotonin transporters. Therefore, suspending medication or using alternative drugs should beconsidered before examination. Anti-parkinsonian drugs such as cholinesterase inhibitors, levodopa and MAOB
inhibitors have little effects on the results 4).
(4) Pregnant women and persons who are allergic to excitatory substances such as cocaine are general contraindications.
Breastfeeding is a relative contraindication 4).
(5) For patients with liver dysfunction, alcohol hypersensitivity, urinary disorder, or allergic constitution, the examination
has to be administered with caution and after obtaining consent.
The hippocampus and parahippocampal gyrus are relatively preserved on brain MRI, but brainstem atrophy may bediagnosed by statistical analysis such as Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) 5).
On cerebral blood flow scintigraphy, both Alzheimer’s disease and DLB show decreased blood flow in the occipital lobe,
posterior cingulate gyrus, and precuneus. Whereas hippocampal blood flow is reduced in Alzheimer’s disease, it is relatively
preserved in DLB. Compared to Alzheimer’s disease, DLB is also characterized by showing earlier decreases in blood flow
and metabolism in the primary visual cortex 6). Study has shown that if the diagnosis of DLB is difficult by brain SPECT
alone, combining with 123I-MIBG myocardial scintigraphy increases the diagnostic accuracy 7).
In summary, characteristic abnormalities for DLB are found in 123I-MIBG myocardial scintigraphy, dopamine transporter
scintigraphy, MRI combined with VSRAD, and cerebral blood flow scintigraphy. When diagnosis is difficult using a single
examination, a combination of multiple examinations is expected to increase diagnostic accuracy.
Furthermore, while amyloid PET shows increased uptake in DLB similar to that in Alzheimer’s disease, cholinesterasePET (ChE-PET) is known to demonstrate decreased ChE uptake mainly in the occipital lobe in DLB 8).
Regarding cerebrospinal fluid (CSF) biomarkers, there are many reports of low CSF α-synuclein levels in DLB as in
Parkinson’s disease, but the usefulness of this marker has not been established. A report has shown that CSF levels ofphosphorylated α-synuclein and α-synuclein oligomers are elevated in DLB as in Parkinson’s disease 9). In addition, low CSF
Aβ42 level has been reported in DLB compared to controls 10).
New diagnostic criteria for DLB have been published in June 2017 (see CQ7-1). Among these criteria, the following

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indicative biomarkers have been added: (1) reduced uptake in basal ganglia demonstrated by dopamine transporter
scintigraphy; (2) reduced uptake on 123I-MIBG myocardial scintigraphy; and (3) REM sleep without atonia (RWA) confirmedby polysomnography (PSG). In particular, abnormal muscle tone during REM sleep is a highly specific phenomenon forpatients with Lewy body pathology, and is recognized as an important sign even if the other biomarkers are negative.

▪ References
1) Yoshita M, et al. Diagnostic Accuracy of 123I-Meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter
study. PLoS ONE. 2015; 10(3): e0120540.
2) McKeith I, O’Brien J, Walker Z, et al.; DLB Study Group. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECTin dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol. 2007; 6(4): 305-313.
3) Shimizu S, Hirao K, Kanetaka H, et al. Utility of the combination of DAT SPECT and MIBG myocardial scintigraphy in differentiating dementia
with Lewy bodies from Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 20154) Japanese Society of Nuclear Medicine, Japanese Council of Nuclear Neuroimaging (Ed.) Ioflupane Clinical Practice Guidelines, First Edition. 2014;
7-8. (In Japanese)5) Nakatsuka T, Imabayashi E, Matsuda H, et al. Discrimination of dementia with Lewy bodies from Alzheimer’s disease using voxel-based
morphometry of white matter by statistical parametric mapping 8 plus diffeomorphic anatomic registration through exponentiated Lie algebra.
Neuroradiology. 2013; 55(5): 559-566.
6) Fujishiro H, et al. A follow up study of non-demented patients with primary visual cortical hypometabolism: Prodromal dementia with Lewy
bodies. J Neurol Sci. 2013; 334(1-2): 48-54.
7) Hanyu H, Shimizu S, Hirao K, et al. Comparative value of brain perfusion SPECT and [(123)I]MIBG myocardial scintigraphy in distinguishing
between dementia with Lewy bodies and Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2006; 33(3): 248-253.
8) Shimada H, Hirano S, Shinotoh H, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology. 2009; 73(4):273-278.
9) Zhou B, Wen M, Yu WF, et al. The diagnostic and differential diagnosis utility of cerebrospinal fluid α-synuclein levels in Parkinson’s disease: ameta-analysis. Parkinsons Dis. 2015; 2015: 567386.
10) Maetzler W, Stapf AK, Schulte C, et al. Serum and cerebrospinal fluid uric acid levels in Lewy body disorders: associations with disease occurrence
and amyloid-β pathway. J Alzheimers Dis. 2011; 27(1): 119-126.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease/diagnosis” [Mesh] OR ((Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (diagnosis[TI] OR diagnoses [TI] OR diagnostic[TI]))) AND “Diagnostic Imaging” [Mesh] OR “3-Iodobenzylguanidine/diagnostic use” [Mesh] OR“Dopamine Plasma Membrane Transport Proteins” [Mesh]) OR “magnetic resonance imaging” OR “single-photon emission computed tomography”
OR “positron emission tomography” OR DAT scan* OR neuroimaging OR MRI OR SPECT OR MIBG OR PET) OR “Lewy Body Disease/cerebrospinal fluid” [Majr] OR (“Lewy Body Disease/radionuclide imaging” [Mesh] OR ((“Lewy body” [TI] OR “Lewy bodies” [TI]) AND
dementia [TI] AND (diagnosis [TI] OR diagnoses [TI] OR diagnostic [TI]))) AND (“Fluorodeoxyglucose F18/diagnostic use” [Mesh] OR“3-Iodobenzylguanidine/diagnostic use” [Mesh] OR “Dopamine Plasma Membrane Transport Proteins/analysis” [Majr] OR Metaiodobenzylguanidine
OR meta-iodobenzylguanidine OR MIBG)
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide
diagnosis, ultrasound diagnosis)OR Diagnosis/TH) AND (Diagnostic imaging/TH OR “Dopamine Plasma Membrane Transport Proteins”/TH
OR DAT scan OR DAT-scan OR DAT imaging OR MRI/TI OR magnetic resonance imaging OR magnetic resonance tomography OR Magnetic
resonance imaging OR Nuclear magnetic resonance imaging OR SPECT/TI OR Single photon emission computed tomography OR Single photon
emission computed tomography OR Single photon computed tomography OR Single photon emission computed tomography OR Single photon
emission computed tomography OR Iobenguane/TH OR MIBG OR PET/TI OR Positron emission tomography)

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CQ 7-4

What are the clinical course and prognosis of dementia with Lewy bodies (DLB)?
AnswerReports have indicated that there is no difference in the progression of cognitive impairment between DLB and
Alzheimer’s disease. There are reports indicating that the time from initial consultation or diagnosis to hospital admission
or death is shorter in patients with DLB.
C

Comments and evidence
Several studies have compared the clinical course and prognosis of DLB and Alzheimer’s disease. Many of them report nodifferences between DLB and Alzheimer’s disease in terms of progression of cognitive impairment 1-6) and progression of
declined functional abilities 1, 2). The result of a recent meta-analysis also confirms no difference in the progression of cognitive
impairment 7). On the other hand, there are reports showing that the DLB group has a shorter time from the first hospital
visit to end point (admission to institutional, admission to hospital, or death) 6), and a shorter survival duration from onset
of dementia 5, 8) or from diagnosis 9). In any case, careful attention should be paid to the complications such as pneumonia,
which worsen the outcome.

▪ References
1) Stavitsky K, Brickman AM, Scarmeas N, et al. The progression of cognition, psychiatric symptoms, and functional abilities in dementia with Lewy
bodies and Alzheimer disease. Arch Neurol. 2006; 63(10): 1450-1456.
2) Lopez OL, Wisniewski S, Hamilton RL, et al. Predictors of progression in patients with AD and Lewy bodies. Neurology. 2000; 54(9): 1774-1779.
3) Ballard C, O’Brien J, Morris CM, et al. e progression of cognitive impairment in dementia with Lewy bodies, vascular dementia and Alzheimer’s
disease. Int J Geriatr Psychiatry. 2001; 16(5): 499-503.
4) Helmes E, Bowler JV, Merskey H, et al. Rates of cognitive decline in Alzheimer’s disease and dementia with Lewy bodies. Dement Geriatr Cogn
Disord. 2003; 15(2): 67-71.
5) Williams MM, Xiong C, Morris JC, et al. Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease. Neurology.
2006; 67(11): 1935-1941.
6) Hanyu H, Sato T, Hirao K, et al. Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease. Eur J Neurol. 2009;16(2): 212-217.
7) Breitve MH, Chwiszczuk LJ, Hynninen MJ, et al. A systematic review of cognitive decline in dementia with Lewy bodies versus Alzheimer’s disease.
Alzheimers Res Ther. 2014; 6(5-8): 53.
8) Matsui Y, Tanizaki Y, Arima H, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol
Neurosurg Psychiatry. 2009; 80(4): 366-370.
9) Stubendorff K, Hansson O, Minthon L, et al. Differences in survival between patients with dementia with Lewy bodies and patients with Alzheimer’s
disease-measured from a fixed cognitive level. Dement Geriatr Cogn Disord. 2011; 32(6): 408-416.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (“Disease Progression”[Mesh] OR “Prognosis” [Mesh] OR clinical course* OR progression OR prognosis) OR (“Lewy Body Disease” [Majr] OR ((“Lewy body” OR “Lewybodies”) AND dementia[TI])) AND (“Disease Progression” [Mesh] OR “Prognosis” [Mesh] OR clinical course* OR progression [TI] OR prognosis[TI])
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND ((SH = Prognosis)OR Prognosis/TH OR Prognosis/TI OR Natural course/AL)

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CQ 7-5

What is the treatment strategy planned for dementia with Lewy bodies (DLB)?
AnswerRegarding treatment strategy for DLB, symptomatic treatment for each of the diverse clinical symptoms is recommended.
The strategy should include pharmacotherapy and non-pharmacological therapies.
A

Comments and evidence
DLB may manifest diverse symptoms including cognitive impairment, hallucinations, delusion, depressive symptoms,
apathy, abnormal REM sleep behavior and other behavioral and psychological symptoms of dementia (BPSD), extrapyramidal
symptoms, and autonomic symptoms. Because of the diversity of symptoms, it is important to determine the major symptoms
that should be the target of treatment, and then plan the treatment strategy.
Since DLB has high risk of drug-induced adverse events, non-pharmacological interventions such as care and environmental
adaptation are particularly important. While donepezil has been used for treating cognitive impairment, symptomatic drugs
should be used for BPSD, motor deficits, and autonomic dysfunction 1).

▪ References
1) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (“Cognition
Disorders/therapy” [Mesh] OR ((cognition disorder* OR cognitive disorder*) AND (therapy OR therapeutic OR treatment))) OR (“Lewy Body
Disease/drug therapy” [Majr] OR ((“Lewy body” [TI] OR “Lewy bodies”[TI]) AND (donepezil OR rivastigmine)) OR (“Dementia/drug therapy”[Majr] AND “Parkinson Disease/ complications” [Mesh])) AND (“Cognition/drug effects” [Majr] OR ((cognitive function* OR cognitive
assessment* OR cognitive subscale*) AND improve*))
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND (Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function
impairment/TI) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation, dietary treatment, psychiatrictreatment, radiologic treatment)OR Treatment/TH OR Treatment/TI OR Therapy/TI)

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CQ 7-6

Are there any drugs for the treatment of cognitive impairment in dementia
with Lewy bodies (DLB)?
Recommendation
Cholinesterase inhibitors have been reported to be effective for cognitive impairment in DLB patients.

1B

Comments and evidence
The usefulness of cholinesterase inhibitors for cognitive impairment in DLB has been reported 1). In Japan, donepezil(Aricept®) is covered by health insurance for the treatment of cognitive impairment in DLB. In a meta-analysis of randomized
controlled trials (RCT), both cholinesterase inhibitors and memantine are safe and improve Clinician’s Global Impressionof Change (CGIC), but only cholinesterase inhibitors enhance cognitive function 1). According to the results of a metaanalysis in 2015 analyzing 17 large-scale studies on Lewy body disease, cholinesterase inhibitors are useful in improving
cognitive function without worsening motor function 2).

1. Cholinesterase inhibitor (ChEI)a. Donepezil
Four open-label trials have shown the efficacy of donepezil in improving cognitive function in DLB patients. In Japan, arandomized controlled trial showed that oral donepezil at doses of 5 mg and 10 mg improved Mini Mental State Examination(MMSE) and Neuropsychiatric Inventory (NPI)-2 scores (hallucination and cognitive function) 3). Although there was no
significant difference in NPI-10 score, effectiveness was observed in change of dementia symptoms. Improvement in caregiver’s
burden was also found in the high-dose (10 mg) group. Furthermore, in a multicenter open label long-term study (52 weeks),change in cognitive function and improvement of NPI-4 score were also observed 4) [See CQ7-7 for details of the effects ofdonepezil on BPSD). Subsequently, a 56-week long-term study confirmed the tolerability and maintenance of cognitive function
improvement in patients treated with donepezil 5 mg and 10 mg 5). A placebo-controlled double-blind study (phase III) in DLB
patients demonstrated improvement in MMSE score with 10 mg, but not with 5 mg of donepezil 6).
On the other hand, a randomized controlled trial has shown the effectiveness of donepezil for cognitive function also in
PDD 7).
b. Rivastigmine
In a RCT conducted in patients with DLB, although the improvements of MMSE score and global clinical evaluation were
not significant in patients treated with oral rivastigmine, the effect of improving attention was particularly remarkable 8). A RCTof rivastigmine in patients with PDD has shown significant improvement in multiple cognitive function evaluation tests
including the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) 9). Regarding the efficacy on cognitive
impairment in PDD, rivastigmine was highly recommended by the European Federation of Neurological Society (EFNS)(clinical evidence class I, recommended level A) and American Academy of Neurology (AAN) (evidence level class II,
recommendation level B) 10).
c. Galantamine
A 24-week open-label study of galantamine in DLB patients showed improvement in global clinical impression and incognitive function (ADAS-cog) 11).

2. NMDA receptor antagonist: memantine
A 24-week placebo-controlled RCT of memantine in 72 DLB or PDD patients showed improvement in a cognitive
function test requiring attention (A Quick Test of Cognitive Speed; AQT) and in CGIC 12). However, the results of a metaanalysis on memantine for Lewy body disorders reported by Matsunaga et al.13) showed no significant improvement incognitive function.

Chapter 7163

▪ References
1) Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease,
Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg
Psychiatry. 2015; 86(2): 135-143.
2) Matsunaga S, Kishi T, Yasue I, Iwata N. Cholinesterase inhibitors for Lewy body disorders: a meta-analysis. Int J Neuropsychopharmacol. 2015; 28:
19(2).
3) Mori E, Ikeda M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Donepezil-DLB Study Investigators.
Ann Neurol. 2012; 72(1): 41-52.
4) Ikeda M, Mori E, Kosaka K, et al.; Donepezil-DLB Study Investigators. Long-term safety and efficacy of donepezil in patients with dementia with
Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord. 2013; 36(3-4): 229-241.
5) Mori E, Ikeda M, Nagai R, et al. Long-term donepezil use for dementia with Lewy bodies: results from an open-label extension of Phase III trial.
Alzheimers Res Ther. 2015; 7(1): 5.
6) Ikeda M, Mori E, Matsuo K, et al. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial.
Alzheimers Res Ther. 2015; 7(1): 4.
7) Dubois B, Tolosa E, Katzenschlager R, et al. Donepezil in Parkinson’s disease dementia: a randomized, double-blind efficacy and safety study. Mov
Disord. 2012; 27(10): 1230-1238.
8) McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlledinternational study. Lancet. 2000; 356(9247): 2031-2036.
9) Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004; 351(24): 2509-2518.
10) Poewe W, Gauthier S, Aarsland D, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008; 62(10): 1581-1587.
11) Edwards K, Royall D, Hershey L, et al. Efficacy and safety of galantamine in patients with dementia with Lewy bodies: a 24-week open-label study.
Dement Geriatr Cogn Disord. 2007; 23(6): 401-405.
12) Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind,placebo-controlled, multicentre trial. Lancet Neurol. 2009; 8(7): 613-618.
13) Matsunaga S, Kishi T, Iwata N. Memantine for Lewy body disorders: systematic review and meta-analysis. Am J Geriatr Psychiatry. 2015; 23(4):373-383.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (“Cognition
Disorders/therapy” [Mesh] OR ((cognition disorder* OR cognitive disorder*) AND (therapy OR therapeutic OR treatment))) OR (“Lewy Body
Disease/drug therapy” [Majr] OR ((“Lewy body” [TI] OR “Lewy bodies” [TI]) AND (donepezil OR rivastigmine)) OR (“Dementia/drug therapy”[Majr] AND “Parkinson Disease/complications” [Mesh])) AND (“Cognition/drug effects” [Majr] OR ((cognitive function* OR cognitive
assessment* OR cognitive subscale*) AND improve*))
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease /TI) AND (Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function
impairment/TI ) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation, dietary treatment, psychiatrictreatment, radiologic treatment)OR Treatment/TH OR Treatment/TI OR Therapy/TI)

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CQ 7-7

Are there any treatments for behavioral and psychological symptoms
of dementia (BPSD) and REM sleep behavior disorder (RBD) in dementia
with Lewy bodies (DLB)?
Recommendation(1) Although Yokukansan and atypical antipsychotics have been reported to be therapeutic drugs for BPSD, sufficientconsideration for safety is required. (2) The effectiveness of clonazepam for RBD has been reported. Some case reports
have indicated that Yokukansan, ramelteon, and donepezil are effective when clonazepam cannot be used.
2C

Comments and evidence
Patients with DLB may show hypersensitivity to antipsychotic drugs. Therefore, non-pharmacological interventions
should take priority over pharmacotherapy for the treatment of BPSD. Donepezil, a therapeutic drug for cognitive impairment
in DLB, may also be effective against BPSD 1).
If there is no response to the above interventions, symptomatic drugs for BPSD are used. Yokukansan has been shown tobe effective in improving NPI total score, hallucinations, delusion, depression, and anxiety symptoms 2). Although Yokukansan
does not cause extrapyramidal symptoms or anticholinergic symptoms, hypokalemia may occur occasionally which requires
attention. In addition, a report indicates the effectiveness of memantine against BPSD such as delusion, hallucinations,abnormal nocturnal behaviors, and abnormal appetite in patients with DLB 3). Antipsychotics have been used for BPSD in
DLB. However, as noted above, patients with DLB may have hypersensitivity to antipsychotics; therefore use of these drugs
requires special caution 4). Haloperidol is contraindicated for Parkinson’s disease, and should also be avoided in patients with
DLB in principle.
Among atypical antipsychotics, quetiapine and aripiprazole that have mild adverse effects on the extrapyramidal system
are considered to be relatively safe 4), but there is little evidence. Although there are reports on the effectiveness of atypicalantipsychotics for BPSD in DLB, discontinuation due to adverse effects is not uncommon. When using these drugs, it isnecessary to use the minimum dose and always pay attention to the occurrence of adverse events.
Clonazepam has been reported to be effective for the treatment for RBD. However, special attention should be paid to oversedation and falls when used in patients with DLB. Case reports have indicated that Yokukansan 5), ramelteon 6), and donepezil 7)
were effective when clonazepam cannot be used due to adverse effects. There is little evidence for the effect of clonazepam on
insomnia in DLB. In patients with DLB, attention should be paid to the effects of sleep medications causing dizziness, falls andhang-over. Two cases of insomnia in DLB responding to ramelteon have been reported 8). A report also indicates the effectivenessof Yokukansan in improving total time and efficiency of sleep, and reducing the number of arousals during sleep 9).

▪ References
1) Mori E, Ikeda M, Kosaka K, et al. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol. 2012; 72(1):41-52.
2) Iwasaki K, Kosaka K, Mori H, et al. Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administrationof yokukansan, a traditional Japanese medicine. Psychogeriatrics. 2012; 12(4): 235-241.
3) Emre M, Tsolaki M, Bonuccelli U, et al. Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised,double-blind, placebo-controlled trial. Lancet Neurol. 2010; 9(10): 969-977.
4) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.
5) Shinno H, Kamei M, Nakamura Y, et al. Successful treatment with Yi-Gan San for rapid eye movement sleep behavior disorder. Prog
Neuropsychopharmacol Biol Psychiatry. 2008; 32(7): 1749-1751.
6) Nomura T, Kawase S, Watanabe Y, et al. Use of ramelteon for the treatment of secondary REM sleep behavior disorder. Intern Med. 2013; 52(18):2123-2126.
7) Ringman JM, Simmons JH. Treatment of REM sleep behavior disorder with donepezil: a report of three cases. Neurology. 2000; 55(6): 870-871.
8) Fujishiro H. Two cases of dementia with Levy body with resolution of visual hallucination by ramelteon. Japanese Journal of Geriatrics. (Nihon
Ronen Igakkai Zasshi) 2012; 49(5): 622-626. (In Japanese)9) Shinno H, Inami Y, Inagaki T, et al. Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychologicalsymptoms of dementia. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(3): 881-885.

Chapter 7165▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND ((“behavioral
psychological symptom dementia” OR BPSD) AND (therapy OR therapeutic OR treatment)) OR “Behavioral Symptoms/therapy” [Mesh] OR((“REM sleep” OR sleep disorder*) AND (therapy OR therapeutic OR treatment)) OR “Sleep Disorders/therapy”[Mesh]) OR ((((“Lewy Body
Disease/psychology” [Mesh] OR (((“Lewy body” [TI] OR “Lewy bodies” [TI]) AND dementia[TI]) AND (mental impairment* OR behaviouralsymptom* [TI]))) AND (“Lewy Body Disease/drug therapy” [Majr] OR “Delusions/drug therapy” [Majr] OR “Psychotic Disorders/drug therapy”[Majr] OR (“Dementia/drug therapy” [Majr] AND “Dementia/psychology” [Mesh]))) OR (“REM Sleep Behavior Disorder/drug therapy” [Majr]
OR (“REM Sleep Behavior Disorder/drug therapy” [Mesh] AND “REM Sleep Behavior Disorder/physiopathology”[Mesh]))) AND (“Nootropic
Agents” [Mesh] OR “Antipsychotic Agents” [Mesh] OR “Drugs, Chinese Herbal” [Mesh] OR “Dibenzothiazepines” [Mesh] OR “Anticonvulsants”[Mesh] OR “Clonazepam” [Mesh] OR “Cholinesterase Inhibitors” [Mesh]))Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment)OR Treatment/TH OR Treatment/TI OR Therapy/TI) AND (Behavioral
psychological symptoms /TH OR Behavioral psychological symptoms/TI OR Behavioral symptoms /TH OR Behavioral symptoms /TI OR
Psychiatric symptoms/TH OR Psychiatric symptoms/TI OR Sleep disorder/TH OR Sleep disorder/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 7-8

Are there any treatments for autonomic symptoms (such as orthostatic
hypotension, constipation, sweating, urination disorder) in dementia
with Lewy bodies (DLB)?
Recommendation
For autonomic symptoms in DLB, drugs for the treatment of autonomic symptoms in Parkinson’s disease (PD) are usedwhile paying attention to deterioration of cognitive function and psychiatric symptoms. Non-pharmacological therapies
are also used.
2C

Comments and evidence
There are no randomized controlled trials (RCT) for autonomic symptoms in DLB, but treatments for orthostatic
hypotension, constipation, abnormal sweating, and urinary disorder are given according to those used for the treatment ofthese conditions in PD 1). In a study of 29 patients with DLB, urinary incontinence (97%) and constipation (83%) were themost common, while hypotension was found in 66%, and a history of syncope in 28% 2).
Not only orthostatic hypotension, but postprandial hypotension also occurs frequently. Especially in older patients,
dehydration is a common triggering factor, which requires attention. For the treatment of orthostatic hypotension, apartfrom non-pharmacological interventions such as salt intake, head-up tilt in bed, and wearing compressive stockings 3),
pharmacotherapy using droxidopa, midodrine, and fludrocortisone is effective.
For constipation, adequate dietary fiber and water intake, and use of laxatives such as magnesium oxide, lubiprostone,
senna, sennoside, and Daikenchuto are useful. In addition, prescribe mosapride and domperidone to improve gastrointestinal
peristalsis. In DLB, pay attention to paralytic ileus as in PD.
Regarding urinary disorder in DLB, avoid using anticholinergic drugs as far as possible because these drugs may deteriorate
cognitive function. Oxybutynin should not be used because this drug readily passes into the central nervous system and its
anticholinergic action on the central nervous system has the risk of worsening cognitive impairment 4). Paroxetine, a selective
serotonin reuptake inhibitor (SSRI), and milnacipran, a serotonin-norepinephrine reuptake inhibitor (SNRI), are sometimes
useful. Donepezil has been reported to improve attention in patients with dementia, and at the same time suppress themicturition reflex via central muscarinic M2 receptor 5). Use of the adrenoreceptor antagonists such as urapidil, tamsulosin,
and naftopidil may be considered in cases of difficulty in urination due to enlarged prostate.

▪ References
1) Low PA, Tomalia VA. Orthostatic hypotension: mechanisms, causes, management. J Clin Neurol. 2015; 11(3): 220-226.
2) Horimoto Y, Matsumoto M, Akatsu H, et al. Autonomic dysfunctions in dementia with Lewy bodies. J Neurol. 2003; 250(5): 530-533.
3) Henry R, Rowe J, O’Mahony D. Haemodynamic analysis of efficacy of compression hosiery in elderly fallers with ortho-static hypotension. Lancet.
1999; 354(9172): 45-46.
4) Orme S, Morris V, Gibson W, et al. Managing urinary incontinence in patients with dementia: pharmacological treatment options and considerations.
Drugs Aging. 2015; 32(7): 559-567.
5) Sakakibara R, Uchiyama T, Yoshiyama M, et al. Preliminary communication: urodynamic assessment of donepezil hydrochloride in patients with
Alzheimer’s disease. Neurourol Urodyn. 2005; 24(3): 273-275.

▪ Search formula

PubMed search: July 5, 2015 (Sunday), August 18, 2015 (Tuesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (“Autonomic Nervous
System Diseases/therapy” [Mesh] OR “Constipation/therapy” [Mesh] OR “Hyperhidrosis/ therapy” [Mesh] OR “Dysuria/therapy” [Mesh] OR((autonomic dysfunction* OR orthostatic hypotension* OR constipation* OR hyperhidrosis OR dysuria) AND (therapy OR therapeutic OR
treatment))) OR ((“Parkinson Disease/therapy” [Majr] OR Parkinson’s disease*) AND (((orthostatic hypotension* OR GI symptom* OR GI
complaint*) AND improve*) OR “Urination Disorders/drug therapy” [Majr] OR “Urinary Bladder Diseases/drug therapy” [Majr]))
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI OR Lewy body disease/TI) AND (Autonomic nervous system disease/TH OR Autonomic
nervous system disease/TI OR Autonomic nervous symptom/TI OR orthostatic hypotension/TI OR Constipation/TH OR Constipation/TI OR
Hyperhidrosis/TH OR Hyperhidrosis/TI OR Sweating/TI OR Urination disorder/TH OR Urination/TI)

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CQ 7-9What are the suitable treatments for parkinsonism in dementia with Lewy
bodies (DLB)?
Recommendation
Levodopa is recommended for parkinsonism in DLB patients, but high doses should be avoided because of the risk ofworsening psychiatric symptoms and involuntary movements (such as dyskinesia). Use of dopamine agonist tends toworsen psychiatric symptoms, and therefore require special caution.
2C

Comments and evidence
Although there is no randomized controlled trial (RCT) for the treatment of parkinsonism in patients with DLB​, levodopa
is recommended according to the recommendation for Parkinson’s disease (PD) 1, 2). However, response to levodopa in DLB
is generally inferior to that in PD 2). Note that high doses should not be used because there is little benefit in improving motor
symptoms, while there is a risk of exacerbating psychiatric symptoms. When levodopa is used, start from a low dose andup-titrate gradually to the minimally required dose. Anticholinergic drugs such as trihexyphenidyl have the risk of impairing
cognitive function and should be avoided in principle 2).
Using high-dose levodopa from the early stage tends to induce not only psychiatric symptoms such as hallucination, butalso motor complications such as dyskinesia and wearing-off symptoms 3),. Therefore, start from a low dose and pay attention
to whether psychiatric symptoms are worsened. Since psychiatric symptoms such as hallucination and impulse control
disorder are easily induced in patients with DLB, dopamine agonists may be used with special caution 4). In the case ofdifficulty with rolling over in bed due to wearing off symptoms at night or in early morning, rotigotine patch has beenreported to be effective for the group of diseases causing atypical parkinsonism including PD with dementia 5), but avoid
using this drug if there is any deterioration in psychiatric symptoms such as hallucination.

▪ References
1) Molloy S, McKeith IG, O’Brien JT, et al. The role of levodopa in the management of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry.
2005; 76(9): 1200-1203.
2) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.
3) Hong JY, Oh JS, Lee I, et al. Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology. 2014;
82(18): 1597-1604.
4) Goldman JG, Goetz CG, Brandabur M, et al. Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies.
Mov Disord. 2008; 23(15): 2248-2250.
5) Moretti DV, Binetti G, Zanetti O, et al. Non-ergot dopamine agonist rotigotine as a promising therapeutic tool in atypical parkinsonism syndromes:a 24 months pilot observational open-label study. Neuropharmacology. 2014; 85: 284-289.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 19, 2015 (Wednesday)#1 (“Lewy Body Disease” [Mesh] OR Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (“Parkinsonian
Disorders/therapy” [Mesh] OR “Neurologic Manifestations/therapy” [Mesh] OR((Parkinsonian disorder* OR Parkinsonism OR dyskinesia OR
motor dysfunction*) AND (therapy OR therapeutic OR treatment))) OR (“Parkinson Disease/drug therapy” [Majr] OR ((Parkinson disease*[TIAB] OR Parkinson’s disease*[TIAB]) AND (therapy [TIAB] OR intervention* [TIAB]))) AND (“Lewy Body Disease/drug therapy” [Mesh] OR((“Lewy body” [TI] OR “Lewy bodies” [TI]) AND dementia [TI] AND (therapy [TI] OR management[TI]))OR “Dyskinesias” [Majr] ORdyskinesia* [TI])
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND ((SH = Therapeutic use, treatment, drug treatment, surgical treatment, transplantation,
dietary treatment, psychiatric treatment, radiologic treatment)OR Treatment/TH OR Treatment/TI OR Therapy/TI) AND (Parkinsonism/TH
OR Parkinsonism/TI OR Parkinson disease/TI OR Involuntary movement/TH OR Involuntary movement/TI OR Dyskinesia/TH OR Dyskinesia/
TI)

168

Clinical Practice Guideline for Dementia 2017

CQ 7-10

What are the non-pharmacological interventions for dementia with Lewy
bodies (DLB)?
AnswerNon-pharmacological interventions are also important for DLB, and appropriate care and environmental adjustment
are recommended.
D

Comments and evidence
Non-pharmacological interventions such as appropriate care and environmental improvement are also important in the
management of DLB. However, although non-pharmacological interventions may be effective in improving behavioral andpsychological symptoms of dementia (BPSD) and functional abilities in patients with DLB, there are no research reports
proving them so far. Since cognitive impairment and visual hallucination are worsened by decline in arousal and attention
levels 1), social interaction and environmental stimulation may be effective. For BPSD in DLB, using a person-centeredapproach to improve caregiver’s burden should be tried first 2). For dementia in general, removal of any trigger of agitation(pain, fear, hallucination, delusion, environment) is recommended 3). The results of a meta-analysis show that giving advice
on care to caregivers, supporting caregivers, and acquiring stress management skills are effective to reduce BPSD 4), and theseapproaches may also be useful in patients with DLB. Parkinsonism is a risk of falls in DLB patients 1, 5). Although some
reports have shown that gait rehabilitation training is useful as a non-pharmacological intervention for falls and gait
disturbances in patients with Parkinson’s disease, there is little evidence for DLB.

▪ References
1) McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005; 65(12): 1863-1872.
2) Ballard C, Aarsland D, Francis P, et al. Neuropsychiatric symptoms in patients with dementias associated with cortical Lewy bodies: pathophysiology,
clinical features, and pharmacological management. Drugs Aging. 2013; 30(8): 603-611.
3) Boot BP, McDade EM, McGinnis SM, et al. Treatment of dementia with Lewy bodies. Curr Treat Options Neurol. 2013; 15(6): 738-764.
4) Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;
169(9): 946-953.
5) Kudo Y, Imamura T, Sato A, et al. Risk factors for falls in community-dwelling patients with Alzheimer’s disease and dementia with Lewy bodies:walking with visuocognitive impairment may cause a fall. Dement Geriatr Cogn Disord. 2009; 27(2): 139-146.

▪ Search formula
PubMed search: July 5, 2015 (Sunday), August 19, 2015 (Wednesday)#1 (“Lewy Body Disease/therapy” [Mesh] OR ((Lewy body disease* OR “Lewy body dementia” OR “dementia with Lewy body”) AND (therapy
OR therapeutic OR treatment OR rehabilitation OR intervention*))) AND (“Rehabilitation” [Mesh] OR rehabilitation* OR “Psychotherapy”[Mesh] OR “Social Support” [Mesh] OR psychosocial intervention*) OR ((“Lewy Body Disease/therapy” [Mesh] OR ((“Lewy body” [TI] OR“Lewy bodies” [TI]) AND dementia [TI] AND (therapy [TI] OR management [TI]))) AND (specific intervention* OR nonpharmacologic OR
cognitive-behavioral intervention*)) OR (“Dementia/therapy” [Majr] AND “Phototherapy” [Mesh])
Ichushi search: July 6, 2015 (Monday)#1 (Lewy body disease/TH OR Lewy body disease/TI) AND ((SH = Rehabilitation)OR Rehabilitation/TH OR Rehabilitation/TI OR Psychologicaltherapy/TH OR Psychological therapy/TI OR Psychotherapy/TI OR Psychosocial therapy/TI OR Psychosocial intervention/TI OR Social support/
TH OR Social support/TI)

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Chapter 8
Frontotemporal Lobar Degeneration

History
Frontotemporal lobar degeneration (FTLD), with Pick’s disease as the prototype, is a progressive non-Alzheimer’s diseaseoften with the presenile onset and is characterized by degeneration and loss of neurons mainly in the frontal and temporal lobes,
causing marked behavioral abnormalities, psychiatric symptoms, and language impairment, while various degrees of motor
disorders may emerge during the course of disease. The concept, name, and classification of FTLD have changed over the years,
and terms such as frontal lobe degeneration of non-Alzheimer type and frontal lobe dementia were once used in the past.

Clinical classification
The term FTLD is used in cases with a definitive pathological and genetic diagnosis, while frontotemporal dementia(FTD) is used in cases with a clinical diagnosis. The term FTLD is adopted as the disease name in designated intractablediseases in Japan. In this guideline, FTLD is used and also includes clinically diagnosed cases.
FTLD is a classified clinically into three types: behavioral variant frontotemporal dementia (bvFTD) with mainly
prefrontal atrophy; semantic dementia (SD) with localized atrophy mainly in the temporal pole and middle/inferior temporalgyrus; and progressive non-fluent aphasia (PNFA), which is left-dominant and shows localized atrophy around the fissure of
Sylvius. Refer to CQ2-6 for the classification by type of aphasia.
Also, parkinsonism and motor neuron symptoms may be observed in patients with FTLD during the course of disease. The
disease type showing motor neuron symptoms is called frontotemporal dementia with motor neuron disease (FTD-MND).

Pathological classification
Pathologically, specific proteins aggregate and deposit as inclusion bodies in neurons and glial cells. Tau protein, TAR
DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS) protein have been identified as the main componentsof the inclusion bodies 1).
Tau protein is one of the microtubule-binding proteins and is broadly classified by the number of repeats in the microtubularbinding region at the C-terminal side into three-repeat tau protein and four-repeat tau protein. Tauopathy is a general termfor diseases in which abnormal accumulation of phosphorylated tau protein is considered to be an essential pathogenic
mechanism. The subgroup of FTLD that exhibits tauopathy is called FTLD-tau. FTLD-tau comprises cases showing
accumulation of mainly three-repeat tau protein (Pick disease) and those showing accumulation of mainly four-repeat tau
protein. Corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain dementia are broadly interpreted
as four-repeat tauopathy with FTLD.
TDP-43 protein and FUS protein exist mainly in the nucleus, and both possess diverse functions such as transcription,
splicing, RNA transport, and stabilization. In FTLD, both TDP-43 protein and FUS protein disappear from the nucleus
and are observed as extracellular aggregates, and these disease types are called FTLD-TDP and FTLD-FUS, respectively.
See CQ1-8 for a detailed description of pathology.

Relationship between clinical classification and pathological classification
It has been reported that more than half of bvFTD cases are FTLD-TDP type, while approximately 70% of PNFA cases
are FTLD-tau type (PSP, CBD, Pick disease), and approximately 80% of SD are FTLD-TDP type 2).

Diagnosis
For diagnostic criteria, see CQ8-1.

Family history
Family history is evident in 30 to 50% of the cases in European and American countries but is almost absent in Japan. In
familial cases, mutations have been identified in several genes, including the tau gene, the TARDBP gene, the FUS gene, andthe progranulin gene. Abnormal expansion of a hexanucleotide repeat in intron 1 of the C9orf72 gene is the most frequentcause in European and American countries, but very rarely in Japan.

Treatment
FTLD is a progressive degenerative disease, and curative treatment that can modify the natural course has not been developed.
When patients show motor neuron symptoms, pay special attention to the onset of respiratory failure and dysphagia.
Parkinsonism and repeated falls may be observed, but levodopa preparations have limited use or are often ineffective.

172

Clinical Practice Guideline for Dementia 2017▪ References
1) Lashley T, Rohrer JD, Mead S, et al. Review: An update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.
Neuropathol Appl Neurobiol. 2015; 41(7): 858-881.
2) D’Alton S, Lewis J. Therapeutic and diagnostic challenges for frontotemporal dementia. Front Aging Neurosci. 2014; 6: 204.

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CQ 8-1

What are the diagnostic key points and diagnostic criteria for frontotemporallobar degeneration (FTLD)?
AnswerAmong various types of frontotemporal lobar degeneration (FTLD), the criteria developed by the International
Behavioral Variant Frontotemporal Dementia Criteria Consortium (FTDC) in 2011 are recommended for the diagnosis
of behavioral variant frontotemporal dementia (bvFTD). For semantic dementia (SD), the use of the clinical diagnostic
characteristics for semantic dementia proposed in 1998 is recommended, with additional reference to the clinical diagnostic
features for semantic variant progressive aphasia proposed in 2011.
B

Comments and evidence
FTLD is classified clinically into behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), andprogressive non-fluent aphasia (PNFA). Among them, bvFTD and SD are included as designated intractable diseases inJapan.

1. Diagnostic criteria for bvFTD
The FTDC diagnostic criteria reported by Rascovsky et al. 1) are used. The sensitivity of the FTDC criteria is 93% forpossible bvFTD and 80% for probable bvFTD, and the positive predictive value of cases diagnosed as possible bvFTD is
90% 2). Harris et al. 3) studied mainly early-onset cases and reported high reliability, with 95% sensitivity and 82% specificity
for possible bvFTD, and 85% sensitivity and 95% specificity for probable bvFTD.
The major false-positive cases are Alzheimer’s disease dementia, while dementia with Lewy bodies also constitutes acertain percentage 2).
For the FTDC criteria, although the κ values (indicating interrater agreement rate) are high, with 0.81 for possible bvFTD
and 0.82 for probable bvFTD, there are some differences in agreement rate among individual items 4).
For characteristic image findings, see CQ8-2. Family history is evident in 30-50% of the patients in European andAmerican countries but in almost none of the Japanese patients.
In the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), the term “neurocognitive disorder(NCD)” is introduced to replace the term “dementia. FTLD is called major or mild frontotemporal NCD, and broadlyclassified into behavioral variant and language variant. For diagnostic criteria of behavior variant, the criteria adopted arealmost the same as the above-mentioned FTDC criteria.

2. Diagnostic criteria of SD and characteristics of aphasia
According to the diagnostic criteria of Gorno-Tempini et al. 5) the diagnostic procedure is first to diagnose progressive
aphasia and then classify into semantic, non-fluent/grammatical, and logopenic (for classification based on aphasia, see
CQ2-6). SD manifests semantic aphasia (loss of word meaning). However, in SD with predominantly right temporal lobe
atrophy, some patients show conspicuous semantic deficits other than semantic aphasia (for example, semantic memory
impairment related to well-known buildings and faces) or behavioral disorders in the early stage. Consequently, there is lessconsensus compared to the bvFTD diagnostic criteria. The diagnostic criteria for designated intractable diseases adopt the
Gorno-Tempini diagnostic criteria for semantic variants characterized by aphasia, together with the diagnostic criteria ofNeary et al. 6) based on the evidence of characteristic semantic memory impairment regardless of the presence or absence ofprogressive aphasia.
In SD, impairment of object naming and word comprehension is consistent, and patients have difficulties with the same
objects and words under different test settings and in daily life. Surface dyslexia is observed in reading kanjis that havedifferent pronunciations, especially in idioms, where the words are read differently from the original kanjis.
Some patients develop impairment in recognizing the face of a known person, or cognitive impairments across multiple
modalities such as visual and auditory comprehension of an object. These patients cannot recognize the faces of well-known
persons, friends, or relatives whom they meet only occasionally. When they see these faces, they would say, “I can’t remember
anything” or “I don’t know”. The fact that recognition is not helped by providing sound or touch cues would indicate that174

Clinical Practice Guideline for Dementia 2017

the condition is different from the usual agnosia.
For clinical diagnosis of SD, after identifying the characteristic aphasia, differentiate from other diseases such as Alzheimer’s
disease dementia carefully from image and other clinical findings.

3. Characteristics of aphasia observed in PNFA
Diagnostic criteria of nonfluent/agrammatic aphasia characteristic of PNFA have been reported by Gorno-Tempini et al. 5).
As mentioned above, when using these criteria, first diagnose whether progressive aphasia is present. Nonfluent/agrammatic
aphasia is characterized by (1) agrammatism in speech, and (2) apraxia of speech characterized by inconsistent speech sounderrors and distortions (pronunciation not found in the Japanese language); at least one of the above should be present. While
single-word comprehension is spared, comprehension of grammatically complex sentences is impaired. Other features are
effortful speech, difficulty in initiating speech, halting speech, and inconsistent speech errors.

▪ References
1) Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of fronto-temporal dementia. Brain.
2011; 134(Pt 9): 2456-2477.
2) Balasa M, Gelpi E, Martin I, et al. Diagnostic accuracy of behavioral variant frontotemporal dementia consortium criteria (FTDC) in aclinicopathological cohort. Neuropathol Appl Neurobiol. 2015; 41(7): 882-892.
3) Harris JM, Gall C, Thompson JC, et al. Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia. Neurology.
2013; 80(20): 1881-1887.
4) Lamarre AK, Rascovsky K, Bostrom A, et al. Interrater reliability of the new criteria for behavioral variant frontotemporal dementia. Neurology.
2013; 80(21): 1973-1977.
5) Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011; 76(11): 10061014.
6) Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998; 51: 15461554.

▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 “Frontotemporal Lobar Degeneration/diagnosis” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND Dementia/diagnosis [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporaldementia” OR FTD OR FTLD bvFTD) AND (diagnosis OR diagnoses OR diagnostic))
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR
Diagnosis/TI)

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CQ 8-2

What are the characteristics of image findings of frontotemporal lobar
degeneration (FTLD)?
AnswerAmong FTLD disorders, behavioral variant frontotemporal dementia (bvFTD) shows MRI/CT findings of localized
atrophy in the frontal and temporal lobes, predominantly in the frontal lobe. On SPECT/PET, decreased metabolism/
decreased blood flow is observed in the frontal lobe and anterior temporal lobe, while the parietal and occipital lobes arespared.
Semantic dementia (SD) shows MRI/CT findings of atrophy in the temporal lobe predominantly involving the anterior
region and inferior temporal gyrus. Usually, atrophy is asymmetrical. As the disease progresses, frontal lobe atrophy also
appears. On SPECT/PET, decreased metabolism/decreased blood flow in the temporal lobe predominantly involving theanterior region and in the inferior temporal gyrus is observed.
Progressive non-fluent aphasia (PNFA) shows MRI/CT findings of atrophy in the left frontal lobe predominantly fromthe posterior region to the insula. On SPECT/PET, decreased metabolism/decreased blood flow in the left frontal lobe
predominantly from the posterior region to the insula is observed.
Imaging examination is useful for the diagnosis of FTLD, but a diagnosis cannot be made with images alone. B

Comments and evidence

1. General head MRI/CT and SPECT/PET findings 1)
For bvFTD, atrophy on MRI/CT and decreased metabolism and blood flow on SPECT/PET are observed in the frontal
lobes and anterior temporal lobes. For SD, atrophy on MRI/CT and decreased metabolism/blood flow on SPECT/PET are
observed in temporal lobes predominantly in the anterior region and in the inferior temporal gyrus. For PNFA, atrophy on
MR/CT and decreased metabolism/blood flow are observed in the left frontal lobe predominantly from the posterior region
to the insula.

2. Brain volumetric imaging
Brain volumetric imaging is useful for the differentiation of Alzheimer’s disease dementia, dementia with Lewy bodies,and FTLD 2).
In bvFTD, atrophy is observed in the frontal lobes involving the medial, dorsolateral, and orbitofrontal regions, as well as
the anterior temporal lobes. Atrophy in the frontal lobe, especially the medial surface, progresses from the earliest stage 1).
The results of a meta-analysis show that bvFTD is characterized by atrophy in the prefrontal cortex, in particular, atrophy of
the regions corresponding to superior and middle frontal gyrus, anterior cingulate gyrus, insula, caudate nucleus, andputamen 3).
SD is characterized by left-right asymmetric inferior temporal gyrus-dominant anterior temporal atrophy or decreased
blood flow/metabolism. The orbitofrontal cortex, insula, and caudate nucleus are also affected. In a longitudinal observational
study, temporal lobe atrophy progresses from the earliest stage, and atrophy in the frontal lobe, insula, caudate nucleus, andthalamus progress in the same manner.
PNFA is characterized by atrophy or decreased blood flow/metabolism in the posterior frontal lobe, including Broca’s area
and the superior premotor cortex, as well as in the insula. Lesions in the superior temporal gyrus and striatum are also
observed.

3. Diffusion tensor imaging 4)
In bvFTD, bilateral and widespread lesions in the white matter tracts are observed. The lesions are severe in the superior
longitudinal fasciculus, anterior cingulate fasciculus, anterior corpus callosum, uncinate fasciculus, and inferior longitudinalfasciculus, and are especially severe, usually in the anterior aspect of superior longitudinal fasciculus and inferior longitudinalfasciculus. In SD, left-dominant degeneration in the uncinate fasciculus and inferior longitudinal fasciculus is observed, andanterior-dominant degeneration in the anterior corpus callosum and arcuate fasciculus is also found. In PNFA, degeneration
is observed in the left superior longitudinal fasciculus, especially in the arcuate bundle projecting to the inferior frontal lobe.

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4. Resting-state functional MRI 4)
In bvFTD, decreased connectivity of the salience network, including the anterior cingulate gyrus and the anterior insula
has been reported.

5. Genetic mutation and brain volumetric imaging 5)
Compared to patients with mutations in tau and progranulin genes and patients with sporadic disease, patients with
mutations in C9orf72 gene show atrophy in the anterior temporal lobe, parietal lobe, occipital lobe, and cerebellum. Patientswith Tau gene mutations are characterized by atrophy in the anteromedial temporal lobe, and patients with progranulin genemutations are characterized by asymmetric atrophy in the temporoparietal lobe. In addition, the speed of atrophy of thebrain as a whole is faster in patients with progranulin gene mutations than in patients with C9orf72 or tau gene mutations.

6. Comparison of brain imaging findings with underlying pathological findings 6)
There is a limitation to estimate underlying pathology based on atrophy patterns observed on MRI. In recent years, highly
sensitive tau PET imaging capable of visualizing tau pathology has become available in some facilities, and further studies
are awaited 7, 8).

7. Phenocopy syndrome 1)
Some bvFTD cases show no apparent atrophy on MRI, and they are termed “bvFTD phenocopy syndrome”. Clinicalprogression in these patients is known to be very slow. FDG-PET also does not show any abnormalities. Various underlying
diseases, such as developmental disorders, are speculated.

▪ References
1) Whitwell JL, Josephs KA. Recent advances in the imaging of frontotemporal dementia. Curr Neurol Neurosci Rep. 2012; 12(6): 715-723.
2) Vemuri P, Simon G, Kantarci K, et al. Antemortem differential diagnosis of dementia pathology using structural MRI: Differential-STAND.
Neuroimage. 2011; 55(2): 522-531.
3) Pan PL, Song W, Yang J, et al. Gray matter atrophy in behavioral variant frontotemporal dementia: a meta-analysis of voxel-based morphometry
studies. Dement Geriatr Cogn Disord. 2012; 33(2-3): 141-148.
4) Risacher SL, Saykin AJ. Neuroimaging biomarkers of neurodegenerative diseases and dementia. Semin Neurol. 2013; 33(4): 386-416.
5) Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin andsporadics. Brain. 2012; 135(Pt 3): 794-806.
6) Whitwell JL, Josephs KA. Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology. Nat Rev Neurol. 2011; 8(3): 131142.
7) Maruyama M, Shimada H, Suhara T, Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal
controls. Neuron. 2013; 79(6): 1094-1108.
8) Okamura N, Furumoto S, Fodero-Tavoletti MT, et al. Non-invasive assessment of Alzheimer’s disease neurobrillary pathology using 18F-THK5105
PET. Brain. 2014; 137(Pt 6): 1762-1771.

▪ Search formula
PubMed search: July 8, 2015 (Wednesday)#1 (“Frontotemporal Lobar Degeneration/diagnosis” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND “Dementia/diagnosis” [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporaldementia” OR FTD OR FTLD bvFTD) AND (diagnosis OR diagnoses OR diagnostic))) AND (“Diagnostic Imaging” [Mesh] OR “magnetic
resonance imaging” OR “single-photon emission computed tomography” OR “positron emission tomography” OR MRI OR SPECT OR PET)
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration /TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR
Diagnosis/TI) AND (Diagnostic imaging/TH OR MRI/TI OR magnetic resonance imaging OR magnetic resonance tomography OR Magnetic
resonance imaging OR Nuclear magnetic resonance imaging OR PET/TI OR Positron emission tomography OR Positron emission tomography OR
SPECT/TI OR Single photon emission computed tomography OR Single photon emission computed tomography OR Single photon computed
tomography OR Single photon emission computed tomography)

Chapter 8

177

CQ 8-3

Are there effective drugs for frontotemporal lobar degeneration (FTLD)?
Recommendation
The use of selective serotonin reuptake inhibitor (SSRI) is recommended for the purpose of improving behavioral
disorders in FTLD (off-label).
2C

Comments and evidence
Because FTLD is a clinical syndrome and has diverse underlying pathologies, there are few studies on pharmacotherapy.
The available studies are small-scale trials, which do not necessarily provide sufficient evidence 1, 2). A review reported by
Nardell and Tampi 2) suggests that SSRIs, trazodone, and amphetamines may be effective in improving some behavioral
symptoms, but none of the medications had an impact on cognition. The authors also pointed out various issues of thestudies reviewed, such as the use of different diagnostic criteria, inconsistent evaluation indicators, and use of indicators suchas Mini-Mental State Examination (MMSE) which are not sensitive to FTLD symptoms. Trazodone has been shown to beeffective in a double-blind, randomized control trial (RCT) 3).
Regarding SSRI, since the report of Swartz et al. 4) in 1997, some reports have shown that these drugs are effective fordisinhibition, stereotyped behavior, and abnormal eating behavior, while other reports observed no effectiveness. In Japan,
an open-label trial has reported the effectiveness of SSRI for repetitive behavior, stereotyped behavior, and compulsive
complaint in FTLD 5). Lanctot et al. 6) used PET to investigate the mechanism of action of SSRI for FTLD, and reported
significant decreases in serotonin 5-HT1A receptor binding potential in all the brain regions examined in FTLD patientscompared with controls. Using electroencephalography and magnetoencephalography, Hughes et al. 7) reported recovery of
the activity of inferior frontal gyrus in FTLD patients treated with SSRI.
Views on the usefulness of cholinesterase inhibitors (ChEIs) remain divided 1, 2). There are reports of no effectiveness of
ChEIs and reports of worsening of disinhibition. Thus caution is required when administering ChEIs. A recent review
concludes that the efficacy of ChEIs for FTD cannot be confirmed and that ChEIs are associated with more gastrointestinal
adverse effects 8). Besides, two RCTs failed to demonstrate the usefulness of memantine, an NMDA receptor antagonist,compared with placebo.
Nasal oxytocin at a dose of 24 IU has been reported to improve the behavioral score of Neuropsychiatric Inventory (NPI)
and reduce episodes of anger and fear compared with placebo 9). Preparation of a large-scale and long-term clinical trial isongoing 10).

▪ References
1) Riedl L, Mackenzie IR, Forstl H, et al. Frontotemporal lobar degeneration: current perspectives. Neuropsychiatr Dis Treat. 2014;10:297-310.
2) Nardell M, Tampi RR. Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials. Am J
Alzheimers Dis Other Demen. 2014;29(2): 123-132.
3) Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord.
2004;17(4): 355-359.
4) Swartz JR, Miller BL, Lesser IM, et al. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry.
1997;58: 212-216.
5) Ikeda M, Shigenobu K, Fukuhara R, et al. Efficacy of fluvoxamine as a treatment for behavioral symptoms in frontotemporal lobar degeneration
patients. Dement Geriatr Cogn Disord. 2004;17(3): 117-121.
6) Lanctot KL, Herrmann N, Ganjavi H, et al. Serotonin-1A receptors in frontotemporal dementia compared with controls. Psychiatry Res.
2007;156(3): 247-250.
7) Hughes LE, Rittman T, Regenthal R, et al. Improving response inhibition systems in frontotemporal dementia with citalopram. Brain. 2015;138(Pt7): 1961-1975.
8) Li Y, Hai S, Zhou Y, et al. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev.
2015;(3): CD009444.
9) Jesso S, Morlog D, Ross S, et al. The effects of oxytocin on social cognition and behaviour in frontotemporal dementia. Brain. 2011;134(Pt 9): 24932501.
10) Finger EC, MacKinley J, Blair M, et al. Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability.
Neurology. 2015;84(2): 174-181.

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▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 “Frontotemporal Lobar Degeneration/drug therapy” [Mesh] OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI]
OR FTD [TI] OR FTLD [TI] OR bvFTD [TI]) AND Dementia/drug therapy [Mesh]) OR ((“frontotemporal lobar degeneration” OR“frontotemporal dementia” OR FTD OR FTLD bvFTD) AND (“drug therapy” OR chemotherapy OR pharmacotherapy OR “pharmacologicaltherapy”))
Ichushi search: July 9, 2015 (Thursday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD)
AND ((SH = Pharmacotherapy) OR Pharmacotherapy/MTH OR Therapeutic use/MTH OR Drug treatment/TI OR Pharmacotherapy/TI OR
Therapeutic drug/TI)

Chapter 8

179

CQ 8-4

Are there effective non-pharmacological therapies for frontotemporal lobar
degeneration (FTLD)?
Recommendation
Non-pharmacotherapy therapies such as care and behavioral therapy based on FTLD symptomatology are recommended.

2C

Comments and evidence
The characteristics described in the diagnostic criteria for behavioral variant frontotemporal dementia (bvFTD) areessential in developing treatment strategies for behavioral disorders of FTLD.
Although there is little evidence, non-pharmacological therapies are useful and are the mainstay of treatment. In particular,
by utilizing the patient’s preserved functions and taking into account the characteristic symptoms and the patient’s lifestyle,it may be possible to mitigate behavioral abnormalities and reduce the burden on caregivers 1).
Shinagawa et al. 2) reviewed case reports, expert opinions, and clinical trials (excluding retrospective studies) of nonpharmacological management 2). Ikeda et al. 3) studied six patients with FTLD, and reported that care that utilized thepatient’s preserved episodic memory, procedural memory, and visuospatial cognitive function was effective and resulted in
the improvement of quality of life (QOL). Mioshi et al. 4) and McKinnon et al. 5) showed that a learning program comprising
mainly of cognitive appraisal and coping strategies improved the burden on caregivers.
Ikeda et al. 6) conducted a detailed assessment of behavioral disorders and behavioral interventions given to patients underhospitalized observation, and reported the effectiveness of conducting individualized family guidance based on behavioral
disorder assessments of the patients and improvement of families’ attitude toward the patients.
Lough et al. 7) reported that the compulsive behaviors of a patient with FTLD were changed to socially acceptable behavior
in response to behavioral modification techniques. Tokikawa et al. 8) reported that the introduction of a daycare program fora patient with FTLD resolved the patient’s obsessive-compulsive behaviors by acquiring a stereotyped behavior pattern.
However, this report also pointed out the problems of newly acquired emotional compulsive behaviors such as coming to
daycare, even on holidays, and not able to wait for the pick-up person.
Tokimasa et al. 9) compared the cooking activities of 2 patients with FTLD and five patients with Alzheimer’s disease
dementia. In patients with Alzheimer’s disease dementia, because of episodic memory impairment and apraxia, constantsupervision is needed from the early stage, and acquisition of generalized compensation method is difficult. On the other
hand, in patients with FTLD, after cautiously forming an intimate relationship, helping the patients form the habit of doing
activities of daily living (ADL) utilizing stereotyped behavior is a crucial point for care.
In daycare and institutional care, reports have emphasized that to respond to severe mental symptoms; there is a need for
one-on-one response at least when care is initiated 6, 8, 10). The usefulness of group homes where meticulous care can beprovided has been reported 11).

▪ References
1) Merrilees J. A model for management of behavioral symptoms in frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord. 2007; 21(4):S64-S69.
2) Shinagawa S, Nakajima S, Plitman E, et al. Non-pharmacological management for patients with frontotemporal dementia: a systematic review. J
Alzheimers Dis. 2015; 45(1): 283-293.
3) Ikeda M, Tanabe H, Horino T, et al. Care for Patients with pick’s disease: by using their preserved procedural memory. Psychiatr Neurol Jpn(Seishin Shinkeigaku Zasshi) 1995; 97(3): 179-192. (In Japanese)4) Mioshi E, McKinnon C, Savage S, et al. Improving burden and coping skills in frontotemporal dementia caregivers: A pilot study. Alzheimer Dis
Assoc Disord. 2013; 27(1): 84-86.
5) McKinnon C, O’Connor CM, Savage S, et al. Qualitative results of a structured group program for carers of people with frontotemporal dementia.
Int J Geriatr Psychiatry. 2013; 28(2): 217-218.
6) Ikeda M, Imamura T, Ikejiri Y, et al. The efficacy of short-term hospitalizations in family care for patients with Pick’s disease. Psychiatr Neurol Jpn(Seishin Shinkeigaku Zasshi) 1996; 98(10): 822-829. (In Japanese)
7) Lough S, Hodges JR. Measuring and modifying abnormal social cognition in frontal variant frontotemporal dementia. J Psychosom Res. 2002;
53(2): 639-646.

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Clinical Practice Guideline for Dementia 20178) Tokikawa S, Ideda M, Shigenobu K, et al. A day care program for a patient with fronto-temporal dementia (Pick type): mainly for her disinhibited
behavior. General Rehabilitation (Sogo Rihabiriteshon) 2000; 28(5): 477-481. (In Japanese)9) Tokimasa A, Ikeda M, Hirono N, et al. Maintaining activity in dementia; study on cooking performance. General Rehabilitation (Sogo
Rihabiriteshon) 1996; 24(9): 861-869. (In Japanese)10) Takahashi J, Yokota O, Fujisawa Y. Person-centered care for demented elderly in a psychiatric hospital- impact on behavioral and psychologicalsymptoms of dementia, quality of life, and caregiver burden-. Japanese Journal of Geriatric Psychiatry (Ronen Seishin Igaku Zasshi) 2007; 18(12):861-869. (In Japanese)11) Yokota O, Fujisawa Y, Takahashi J, et al. Effects of group-home care on behavioral symptoms, quality of life, and psychotropic drug use in patientswith frontotemporal dementia. J Am Med Dir Assoc. 2006; 7(5): 335-337.

▪ Search formula
PubMed search: July 10, 2015 (Friday)#1 ((“Frontotemporal Lobar Degeneration/therapy” [Mesh] OR(“Frontotemporal Lobar Degeneration” [Majr]AND “Therapeutics” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND Dementia/therapy [Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (therapy OR therapeutic OR treatment OR intervention*))) NOT (“Frontotemporal Lobar Degeneration/drug therapy” [Mesh]
OR (“Frontotemporal Lobar Degeneration” [Majr] AND “Drug therapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR“frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe
dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND Dementia/drug therapy[Mesh]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks
disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”) AND (“drug therapy” ORchemotherapy OR pharmacotherapy OR “pharmacological therapy”)))) OR (“nonpharmacological therapy” OR “non pharmacological therapy” OR“nonpharmacologic therapy” OR “non pharmacologic therapy” OR “nonpharmacological treatment” OR “non pharmacological treatment” OR“nonpharmacologic treatment” OR “non pharmacologic treatment” OR nonpharmacological intervention* OR non pharmacological intervention*
OR nonpharmacologic intervention* OR non pharmacologic intervention* OR “nonpharmacological management” OR “non pharmacologicalmanagement” OR “nonpharmacologic management” OR “non pharmacologic management”) AND (“Frontotemporal Lobar Degeneration” [Mesh]
OR “frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR“frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”)OR “Frontotemporal Lobar
Degeneration/rehabilitation” [Mesh] OR(“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Rehabilitation” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (rehabilitation [TI] OR “occupational therapy” [TI] OR “activities of daily living” [TI] OR “activity of daily living” [TI]))
OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease*
OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”) AND (rehabilitation OR“occupational therapy” OR “activities of daily living” OR “activity of daily living”)) OR “Frontotemporal Lobar Degeneration/nursing” [Mesh] OR(“Frontotemporal Lobar Degeneration/ therapy” [Mesh] AND “Nursing” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR“frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe
dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]))AND nursing [TI] OR((“frontotemporallobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe
dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporal dementia”)AND nursing)OR “Frontotemporal Lobar
Degeneration/diet therapy” [Mesh] OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Nutrition therapy” [Mesh]) OR((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease*[TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (nutrition therapy* [TI] OR diet therapy* [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia”
OR FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal
variant frontotemporal dementia”) AND (nutrition therapy* OR diet therapy*))OR “Frontotemporal Lobar Degeneration/ surgery” [Mesh]
OR(“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND “Surgical Procedures, Operative” [Mesh]) OR ((“frontotemporal lobar
degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease*[TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND (surgery[TI] OR surgical [TI] OR operation [TI] OR operative [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD
OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant
frontotemporal dementia”) AND (surgery OR surgical OR operation OR operative)) OR “Frontotemporal Lobar Degeneration/radiotherapy”[Mesh] OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh] AND “Radiotherapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI]
OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal
lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporal dementia” [TI]) AND (radiotherapy* [TI] OR
chemoradiotherapy* [TI] OR radiosurgery* [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (radiotherapy* OR chemoradiotherapy* OR radiosurgery*)) OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND“Psychotherapy” [Mesh]) OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR
bvFTD [TI] OR pick disease* [TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal

Chapter 8181variant frontotemporal dementia” [TI]) AND psychotherapy* [TI]) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR
FTD OR FTLD OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal
variant frontotemporal dementia”)AND psychotherapy*) OR (“Frontotemporal Lobar Degeneration/therapy” [Mesh]AND “Patient Care” [Mesh])
OR ((“frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI] OR FTLD [TI] OR bvFTD [TI] OR pickdisease* [TI] OR picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia” [TI] OR “frontal variant frontotemporaldementia” [TI]) AND (care [TI] OR cares [TI])) OR ((“frontotemporal lobar degeneration” OR “frontotemporal dementia” OR FTD OR FTLD
OR bvFTD OR pick disease* OR picks disease* OR “frontal lobe dementia” OR “frontotemporal lobe dementia” OR “frontal variant frontotemporaldementia”) AND (care OR cares))
Ichushi search: July 9, 2015 (Thursday)#1 (((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR
Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior type dementia/TI OR Frontotemporal dementia/TI) AND ((SH =Therapeutic use, Treatment, Surgical therapy, Transplantation, Dietary therapy, Radiotherapy, Nursing, Rehabilitation, Prevention)OR Treatment/
MTH OR Treatment/TI OR Therapy/TI)) NOT ((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR
Dementia-frontotemporal type/TH OR Frontotemporal type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal
Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior typedementia/TI OR Frontotemporal dementia/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Therapeutic use/MTH OR Drugtreatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI))) OR ((Frontotemporal lobar degeneration/TH OR Frontotemporal lobar
degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR“Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pick disease/TI OR Pick disease OR Anterior type dementia/TI OR
Anterior type dementia/TI OR Frontotemporal dementia/TI) AND ((SH = Surgical therapy, Transplantation, Radiation therapy, Dietary therapy,
Psychological therapy, Nursing, Rehabilitation) OR Non-pharmacotherapy/TI OR Non-pharmacological treatment/TI OR Rehabilitation/MTH
OR Rehabilitation/TI OR Nursing/MTH OR Nursing/TI OR Surgical operation/MTH OR Surgery/TI OR Surgery/TI OR Transplantation/TI
OR Nutritional management/MTH OR Nutritional therapy/TI OR Dietary therapy/TI OR Diet therapy/TI OR Therapeutic food/TI OR
Psychological therapy/TH OR Psychological therapy/TI OR Psychotherapy/TI OR Psychotherapy/TI OR Radiation treatment/MTH OR
Radiation treatment/TI OR Radiation therapy/TI))

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Clinical Practice Guideline for Dementia 2017

CQ 8-5

What kind of instructions should be given to families and caregiversof frontotemporal lobar degeneration (FTLD) patients?
AnswerFamily and caregiver education based on FTLD symptomatology is recommended.

C

Comments and evidence
In FTLD, psychiatric symptoms and behavioral disorders such as disinhibition, asocial behaviors, stereotypic behaviors,
abnormal eating behaviors, and increased emotional susceptibility become evident from an earlier stage compared to Alzheimer’s
disease dementia 1-3). Due to these various behavioral disorders, caregivers of FTLD patients have a more significant care burden
than caregivers of Alzheimer’s disease dementia patients 4-7). Based on the assessments of patients’ behavioral abnormalities andlanguage impairment, it is vital to help patients’ families understand the disease conditions of individual patients and to provide
them guidance on interventions. Also, FTLD has been designated an intractable disease in Japan since July 1, 2015, and it isimperative to explain and provide guidance on how to apply for a subsidy of medical expenses.
Kumamoto et al. 7) studied two FTLD patients and found that behavioral abnormalities exhibited by these patients,
particularly behaviors of stuffing food into the mouth, poor table manners, resistance to care, and restlessness, were associatedwith substantial care burden 7). Therefore, for family caregivers, individual guidance and support are required according to
the patient’s conditions. Understanding of the disease condition by the family changes the way caregivers interact with thepatients, and the burden on caregivers is often significantly reduced 8).
Nunnemann et al. 9) pointed out that there are very few publications on the burden, problems, and needs of caregivers of
FTLD patients. Specific problems include delayed diagnosis, young-onset age, behavioral disturbances, lack of informationand suitable care facilities, caregivers’ depression, social isolation, and personal needs. Research is needed to identify the realneeds of caregivers of FTLD patients.

▪ References

1) Bozeat S, Gregory CA, Ralph MA, et al. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporaldementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry. 2000; 69(2): 178-186.
2) Bathgate D, Snowden JS, Varma A, et al. Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scand.
2001; 103(6): 367-378.
3) Ikeda M, Brown J, Holland AJ, et al. Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease.
J Neurol Neurosurg Psychiatry. 2002; 73(4): 371-376.
4) Shigenobu K. Care burden for frontotemporal lobar degeneration: comparison with care burden for Alzheimer’s disease dementia. Japanese Journalof Geriatric Psychiatry (Ronen Seishinigaku Zasshi) 2004; 15(Suppl 1): 88-94. (In Japanese)5) de Vugt ME, Riedijk SR, Aalten P, et al. Impact of behavioural problems on spousal caregivers: a comparison between Alzheimer’s disease andfrontotemporal dementia. Dement Geriatr Cogn Disord. 2006; 22(1): 35-41.
6) Boutoleau-Bretonniere C, Vercelletto M, Volteau C, et al. Zarit burden inventory and activities of daily living in the behavioral variant offrontotemporal dementia. Dement Geriatr Cogn Disord. 2008; 25(3): 272-277.
7) Kumamoto K, Arai Y, Hashimoto N, et al. Problems family caregivers encounter in home care of patients with frontotemporal lobar degeneration.
Psychogeriatrics. 2004; 4(2): 33-39.
8) Kaneda K, Hashimoto M, Ikeda M. Degenerate dementia- frontotemporal lobar dementia. Med Rehabil. 2008; 91: 47-54.
9) Nunnemann S, Kurz A, Leucht S, et al. Caregivers of patients with frontotemporal lobar degeneration: a review of burden, problems, needs, andinterventions. Int Psychogeriatr. 2012; 24(9): 1368-1386.

▪ Search formula

PubMed search: July 10, 2015 (Friday)#1 (“Frontotemporal Lobar Degeneration” [Majr] OR “frontotemporal lobar degeneration” [TI] OR “frontotemporal dementia” [TI] OR FTD [TI]
OR FTLD [TI] OR bvFTD [TI] OR Pick disease* [TI] OR Picks disease* [TI] OR “frontal lobe dementia” [TI] OR “frontotemporal lobe dementia”[TI] OR “frontal variant frontotemporal dementia” [TI]) AND (care OR education OR burden OR support*) AND (caregiver* OR family)
Ichushi search: July 10, 2015 (Friday)#1 (Frontotemporal lobar degeneration/TH OR Frontotemporal lobar degeneration/TI OR Dementia-frontotemporal type/TH OR Frontotemporal
type dementia/TI OR “Frontotemporal Lobar Degeneration”/TI OR “Frontotemporal Dementia”/TI OR FTD/TI OR FTLD/TI OR bvFTD OR Pickdisease/TI OR Pick disease OR Anterior type dementia/TI OR Anterior type dementia/TI OR Frontotemporal dementia/TI) AND (Family/TH OR
Family OR Caregiver/TH OR Care) AND (Care burden/TH OR Burden OR Stress/TH OR Stress OR Guidance OR Education OR Support)

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Chapter 9
Progressive Supranuclear Palsy (PSP)Objective
To describe the history, core symptoms, pathology, and etiology of progressive supranuclear palsy (PSP).

Disease Overview
PSP is a group of diseases that exhibit parkinsonism and is a neurodegenerative disease that develops after middle age. The
prevalence was 5.3-5.8 per 100,000 population according to most reports in the world. but recently a prevalence of 17-20 per
100,000 has been reported with ageing of the population. The main symptoms are supranuclear ocular motor dysfunction,
dorsiflexion of the neck (cervical dystonia), akinesia, subcortical dementia, and impulsive behavioral disorder. In recent
years, pathological studies have identified various disease types. Biochemical studies have shown that PSP is one of thediseases belonging to 4-repeat tauopathy (4RT), but the mechanism of tau accumulation and the pathogenesis of neuronalloss remain unclear. Many cases are sporadic, but hereditary PSP is also found. Most hereditary PSP cases are autosomal
dominant. There are no obvious risk factors for disease development, but education history is the only weak risk factor. Tau
haplotype analysis has indicated that PSP is associated with the H1 haplotype, while the frequency of H2 haplotype is low.
However, from the studies of tau haplotypes in Japan, the Japanese population has exclusively H1 haplotype. According toWilliams et al.1), Richardson syndrome (PSP-RS) tends to be more common in men, but there is no gender difference in
PSP-parkinsonism (PSP-P). The disease duration is 5.9 years for Richardson syndrome and 9.1 years for PSP-P. The mostfrequent causes of death are aspiration pneumonia, asphyxia, malnutrition, and trauma. Falls within 1 year of onset,
dysphagia in early stage, and urinary incontinence are poor prognostic factors. There is no effective curative therapy, andonly symptomatic therapies are available.

History and Classification
In 1964, Steele et al.2) reported PSP as a disease entity with main clinical symptoms of axial rigidity, akinesia, tendency tofall, cognitive impairment, and supranuclear ocular motor dysfunction in the vertical direction; as well as pathological findingsof neurogenic changes in the globus pallidus, substantia nigra, subthalamic nucleus, eye movement-related nucleus, tegentum,
dentate nucleus, and inferior olivary nucleus. The first diagnostic criteria for PSP were conducted by Litvan et al. 3) in 1996. Thenin 2007 and 2009, Williams et al. 1) classified PSP cases into Richardson syndrome (54%) that exhibits classical PSP; PSPparkinsonism (PSP-P; 32%) which shows a clinical picture resembling Parkinson’s disease with left-right asymmetric symptoms
partially responsive to L-dopa; and atypical PSP (14%) that includes pure akinesia with gait freezing (PAGF), PSP withcorticobasal syndrome (PSP-CBS), and PSP with progressive non-fluent aphasia (PSP-PNFA) (2009). Researchers in Japan andoverseas have also reported a cerebellar variant of PSP (PSP-C) 4). New diagnostic criteria have been proposed by the International
Movement Disorder Society 5). At present, the disease concept of PSP tends to be expanding, and elucidation of the pathogenesis
is expected to control the etiology of PSP.

▪ References
1) Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009; 8: 270-279.
2) Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A Heterogeneous degeneration involving the brain stem, basal ganglia andcerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10: 333-359.
3) Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski
syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47: 1-9.
4) Koga S, Aoki N, Uitti RJ, et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 2015; 85: 404-412.
5) Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov
Disord 2017; 32: 853-864.

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CQ 9-1

What are the features of dementia symptoms in progressive supranuclear
palsy (PSP)?
Answer• The characteristic dementia symptoms of classical PSP (also termed Richardson syndrome; PSP-RS) are generally referred
to as subcortical dementia. The symptoms include slowed thinking, impulsiveness, stubbornness, and perseveration.
• One-third of the patients with PSP-RS present dementia, personality change, emotional disorder, and memory
impairment as onset symptoms.

Comments and evidence
PSP-RS accounts for approximately one-half of the PSP cases. The clinical features of the cognitive symptoms are described
below.
• Initial symptoms of PSP:
Two-thirds of the cases present motor symptoms and ocular motor-related symptoms as onset symptoms. One-third of thecases present dementia symptoms or psychiatric symptoms at onset. These symptoms include depression, irritability,
aggression, emotional lability, apathy, slowed thinking, and memory impairment. Approximately one-half of them manifest
behavioral disorders as onset symptoms.
• Features of behavioral disorders and cognitive impairment in PSP:The basic symptoms are attention deficit, indifference, and reduced level of interest to the surrounding. These symptoms
were called subcortical dementia in the past, and they show features of frontotemporal dementia including slowed thinking,attention deficit, executive impairment, amnesia, apathy, reduced vocabulary, and depression. The speed of response becomesmarked reduced due to slowed thinking. Initially it seems that the patient has no response to a question, but after a while he/she would give an accurate response. The behavioral disorders are mainly impulsive behavioral disorders and sociallyinappropriate behaviors such as compulsive eating, addiction to gambling, and impulse buying. Some of the behaviors are
considered to be drug-induced, but there is no consensus. Tendency to fall and “applause sign” are manifestations of
behavioral disorder and cognitive impairment. In the study of Yatabe et al. using Neuropsychiatric Inventory (NPI) andStereotypy Rating Inventory (SRI), there were no differences between frontotemporal lobar degeneration (FTD) and PSP.

▪ Further reading
1) Respondek G Stamelou M, Kurz C et al: The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100
definite cases. Mov Disord. 2014; 29: 1758-1766.
2) Williams DR, Lees AJ: Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009; 8: 270-279.
3) O’Sullivn SS, Djamshidian A et al: Impulsive-compulsive spectrum behaviors in pathologically comfirmed progressive supranuclear palsy. Mov
Disord. 2010; 25: 638-642.
4) Yatabe Y, Hashimoto M, et al: Neuropsychiatric symptoms of progressive supranuclear palsy in a dementia clinic. Psychogeriatrics. 2011; 11: 54-59.
5) Hoglinger GU, Respondek G, Stamelou M et al. Clinical diagnosis of progressive supranuclear palsy: The Movement Disorder Society Criteria. Mov
Disord. 2017; 32: 853-864.

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CQ 9-2

Are there useful therapies for cognitive impairment in progressive supranuclear
palsy (PSP)?
Recommendation
Although no therapies for PSP have been developed, there are symptomatic treatments for individual symptoms but notreatment specific for cognitive symptoms.
2C

Comments and evidenceNo curative therapies and no therapies for symptom relief and prevention specifically for PSP have been developed. At
present, symptoms are treated individually. Although drugs that are useful for other diseases are being used for the treatment
of PSP, the efficacy of most of these drug for PSP has not been proven 1, 2).

Pharmacotherapy for psychiatric symptoms of PSP
According to the report of Liepelt et al. 3) in 2010, among the cholinesterase inhibitors, only rivastigmine has been foundto improve cognitive function, but the trial was a small observational study. Clinical trials of drugs for PSP reported since
the last guideline failed to show good results 2, 3). Recently, trial of mesenchymal stem cell transplantation has been started,and experimental therapeutic methods are being developed 4).

▪ References
1) Sorbi S, Hort J et al. EFNS-ENS guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurology. 2012; 19:1159-1179.
2) Poewe W, Mahlknecht P et al: Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. Mov Disord. 2015; 30: 15281538.
3) Liepelt I, Gaenslen A, Godau J, et al: Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: clinical observations
as a basis for power calculations and safety analysis. Alzheimers Dement. 2010; 6: 70-74.
4) Giardano R, Canesi M, Isalberti M et al: Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase 1
controlled, randomized clinical study. J Translat Med. 2014; 12: 14.

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Chapter 10
Corticobasal Degeneration

History
In 1968, Rebeiz et al. reported corticobasal degeneration (CBD) as a clinicopathologically independent disease.
Pathologically, CBD manifests strong asymmetric cerebral cortical atrophy in the frontoparietal lobe, together withdegeneration in the basal ganglia and substantia nigra. Histologically, accumulation of abnormal phosphorylated tau isobserved in neurons and glial cells. CBD is characterized by astrocytic plaque, and is classified as 4-repeat tauopathy (4RT),
like progressive supranuclear palsy (PSP).
The typical clinical features of CBD are cerebral cortical signs including progressive and asymmetric apraxia, as well as
extrapyramidal signs including muscle stiffness. Currently, these signs are referred to as corticobasal syndrome (CBS).
Recently, CBD is used when the disease is pathologically diagnosed, and CBS is used when the disease is clinically diagnosed.

Diagnosis
In the diagnostic criteria of Armstrong et al. (2013), clinical symptoms of CBD were extracted from brain banks andpublished articles reporting at least 5 pathologically proven cases, and four clinical phenotypes associated with CBD
pathology were proposed (CQ10-1). Furthermore, the four clinical phenotypes and other features were combined to create
clinical research criteria for “probable sporadic CBD” that corresponds to pure CBD, and clinical criteria for “possible CBD”
that includes tauopathy other than CBD (CQ10-1). However, subsequent validation study shows that the sensitivity of the
new classification is not different from the conventional diagnostic criteria. Furthermore, the specificity is not high. Therefore,
search for clinical diagnostic criteria with higher sensitivity and specificity or biomarkers will be a challenge for future
research. The definitive diagnosis of CBD is pathological diagnosis.

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CQ 10-1

What are the features of cognitive impairment in corticobasal degeneration(CBD), and what are the test methods?
AnswerIn CBD, cognitive impairment often appears, and impaired executive function, behavioral and personality changes
such as disinhibition, visuospatial disorder, and non-fluent aphasia are observed. A useful test for differentiating CBDfrom other diseases has not been established.
D

Comments and evidence

1. Features of cognitive impairment in CBD
The clinical phenotypes of CBD proposed in the clinical diagnostic criteria of CBD by Armstrong et al. 1) in 2013 consistof the following: (1) corticobasal syndrome (CBS), (2) frontal behavioral-spatial syndrome (FBS), (3) non-fluent/agrammatic
variant of primary progressive aphasia (naPPA), and (4) progressive supranuclear palsy syndrome (PSPS). Apart from thesetypes, cases with a clinical picture resembling Alzheimer’s disease dementia have also been reported. Among the clinicalsymptoms of pathologically confirmed CBD cases, general cognitive impairment is the most frequently seen cerebral corticalsymptom, and is found in 52% of the patients at onset and in 70% during the course of disease 1). Among the four CBDphenotypes, FBS manifests impaired executive function, behavioral/personality changes such as disinhibition, andvisuospatial deficit. Moreover, naPPA manifests effortful, non-fluent speech, and apraxia of speech with distorted speech
production and agrammatism. These symptoms appear before onset of dementia 1).
Lee et al. 2) studied 18 patients with histopathologically confirmed CBD, and found 4 clinical syndromes: progressive nonfluent aphasia (5 patients), behavioral variant frontotemporal dementia (5 patients), executive-motor (7 patients), and posteriorcortical atrophy (1 patient). They reported that behavioral or cognitive problems were the initial symptoms in 15 of 18 patients.

2. Methods for assessing cognitive impairment in CBD
Scales used to assess cognitive impairment in CBD include Mini Mental State Examination (MMSE), Addenbrooke’s
Cognitive Examination (ACE) 3), Dementia Rating Scale (DRS), Frontal Assessment Battery (FAB) 4), and NeuropsychiatricInventory (NPI). A meta-analysis examined whether several higher brain function tests were useful in differentiating
parkinsonian disorders, but evaluation of these tests was difficult due to inadequate sample size 5).

▪ References
1) Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013; 80(5): 496-503.
2) Lee SE, Rabinovici GD, Mayo MC, Clinicopathological correlations in corticobasal degeneration. Ann Neurol. 2011; 70(2): 327-340.
3) Rittman T, Ghosh BC, McColgan P, et al. e Addenbrooke’s Cognitive Examination for the differential diagnosis and longitudinal assessment ofpatients with parkinsonian disorders. J Neurol Neurosurg Psychiatry. 2013; 84(5): 544-551.
4) Marconi R, Antonini A, Barone P, et al. Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders. Neurol Sci. 2012;33(3): 585-593.
5) Lee W, Williams DR, Storey E. Cognitive testing in the diagnosis of parkinsonian disorders: a critical appraisal of the literature. Mov Disord. 2012;27(10): 1243-1254.

▪ Search formula

PubMed search: June 23, 2015 (Tuesday), July 7, 2015 (Tuesday), July 13, 2015 (Monday), August 12, 2015 (Monday)#1 ((“Dementia/diagnosis” [Mesh] OR (dementia [TI] AND (diagnosis [TI] OR diagnostic [TI])) OR “Cognition Disorders/diagnosis” [Mesh] OR(“cognition disorder*” [TI] AND (diagnosis [TI] OR diagnostic [TI]))) AND “corticobasal degeneration”) OR ((corticobasal [TI] OR (“Basal Ganglia/
pathology” [Mesh] AND “Cerebral Cortex/ pathology” [Mesh] AND “Neurodegenerative Diseases/pathology” [Mesh]) OR “Primary Progressive
Nonfluent Aphasia” [Majr] OR “progressive nonfluent aphasia” [TI]) AND (“Cognition Disorders/etiology” [Majr] OR “Cognition” [Majr] OR
cognition [TI] OR cognitive feature* OR behavioral feature* OR cognitive mechanism* OR “emotion processing” OR “Emotions” [Majr]))
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis,
radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH OR Diagnosis/TI)

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CQ 10-2

Are there effective pharmacological and non-pharmacological therapies
for cognitive impairment in corticobasal degeneration (CBD)?
Recommendation

No pharmacological and no non-pharmacological therapies have been confirmed to be effective for treating cognitive
impairment in CBD. When Alzheimer’s disease is considered to be the underlying pathology for CBS, cholinesterase
inhibitor or N-methyl-D-aspartate (NMDA) receptor antagonist may be tried. Rehabilitation is recommended for
language disorders, behavioral disorders, and visuospatial deficits.
2D

Comments and evidence

1. Pharmacotherapy for cognitive impairment
Regarding pharmacotherapy for cognitive impairment in CBD, no effective drugs with an adequate level of evidence havebeen reported. For CBS, cholinesterase inhibitors have been tried based on the personal opinions of experts 1, 2). The effect ofNMDA receptor antagonist is unknown.

2. Pharmacotherapy for behavioral and psychological disorders
There is little evidence of pharmacotherapy for behavioral and psychological symptoms in CBD. Sertraline hydrochloride,
which is a selective serotonin reuptake inhibitor (SSRI) may be effective for depression 1). Cholinesterase inhibitors are used
for apathy and anxiety, but these symptoms are difficult to treat 1).

3. Non-pharmacological therapies
Although evidence of a certain level is lacking, physiotherapy, occupational therapy, and speech therapy may be effective
for cognitive impairment in CBD 1, 2). Cognitive behavioral therapy may be effective in some cases of depression in CBD,
according to expert opinion 2).

▪ References
1) Armstrong MJ. Diagnosis and treatment of corticobasal degeneration. Curr Treat Options Neurol. 2014; 16(3): 282.
2) Boeve BF, Josephs KA, Drubach DA. Current and future management of the corticobasal syndrome and corticobasal degeneration. Handb Clin
Neurol 2008; 89: 533-548.

▪ Search formula

Pharmacotherapy
PubMed search: June 23, 2015 (Tuesday), August 12, 2015 (Monday)#1 (“Dementia/drug therapy” [Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy”[Mesh] OR (“cognition disorder*” [TI] AND (“drug therapy” OR chemotherapy))) AND (“corticobasal degeneration” OR ((“Basal Ganglia”[Mesh] OR “Basal Ganglia Diseases” [Mesh]) AND “Neurodegenerative Diseases” [Mesh]))Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND ((SH = Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/
TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)
Non-pharmacological therapies
PubMed search: June 23, 2015 (Tuesday), August 12, 2015 (Monday)#1 (“Dementia/therapy” [Mesh] OR (dementia [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “Cognition Disorders/therapy” [Mesh] OR (“cognition disorder*” [TI] AND (therapy [TI] OR therapeutic [TI] OR treatment [TI]))) AND (“corticobasal degeneration”
OR ((“Basal Ganglia” [Mesh] OR “Basal Ganglia Diseases” [Mesh]) AND “Neurodegenerative Diseases” [Mesh])) NOT (“Dementia/drug therapy”[Mesh] OR (dementia [TI] AND (“drug therapy” OR chemotherapy)) OR “Cognition Disorders/drug therapy” [Mesh] OR (“cognition disorder*”[TI] AND (“drug therapy” OR chemotherapy)))
Ichushi search: June 23, 2015 (Tuesday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI) AND(corticobasal degeneration/TH OR corticobasal degeneration/TI) AND (Treatment/TH OR Treatment/TI OR Therapy/TI OR (SH = Therapeuticuse, treatment, drug treatment, surgical treatment, transplantation, dietary treatment, psychiatric treatment, radiologic treatment)) NOT ((SH =Pharmacotherapy) OR Pharmacotherapy/TH OR Drug treatment/TI OR Pharmacotherapy/TI OR Therapeutic drug/TI)

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Chapter 11
Argyrophilic Grain Dementia

CQ 11-1

What is the frequency of argyrophilic grain disease (AGD)?
Answer
The frequency of AGD in older people is estimated to be approximately 5-9%, and this disease is by no means rare.
AGD is also known to be associated at high frequencies with other degenerative diseases, especially with corticobasal
degeneration (CBD).
C

Comments and evidence
AGD is a degenerative disease characterized pathologically by argyrophilic granular structures in the brain. Argyrophilic
grains were first reported by Braak and Braak 1) in 1987. Since argyrophilic grains were first found in autopsied brains frompersons with dementia, the condition was called argyrophilic grain dementia (or dementia with grains). However, as
argyrophilic grains were also present in persons without dementia, the disease is now generally called AGD. There are few
studies on the frequency of AGD and its relationship with dementia. The frequency of AGD in older people is estimated tobe approximately 5-9%, and is therefore by no means rare. AGD is known to be associated at high frequencies with otherdegenerative diseases including Alzheimer’s disease and dementia with Lewy body 2, 3). In particular, AGD coexists with
progressive supranuclear palsy and corticobasal degeneration at frequencies of 19% and 41%, respectively.4) Tatsumi et al. 5)
reported that argyrophilic grains were observed in 100% of corticobasal degeneration cases.

▪ References
1) Braak H, Braak E. Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult dementia without Alzheimer changes. Neurosci
Lett. 1987; 76(1): 124-127.
2) Martinez.Lage P, Munoz DG. Prevalence and disease associations of argyrophilic grains of Braak. J Neuropathol Exp Neurol. 1997; 56(2): 157.164.
3) Iseki E, Togo T, Suzuki K, et al. Dementia with Lewy bodies from the perspective of tauopathy. Acta Neuropathol. 2003; 105(3): 265-270.
4) Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol. 2002; 61(6): 547-556.
5) Tatsumi S, Mimuro M, Iwasaki Y, et al. Argyrophilic grains are reliable disease-specific features of corticobasal degeneration. J Neuropathol Exp
Neurol. 2014; 73(1): 30-38.

▪ Search formula
PubMed search: June 19, 2015 (Friday), August 125, 2015 (Tuesday)#1 ((argyrophilic grain disease* OR (“argyrophilic grain” AND (“Dementia” [Mesh] OR dementia OR “Cognition Disorders” [Mesh] OR cognition
disorder*))) AND (“Morbidity” [Mesh] OR morbidity [TI] OR prevalence [TI])) OR (argyrophilic grain* AND (“Dementia/pathology” [Mesh] OR“Nerve Degeneration/pathology” [Mesh]) AND (“Morbidity” [Mesh] OR morbidity OR prevalence OR incidence)) OR (“Dementia/pathology”[Mesh] AND argyrophilic grain disease* [TI] ) OR (argyrophilic grain* [TI] AND “Dementia/pathology” [Majr])
Ichushi search: June 19, 2015 (Friday)#1 (Argyrophilic grain dementia/AL OR ((Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND(Argyrophilic grain/AL OR Argyrophilic cell/TH OR Argyrophilic cell/AL))) AND (prevalence OR incidence OR incidence OR(SH = Epidemiology)
OR Epidemiology/TH)

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CQ 11-2

How is a clinical diagnosis made for argyrophilic grain dementia?
AnswerThe clinical features of argyrophilic grain dementia are as follows: (1) elderly onset; (2) although onset symptom ismemory impairment, behavioral and psychological symptoms such as stubbornness, irritability, delusion, personalitychange, and violent behavior are observed; (3) progresses slowly; (4) cholinesterase inhibitors have limited effectiveness;(5) left-right asymmetrical atrophy of the anterior side of medial temporal lobe, mainly at the ambient gyrus, (6) degreeof atrophy of parahippocampal gyrus measured by volumetry tends to increase proportional to the Mini Mental State
Examination (MMSE) score; (7) functional imaging shows left-right asymmetrically decreased uptake at the medial
temporal lobe, (8) for cerebral spinal fluid biomarkers, amyloid-β (Aβ)42, tau and phosphorylated tau are normal in mostcases.
C

Comments and evidence
In a study of the pattern of progression of argyrophilic grains in serial autopsy brains from older persons, the progressionof argyrophilic grains was classified into: stage 1; localization in the ambient gyrus only, stage 2; progression to the medial
side of temporal lobe, and stage 3; progression to involve the frontobasal region and anterior cingulate gyrus. Among stage
3 cases, 71% had dementia, 21% had mild cognitive impairment, and 8% had some psychiatric symptoms. The stage ofprogression tended to increase with aging, suggesting that argyrophilic grains are aging-related changes 1, 2). In another study,
stage 3 cases were extracted, and the left-right differences of atrophy at the anterior side of medial temporal lobe on
morphological images and those of functional decline on functional images were examined. Left-right asymmetry wasobserved in 90.8% of the cases by histopathological examination, in 42.6% by morphological CT and MR images, and in
all cases by functional SPECT and PET images 3).
Clinical signs of patients with argyrophilic grain dementia confirmed at autopsy include not only memory impairment 4),
but also irritability, stubbornness, and delusional jealousy 5). In argyrophilic grain dementia cases, tau and phosphorylated
tau levels in cerebrospinal fluid are mostly normal, with a few cases showing levels slightly above the cut-off; and Aβ42 levelis also normal, with only a few cases showing low levels 6). Based on the above findings, the clinical features of argyrophilic
grain dementia are listed above in “Answer” section.

▪ References
1) Saito Y, Nakahara K, Yamanouchi H, et al. Severe involvement of ambient gyrus in dementia with grains. J Neuropathol Exp Neurol. 2002; 61(9):789-796.
2) Saito Y, Ruberu NN, Sawabe M, et al: Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004; 63(9): 911-918.
3) Adachi T, Saito Y, Hatsuta H, et al. Neuropathological asymmetry in argyrophilic grain disease. J Neuropathol Exp Neurol. 2010; 69(7): 737-744.
4) Jicha GA, Petersen RC, Knopman DS, et al. Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive
impairment. J Neuropathol Exp Neurol. 2006; 65(6): 602-609.
5) Togo T, Isojima D, Akatsu H, et al. Clinical features of argyrophilic grain disease: a retrospective survey of cases with neuropsychiatric symptoms.
Am J Geriatr Psychiatry. 2005; 13(12): 1083-1091.
6) Adachi S, Sato Y, Nakajima K, et al. Diagnosis of argyrophilic grain dementia. Dementia Japan. 2014; 28(2): 182-188. (In Japanese)▪ Search formula
PubMed search: June 19, 2015 (Friday), August 125, 2015 (Tuesday)#1 ((argyrophilic grain disease* AND (“Diagnosis” [Mesh] OR diagnosis [TI] OR diagnostic[TI])) OR (“argyrophilic grain” AND (“Dementia/
diagnosis” [Mesh] OR (dementia AND (diagnosis OR diagnostic)) OR “Cognition Disorders/diagnosis” [Mesh] OR (cognition disorder* AND(diagnosis OR diagnostic))))) OR (“Dementia/diagnosis” [Majr] AND grain* [TI] AND argyrophilic grain*)
Ichushi search: June 19, 2015 (Friday)#1 (argyrophilic grain dementia/AL OR ((Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND(Argyrophilic grain/AL OR Argyrophilic cell/TH OR Argyrophilic cell/AL))) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray
diagnosis, radionuclide diagnosis, ultrasound diagnosis)OR Diagnosis/TH OR Diagnosis/TI)

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CQ 11-3

What kinds of treatments are available for argyrophilic grain dementia?
Recommendation
There are no specific therapies for argyrophilic grain dementia. In practice, argyrophilic grain dementia is treatedaccording to the therapies used for Alzheimer’s disease dementia. However, cholinesterase inhibitors for argyrophilic graindementia cannot be expected to be as effective as for Alzheimer’s disease dementia and dementia with Lewy body.

2DComments and evidence
There are no therapies specifically for argyrophilic grain dementia. Even if this disease is clinically suspected, treatments
are given according to those used for Alzheimer’s disease dementia. In this disease, loss of cholinergic neurons in the basal
nucleus of Meynert is mild 1). Therefore, cholinesterase inhibitors for this disease cannot be expected to be as effective as for
Alzheimer’s disease dementia and dementia with Lewy body.

▪ References
1) Tolnay M, Schwietert M, Monsch AU, et al. Argyrophilic grain disease: distribution of grains in patients with and without dementia. Acta
Neuropathol. 1997; 94(4): 353-358.

▪ Search formula#1 ((argyrophilic grain disease* AND (Therapy [Mesh] OR therapy [TI] OR therapeutic [TI] OR treatment [TI])) OR “argyrophilic grain” AND(“Dementia/therapy” [Mesh] OR(dementia AND (therapy OR therapeutic OR treatment)) OR “Cognition Disorders/therapy” [Mesh] OR(“cognition disorder*” AND (therapy OR therapeutic OR treatment)))) OR (argyrophilic grain* AND (therapy [Mesh] OR therapy [TI] ORtherapeutic [TI] OR treatment [TI] OR “Dementia/therapy” [Mesh]))Ichushi search: June 21, 2015 (Sunday)#1 (Argyrophilic grain dementia/AL OR ((Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI) AND(Argyrophilic grain/AL OR Argyrophilic cell/TH OR Argyrophilic cell/AL))) AND ((SH = Therapeutic use, treatment, drug treatment, surgicaltreatment, transplantation, dietary treatment, psychiatric treatment, radiologic treatment, nursing, rehabilitation, prevention) OR Treatment/TH
OR Treatment/TI OR Therapy /TI)

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Chapter 12
Senile Dementia of the Neurofibrillary
Tangle TypeCQ 12-1

What kind of disease is senile dementia of the neurofibrillary tangle type
(SD-NFT)?
AnswerSD-NFT is a subtype of senile dementia characterized by numerous neurofibrillary tangles (NFTs) mainly in the
hippocampus but very few senile plaques. This disease is often diagnosed clinically as Alzheimer’s disease dementia.

Comments and evidence
1. Concept

SD-NFT is a subtype of senile dementia characterized by the presence of numerous NFTs mainly in the hippocampus,
and the incidence increases with aging. SD-NFT is reported to constitute 1.7-5.6% of autopsy cases of dementia in older
people and account for 20% of dementia cases in those over 90 years of age 1). Among the dementia cases in the Hisayama
study, 2.9% was classified as SD-NFT, and the percentage was 4.9% when limited to autopsy cases 2). On the other hand,
the term “primary age-related tauopathy (PART)” has been proposed as a pathological term for the condition in which NFTs
are chiefly distributed in the medial temporal lobe while senile plaques are absent or very scarce 3, 4). Clinically, this isperceived as a concept of spectrum including the states from normal cognitive function to dementia through mild cognitive
impairment.

2. Clinical features
SD-NFT is considered to be a pathological condition of accelerated aging process of the brain. The clinical features are as
follows 1, 3, 5):(1) Common in the late old age(2) Progresses slowly(3) Memory impairment as onset symptom(4) Other cognitive impairments and personality changes are relatively mild
(5) Rare appearance of delirium and extrapyramidal symptoms(6) Imaging study shows atrophy of hippocampal region and expansion of inferior horn of lateral ventricle.

3. Differential diagnosis
Many cases of SD-NFT are diagnosed during life as Alzheimer’s disease dementia, and many pathological findings of
SD-NFT overlap with those of argyrophilic grain dementia and vascular lesions.
Although SD-NFT shares many common clinical features with late-onset Alzheimer’s disease dementia, such as memory
impairment as the core symptom and lesions enhanced in the medial temporal lobe, SD-NFT is a more slowly progressive
disease, and amyloid PET is useful for differentiation.
Both argyrophilic grain dementia and SD-NFT are classified as late-onset tauopathy, and the two share common features
including lesion in the medial temporal lobe and memory impairment as onset symptom. However, in argyrophilic graindementia, although memory impairment is the main feature, other symptoms such as irritability, behavioral abnormalities,
and personality change are a characteristic feature and useful for differentiation. In addition, the medial temporal lobe
atrophy in argyrophilic grain dementia is asymmetric, which is also a differentiation feature. The medial temporal lobe
atrophy is anterior-dominant in argyrophilic grain dementia but is relatively prominent at the posterior side in SD-NFT .
These features are helpful in differential diagnosis 1, 3, 5).

4. Treatment
In clinical practice, SD-NFT is often diagnosed as Alzheimer’s disease dementia and treated with cholinesterase inhibitors.
There are currently no therapies that have proven efficacy for SD-NFT 1, 3, 5).

198

Clinical Practice Guideline for Dementia 2017▪ References
1) Yamada M. Neurological syndromes (second edition) II: Senile dementia of the neurofibrillary tangle type. Japanese Journal of Clinical Medicine
Supplement (Bessatsu Nippon Rinsho) 2014; (27): 51-56. (In Japanese)
2) Matsui Y, Tanizaki Y, Arima H, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol
Neurosurg Psychiatry. 2009; 80(4): 366-370.
3) Yamada M. Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis.
Neuropathology. 2003; 23(4): 311-317.
4) Yamada M. On the concept of senile dementia of the neurofibrillary tangle type (SD-NFT) and primary age-related tauopathy (PART). Dementia
Jpn. 2016; 30: 103-111. (In Japanese)
5) Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta
Neuropathol. 2014; 128(6): 755-766.

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Chapter 13
Huntington Disease

CQ 13-1

What are the features and diagnosis of cognitive symptoms in Huntington
disease?
AnswerAmong the cognitive impairments in Huntington’s disease, memory function and executive function are particularly
affected. Psychiatric symptoms such as depression, anxiety, irritability, apathy, and perseveration are often observed. The
definitive diagnosis is by genetic diagnosis.
B

Comments and evidence
Huntington’s disease is an autosomal dominant hereditary disease, manifesting adult-onset chorea and psychiatric
symptoms as the main symptoms. The causative gene of Huntington’s disease is the huntingtin (HTT ) gene located in the
short arm of chromosome 4 (4q16.3). The gene consists of an unstable repeated CAG sequence, and abnormal expansion ofthis sequence leads to the development of Huntington’s disease. While the number of CAG repeats in a normal allele is lessthan 26, an increase in number of repeats to over 36 is considered to cause Huntington’s disease. In addition, the onset age
becomes younger and the disease becomes more severe in successive generations (genetic anticipation), and inheritance fromthe father may result in more severe disease. Core dementia symptoms are personality changes and cognitive impairment.
On the other hand, affective symptoms such as emotional lability, losing temper, irritability, stubbornness and apathy arepresent to various degrees 1). The definitive diagnosis is by genetic testing 2, 3), and this genetic test (HTT gene CAG repeat
sequence analysis) is covered by health insurance in Japan.

▪ References
1) Shannon KM. Huntington’s disease-clinical signs, symptoms, presymptomatic diagnosis, and diagnosis. Handb Clin Neurol. 2011; 100: 3-13.
2) Ross CA, Aylward EH, Wild EJ, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014;10(4):204-216.
3) Reilmann R, Leavitt BR, Ross CA, et al. Diagnostic criteria for Huntington’s disease based on natural history. Mov Disord. 2014; 29(11): 13351341.

▪ Search formula
PubMed search: May 28, 2015 (Thursday)#1 “Huntington Disease/diagnosis” [Mesh]
Ichushi search: May 28, 2015 (Thursday)#1 (Huntington disease OR “Huntington Disease”) AND ((SH = Diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, radionuclide
diagnosis, ultrasound diagnosis) OR Symptom OR Feature OR Syndrome OR Sign OR Finding)202

Clinical Practice Guideline for Dementia 2017

Chapter 14
Vascular Dementia

CQ 14-1

What are the diagnostic criteria for vascular dementia (VaD)?
AnswerRepresentative diagnostic criteria for VaD include the International Statistical Classification of Diseases and Related
Health Problems (ICD-10) published by the World Health Organization (WHO), the Diagnostic and Statistical Manualof Mental Disorders, Fifth Edition (DSM-5) published by American Psychiatric Association, the diagnostic criteria forischemic vascular dementia proposed by Alzheimer’s Disease Diagnostic and Treatment Center (ADDTC) in California,
and the NINDS-AIREN diagnostic criteria published by the National Institute of Neurological Disorders and Stroke(NINDS) and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN).
In the statement for healthcare professionals from the American Heart Association/ American Stroke Association(AHA/ASA), the prodromal stage of VaD is termed vascular mild cognitive impairment (VaMCI, or VCI-no dementia),
and the term vascular cognitive impairment (VCI) is proposed to include the spectrum of severity from the prodromal
stage to VaD.
A

Comments and evidence
VaD is a subtype of dementia caused by cerebrovascular disorder, with heterogeneous underlying pathology. The NINDSAIREN diagnostic criteria, which was developed for research, have high specificity and are widely used clinically, but the low
sensitivity is a drawback 1).
In 2011, AHA/ASA proposed an inclusive term “vascular cognitive impairment (VCI)” from the viewpoint of treatment
priority 2). VCI includes VaD and VCI-no dementia or vascular mild cognitive impairment (VaMCI). Note that although theterm VCI in the broad sense includes not only the prodromal stage but also the dementia stage, “VCI-no dementia” is also
used to describe the prodromal stage 2, 3).
On the other hand, in DSM-5 published in 2013, dementia is positioned as a major neurocognitive disorder. Within thiscategory, VaD is classified as “major vascular neurocognitive disorder” 4).

▪ References
1) Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS. AIREN
International Workshop. Neurology. 1993; 43(2): 250-260.
2) Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals fromthe American Heart Association/American Stroke Association. Stroke. 2011; 42(9): 2672- 2713.
3) Gorelick PB, Nyenhuis D. Understanding and treating vascular cognitive impairment. Continuum (Minneap Minn). 2013; 19(2 Dementia): 425437.
4) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM.5. Arlington, VA: American
Psychiatric Association; 2013.

▪ Search formula
PubMed search: June 18, 2015 (Thursday)#1 “Dementia, Vascular/diagnosis” [Mesh] OR (“vascular dementia” AND (diagnosis OR diagnostic)) OR (“vascular cognitive impairment” AND(diagnosis OR diagnostic)) OR (“Vascular Diseases/complications” [Mesh] AND “Cognition Disorders/diagnosis” [Mesh])
Ichushi search: June 18, 2015 (Thursday)#1 (Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic
imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH) AND (Diagnostic criteria/AL OR Judgment criteria/
AL OR Criteria/TI OR Evaluation criteria/TH OR Classification/TH OR Classification/TI OR ICD classification /TH OR DSM/TH)

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Clinical Practice Guideline for Dementia 2017

CQ 14-2

How are the types of vascular dementia (VaD) classified?
Answer
According to the NINDS-AIREN diagnostic criteria, VaD is classified into the following types: (1) multi-infarctdementia (MID), (2) strategic single infarct dementia, (3) small vessel disease dementia, (4) hypoperfusion vasculardementia, (5) hemorrhagic vascular dementia, and (6) others.
A

Comments and evidence
VaD is a type of dementia caused by cerebrovascular disorder, and its underlying pathology is heterogeneous.
The NINDS-AIREN diagnostic criteria which were developed for research classify VaD into the following clinicalsubtypes 1).
(1) Multi-infarct dementia (MID)(2) Strategic single infarct dementia(3) Small vessel disease dementia(4) Hypoperfusion vascular dementia(5) Hemorrhagic vascular dementia(6) Others
In small vessel disease dementia, lacunar infarction, white matter lesions (leukoaraiosis), cerebral hemorrhage, andmicrobleeds are observed in the territory of penetrating arteries as a result of arteriolosclerosis, while cerebral amyloid
angiopathy is observed in cortical regions. Small vessel disease dementia that develops as a result of arteriolosclerosis is called
subcortical vascular dementia. Subcortical vascular dementia is divided into two types: multiple lacunar infarct dementia
when lacunar infarcts are the main cause, and Binswanger disease when white matter lesions are the main cause.
MID is mainly caused by multiple large and small cerebral infarcts in the cortical region. The clinical course is characterized
by acute onset or step-wise deterioration, and the symptoms include aphasia, apraxia, agnosia, visuospatial deficit,
constitutional impairment and executive dysfunction, together with motor paralysis. Strategic single infarct dementia iscaused by cerebral infarcts in areas important for higher brain function. These include the cortical region in the dominanthemisphere such as the angular gyrus and territories of the anterior cerebral artery, the middle cerebral artery, and theposterior cerebral artery, and the subcortical region in the thalamus or basal forebrain.

▪ References
1) Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN
International Workshop. Neurology. 1993; 43(2): 250-260.

▪ Search formula
PubMed search: June 18, 2015 (Thursday)#1 “Dementia, Vascular/diagnosis” [Mesh] OR (“vascular dementia” AND (diagnosis OR diagnostic)) OR (“vascular cognitive impairment” AND(diagnosis OR diagnostic)) OR (“Vascular Diseases/complications” [Mesh] AND “Cognition Disorders/diagnosis” [Mesh])
Ichushi search: June 18, 2015 (Thursday)#1 (Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic
imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH) AND Diagnostic criteria/AL OR Judgment criteria/AL
OR Criteria/TI OR Evaluation criteria/TH OR Classification/TH OR Classification/TI OR ICD classification/TH OR DSM/TH)

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CQ 14-3

What are the imaging features of vascular dementia (VaD)?
AnswerSmall vessel disease dementia, the most common type of VaD, is characterized by lacunar infarcts and white matterlesions. If the extent and distribution of a lesion adequately explain the neurological symptoms, it is considered to be theculprit lesion of dementia. On the other hand, the temporal relationship between stroke and onset of dementia may
support the culprit lesion in some cases, including multi-infarct dementia and strategic single infarct dementia. Hereditaryvascular dementia includes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).
They show extensive white matter lesions, lacunar infarcts, microbleeds, and brain atrophy, and are characterized by whitematter lesion in the temporal pole.
A

Comments and evidence
The most common type of VaD is cerebral small vessel disease dementia. Although lacunar infarcts and white matter lesions
are characteristic of this disease, patients may remain asymptomatic even after lacunar infarcts have occurred, and do notnecessarily show a course of cognitive impairment characterized by stepwise deterioration of dementia after stroke. In suchcases, if the extent, distribution, and location of the small blood vessel lesion adequately explain the neurological symptoms(neuroimaging-supported), the lesion is considered to be the culprit lesion of dementia. On the other hand, the temporal
relationship between stroke and dementia may provide support for a culprit lesion of dementia (temporally supported) as
evidence for diagnosis, and multi-infarct dementia and strategic single infarct dementia belong to this type 1, 2).
The MRI features of VaD include lacunar infarct, white matter lesion, cerebral hemorrhage (deep type, subcortical type),
multiple cortical infarcts, microbleeds, cortical micro-infarct, localized brain surface hemosiderin deposition, perivascularspace enlargement, watershed infarct, and cortical laminar necrosis. Lacunar infarct is an infarct with a diameter of 3 to 13
mm occurring in the territory of penetrating arteries, and is observed as hypointensity on T1-weighted MRI, hyperintensity
on T2-weighted image, and hypointensity with a rim of hyperintensity on FLAIR image 3). White matter lesion is observed
as normal to hypointensity on T1-weighted image, and hyperintensity on T2-weighted and FLAIR images. White matterlesions are relatively infrequent in the occipital lobe and temporal lobe, although CADASIL and CARASIL are characterized
by lesions in the temporal pole 4, 5).
Iadecola 2) described the correlation of image abnormalities with clinical subtypes. Changes in cerebral small blood vessels
caused by arteriolosclerosis and amyloid angiopathy are difficult to visualize by conventional MRI. However, since detailed
brain imaging has accurately detected vascular lesions caused by cerebral small vessel disease, clinical and imaging findings
together have provided insight on the concept of cerebral small vessel disease 6, 7).

▪ References
1) Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS.AIREN
International Workshop. Neurology. 1993; 43(2): 250-260.
2) Iadecola C. The pathobiology of vascular dementia. Neuron. 2013; 80(4): 844.866.
3) Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing andneurodegeneration. Lancet Neurol. 2013; 12(8): 822-838.
4) O’Sullivan M, Jarosz JM, Martin RJ, et al. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology.
2001; 56(5): 628-634.
5) Tomimoto H, Ohtani R, Wakita H, et al. Small artery dementia in Japan: radiological differences between CADASIL, leukoaraiosis and Binswanger’s
disease. Dement Geriatr Cogn Disord. 2006; 21(3): 162-169.
6) Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010; 9(7): 689701.
7) Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013; 12(5):483-497.

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▪ Search formula
PubMed search: June 18, 2015 (Thursday)#1 (“Dementia, Vascular/diagnosis” [Mesh] OR (“vascular dementia” AND (diagnosis OR diagnostic)) OR (“vascular cognitive impairment” AND(diagnosis OR diagnostic)) OR (“Vascular Diseases/complications” [Mesh] AND “Cognition Disorders/diagnosis” [Mesh])) AND (“Diagnostic
Imaging” [Mesh] OR CT [TIAB] OR “computed tomography” OR MRI OR “magnetic resonance imaging” OR SPECT OR “single-photon
emission computed tomography” OR PET OR “positron emission tomography”)
Ichushi search: June 18, 2015 (Thursday)#1 (Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND ((SH = Diagnostic use, diagnosis, diagnostic
imaging, X ray diagnosis, radionuclide diagnosis, ultrasound diagnosis) OR Diagnosis/TH) AND (Diagnostic imaging/TH OR CT/TI OR
Computer tomography OR Computer tomography OR MRI/TI OR magnetic resonance imaging OR magnetic resonance tomography OR
Magnetic resonance imaging OR Nuclear magnetic resonance imaging OR SPECT/TI OR Single photon emission computed tomography OR
Single photon emission computed tomography OR Single photon computed tomography OR Single photon emission computed tomography OR
Single photon emission computed tomography OR PET/TI OR Positron emission tomography OR Positron emission tomography)

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CQ 14-4What is the condition when vascular dementia (VaD) coexists with
Alzheimer’s disease dementia?
AnswerAlzheimer’s disease dementia and cerebrovascular disorders have common risk factors, and they tend to coexist. Thereis a disease concept of Alzheimer’s disease with cerebrovascular disorder (CVD) (AD with CVD), or mixed dementia. In
the advanced stage of Alzheimer’s disease dementia, CVD has little effect on cognitive function. In the early stage of
Alzheimer’s disease dementia, however, CVD is a factor that promotes cognitive impairment.
B

Comments and evidence
The proportion of patients with mixed dementia; Alzheimer’s disease dementia coexisting with VaD, increases with aging.
The percentage of mixed dementia among all dementia cases varies widely from 0 to 55% even in pathological reports 1). In
general, when cerebrovascular disorder and Alzheimer pathology coexist with either one of them capable of causing dementia,
the condition is called mixed dementia. However, there is also opinion that mixed dementia should be defined as the coexistence of both diseases (Alzheimer’s disease with CVD). This difference in definition may be a reason for the widely
variable frequency reported 1).
Patients with mixed brain pathologies such as Alzheimer’s disease dementia, CVD, and dementia with Lewy body are 2.8
times more likely to manifest dementia compared to those with only one disease 2). CVD has little effect on cognitive
function in the advanced stage of Alzheimer’s disease dementia, but CVD is a factor that promotes cognitive impairment in
the early stage of Alzheimer’s disease dementia 3).

▪ References
1) Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc. 2002; 50(8): 1431-1438.
2) Schneider JA, Arvanitakis Z, Bang W, et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.
Neurology. 2007; 69(24): 2197-2204.
3) Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer’s disease—lessons from pathology. BMC Med. 2014; 12: 206.

▪ Search formula
PubMed search: June 18, 2015 (Thursday)#1 ((“Dementia, Vascular” [Mesh] OR “vascular dementia” OR “vascular cognitive impairment” OR (“Vascular Diseases/ complications” [Mesh]
AND “Cognition Disorders” [Mesh])) AND (“Alzheimer Disease” [Mesh] OR alzheimer*)) OR (“Alzheimer Disease” [Majr] AND “Cerebrovascular
Disorders” [Majr]) OR (“mixed dementia” [TI] AND “Dementia” [Mesh])
Ichushi search: June 18, 2015 (Thursday)#1 ((Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI OR Cardiovascular disorder/MTH OR Cardiovasculardisorder/TI) AND (Alzheimer’s disease/TH OR Alzheimer’s disease/TI OR Alzheimer type/TI)) OR (Mixed dementia/TI OR Mixed dementia/
TI OR Mixed type dementia/TI OR Mixed type dementia/TI OR Mixed dementia/TI OR Mixed dementia/TI)

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Clinical Practice Guideline for Dementia 2017

CQ 14-5

What are the clinical course and prognosis of vascular dementia (VaD)?
Answer
The typical clinical course of VaD starts with post-stroke dementia in which dementia develops after a stroke, followed
by stepwise deterioration of cognitive function after each stroke episode. However, cerebral small vessel disease has aslowly progressive course and may be difficult to differentiate from degenerative dementia.
Patients with VaD has significantly shorter survival than persons without dementia. Although survival has beenreported to be shorter in VaD patients than in those with Alzheimer’s disease dementia, there is no sufficient scientificevidence.
C

Comments and evidence
In VaD, cognitive impairment typically deteriorates in a stepwise manner after or associated with each stroke episode.
Dementia that develops after the first stroke is called post-stroke dementia. In community epidemiological studies, post-stroke
dementia occurs in 30% of stroke patients, and the prevalence increases from 7% after 1 year to 48% after 25 years 1). Somecases of post-stroke dementia are caused by Alzheimer’s disease dementia, accounting for 19-61% of post-stroke dementia.
The survival of patients with VaD is worse than control subjects without dementia 2-4). Compared to Alzheimer’s disease
dementia, survival of VaD is significantly poorer in some reports 5-8), but not significantly different in others 4, 9), withinconsistent results. The average survival time after onset of VaD was 5.1 years for males and 6.7 years for females, andsurvival after onset of Alzheimer’s disease dementia patients was 5.0 years for males and 7.8 years for females, showing atendency of shorter overall survival in VaD patients 5). In the Hisayama study that followed 828 older people for over 17
years, 275 persons developed dementia and 164 were autopsied. The results showed that the 10-year survival rate was lower
in dementia with Lewy bodies (2.2%), while there was no significant difference between Alzheimer’s disease dementia(18.9%) and VaD (13.2%) 4).
Many reports have shown age and severity of stroke to be predictors of cognitive impairment after stroke. In the Efficacy
of Nitric Oxide in Stroke (ENOS) trial that analyzed 1,572 stroke patients, 38% showed cognitive decline within 3 months,
and was associated with not only age and stroke severity, but also hypertension, atrial fibrillation, and brain atrophy 10).

▪ References
1) Leys D, Henon H, Mackowiak-Cordoliani MA, et al. Poststroke dementia. Lancet Neurol. 2005; 4(11): 752-759.
2) Barclay LL, Zemcov A, Blass JP, et al. Survival in Alzheimer’s disease and vascular dementias. Neurology. 1985; 35(6): 834-840.
3) Martin DC, Miller JK, Kapoor W, et al. A controlled study of survival with dementia. Arch Neurol. 1987; 44(11): 1122-1126.
4) Matsui Y, Tanizaki Y, Arima H, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol
Neurosurg Psychiatry. 2009; 80(4): 366-370.
5) Molsa PK, Marttila RJ, Rinne UK. Long-term survival and predictors of mortality in Alzheimer’s disease and multi-infarct dementia. Acta Neurol
Scand. 1995; 91(3): 159-164.
6) Chui H, Gonthier R. Natural history of vascular dementia. Alzheimer Dis Assoc Disord. 1999; 13 Suppl 3: S124-S130.
7) van Dijk PT, Dippel DW, Habbema JD. Survival of patients with dementia. J Am Geriatr Soc. 1991; 39(6): 603-610.
8) Kua EH, Ho E, Tan HH, et al. e natural history of dementia. Psychogeriatrics. 2014; 14(3): 196-201.
9) Freels S, Nyenhuis DL, Gorelick PB. Predictors of survival in African American patients with AD, VaD, or stroke without dementia. Neurology.
2002; 59(8): 1146-1153.
10) Ankolekar S, Renton C, Sare G, et al. Relationship between poststroke cognition, baseline factors, and functional outcome: data from “efficacy of
nitric oxide in stroke” trial. J Stroke Cerebrovasc Dis. 2014; 23(7): 1821-1829.

▪ Search formula
PubMed search: June 18, 2015 (Thursday)#1 (“Dementia, Vascular” [Majr] OR “vascular dementia” [TI] OR “vascular cognitive impairment” [TI] OR (“Vascular Diseases/complications”[Majr] AND “Cognition Disorders” [Majr])) AND (“Prognosis” [Mesh] OR “Disease Progression” [Mesh] OR prognosis [TI] OR prole [TI] OR
course[TI] OR outcome[TI] OR “natural history” [TI])
Ichushi search: June 18, 2015 (Thursday)#1 (Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND (Prognosis/TH OR Prognosis/TI OR Natural
course/TI)

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CQ 14-6

What are the systemic complications and associated symptoms of vasculardementia (VaD)?
Answer(1) VaD is often accompanied by gait disturbance, falls, urinary disorder, pseudobulbar paralysis, and mood disorders
such as depression. In addition to stroke, VaD may be complicated by systemic vascular disorders such as ischemic heartdisease and peripheral artery disease.
(2) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is
associated with migraine with aura, mood disorder (depression), and arteriosclerotic changes in the fundus.
(3) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is
associated with not only dementia but also alopecia (baldness) and low back pain associated with spondylosis deformans.

Comments and evidence
The most widely used diagnostic criteria for VaD are the diagnostic criteria of the National Institute of Neurological
Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDSAIREN) 1). The NINDS-AIREN diagnostic criteria describe specific systemic complications and associated symptoms
including early presence of gait disturbance, unstable gait and frequent falls, early presence of urinary disorder, pseudobulbar
palsy, personality disorder, abulia, depression, and emotional incontinence. On the other hand, “features that make thediagnosis of VaD unlikely” include (1) early onset of memory deficit or cognitive impairments including aphasia, apraxia,
and agnosia, in the absence of corresponding focal lesions on brain imaging; (2) absence of neurological signs; and absenceof cerebrovascular lesions on brain CT or MRI. Compared to Alzheimer’s disease dementia, VaD is often accompanied by
impaired physical functions such as neurologic deficit symptoms.
Depression is significantly more common in VaD than in Alzheimer’s disease dementia, suggesting that VaD may worsen
depression 2-4). The manifestation of depression after onset of stroke is attracting attention as post-stroke depression.
CADASIL, which is a hereditary VaD, is known to be accompanied by migraine with aura, mood disorder (depression),and arteriosclerotic changes in the fundus 5).
Furthermore, CARASIL, also a hereditary VaD, is known to be associated with not only dementia but also alopecia andlower back pain associated with spondylosis deformans 6).

▪ References
1) Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN
International Workshop. Neurology. 1993; 43(2): 250-260.
2) Rockwood K, Moorhouse PK, Song X, et al. Consortium to Investigate Vascular Impairment of Cognition (CIVIC) Cohort. Disease progression
in vascular cognitive impairment, cognitive, functional and behavioural outcomes in the Consortium to Investigate Vascular Impairment of
Cognition (CIVIC) cohort study. J Neurol Sci. 2007; 252(2): 106-112.
3) Looi JC, Sachdev PS. Differentiation of vascular dementia from AD on neuropsychological tests. Neurology. 1999; 53(4): 670-678.
4) Health, Welfare and Labor Sciences Research Grant for Longevity Science Research Project. Study on diagnostic procedure for cerebrovasculardementia based on ICD-10 classification (Principal investigator: Ken Nagata). Summary research report for 2005. 2006. (In Japanese)
5) Benisty S, Hernandez K, Viswanathan A, et al. Diagnostic criteria of vascular dementia in CADASIL. Stroke. 2008; 39(3): 838-844.
6) Nozaki H, Nishizawa M, Onodera O. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.
Stroke. 2014; 45(11): 3447-3453.

▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 “Dementia, Vascular/complications” [Majr] OR (“vascular dementia” [TI]AND complication* [TI]) OR (“vascular cognitive impairment*” [TI]
AND complication* [TI])
Ichushi search: June 27, 2015 (Saturday)#1 (Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND (Complication/TI OR Associated symptom/TI)

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CQ 14-7

What are the risk factors for vascular dementia (VaD) and how are they
controlled?
Recommendation(1) VaD risk factors include aging, lack of exercise, a history of stroke (especially recurrent), hypertension, diabetes,
dyslipidemia, obesity, atrial fibrillation, and smoking.
(2) For prevention of VaD, antihypertensive therapy for midlife hypertension is recommended. 1B However, noconsensus has been reached regarding the target blood pressure reduction.
(3) Smoking cessation is recommended for VaD prevention. 1B(4) Physical exercise is recommended for VaD prevention. 2C(5) Continuous weight control from midlife (prevention of obesity) is recommended for VaD prevention. 2C

Comments and evidence
The Hisayama Study in Japan identified aging, low score in Hasegawa Dementia Scale, a history of stroke, and highsystolic blood pressure as significant risk factors for VaD, while high hematocrit also tended to be a risk. In particular, midlife
hypertension has been shown to be a strong risk factor for VaD 1, 2), and midlife hypertension should be treated actively fromthe viewpoint of dementia prevention.
On the other hand, among the large-scale randomized trials of antihypertensive drugs conducted mainly in older people,
6 trials also assessed cognitive function as an outcome measure. Among these 6 trials, 4 trials found no definitive effects ofantihypertensives on the risk of dementia and on cognitive function 3), while the remaining 2 trials showed usefulness ofthese agents in reducing the risk of dementia in one trial (Syst-Eur trial) 4) and demonstrated efficacy for post-stroke dementia
in the other trial (PROGRESS trial) 5, 6).
As described above, there is inadequate scientific evidence for antihypertensive treatment and the optimal target of bloodpressure reduction in older people. Therefore, no conclusions have been reached regarding the effect of antihypertensive
treatment for late-life hypertension on the prevention of dementia. However, antihypertensives are prescribed because there
is no evidence that they deteriorate cognitive function.
Diabetes is a risk factor for stroke, but glycemic control alone does not prevent the recurrence of stroke, and control ofother risk factors including hypertension is important. There is insufficient scientific evidence that using insulin therapy for
glycemic control improves cognitive function 7). Statin use reduces stroke by 17% 98), but the effects on cognitive function areinconsistent among reports 9). In one study, use of strong statins for more than 1 year reduced new-onset dementia (hazard
ratio 0.71, 95% confidence interval 0.61 to 0.82) 10), but dementia was not classified into subtypes in that study. In addition,a cohort study in residents aged over 60 years in Taiwan showed that the use of strong statins reduced the incidence of newonset dementia [hazard ratio 0.73 (95% confidence interval 0.65 to 0.81)]. The effect was not significant when analysis was
focused only on VaD [hazard ratio: 0.92 (95% confidence interval 0.72-1.18)].
A meta-analysis (19 prospective studies with follow-up periods of 2 to 30 years) has revealed that smoking is a risk factor
of VaD, as is for Alzheimer’s disease dementia 11). The relative risk of VaD in current smokers is 1.78-fold compared withthose who have never smoked, and this result is almost the same as that for Alzheimer’s disease dementia (1.79-fold) 11).
Although further studies are needed to determine the extent of VaD risk reduction by smoking cessation, smoking cessation
is desirable for VaD prevention.
In terms of physical activity, a prospective study of 749 older people observed for an average of 3.9 years evaluated theeffects of exercise in 54 persons who developed Alzheimer’s disease dementia and 27 people who developed VaD. In thisanalysis, exercise and walking reduced the risk of developing VaD 12). Therefore, moderate physical activity is desirable.
In relation to eating habits, antioxidants (vitamins E and C) and fish-derived lipids (consumption of fatty fish) protect against
VaD, while fried fish, elevated homocysteine, and low levels of folic acid and vitamins B12 increase the risk of VaD 13). However,for older people with high blood levels of homocysteine, the risk of dementia cannot be reduced by supplementation withvitamin B complex 14).
It has been shown that both underweight and obesity correlate with dementia (U-shape phenomenon) 15). In particular,
obesity (BMI ≥ 30) increases the risk of developing VaD by a factor of 5.01 in a prospective study of 10,136 persons aged 40

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to 45 years with a mean follow-up period of 36 years. However, in a short-term (3-5 years) study in older people, thecorrelation between obesity and VaD is poor 15). Therefore, continuous weight control (prevention of obesity) from midlife isdesirable for VaD prevention.
Atrial fibrillation increases the risk of dementia through various mechanisms 16). Although there are few studies thatclassify and analyze VaD and Alzheimer’s disease dementia separately, many reports have shown that the risk of dementia isincreased 2 to 3 times in patients with atrial fibrillation associated with stroke.

▪ References
1) Ninomiya T, Ohara T, Hirakawa Y, et al. Midlife and late life blood pressure and dementia in Japanese elderly: the Hisayama study. Hypertension
2011; 58: 22.28.
2) Novak V, Hajjar I. The relationship between blood pressure and cognitive function. Nat Rev Cardiol. 2010; 7: 686-698.
3) Peters R, Beckett N, Forette F, et al; HYVET investigators. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly
Trial cognitive function assessment (HYVET.COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008; 7(8): 683-689.
4) Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomized double-blind placebo controlled Systolic Hypertension in Europe(Syst-Eur) trial. Lancet. 1998; 352(9137): 1347-1351.
5) Dufouil C, Chalmers J, Coskun O, et al; PROGRESS MRI Substudy Investigators. Effects of blood pressure lowering on cerebral white matter
hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging
Substudy. Circulation. 2005; 112(11): 1644-1650.
6) Tzourio C, Anderson C, Chapman N, et al; PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide
therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003; 163(9): 1069-1075.
7) Meneilly GS, Cheung E, Tessier D, et al. e effect of improved glycemic control on cognitive functions in the elderly patient with diabetes. J Gerontol.
1993; 48(4): M117-M121.
8) Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’(CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366(9493): 1267-1278.
9) Rea TD, Breitner JC, Psaty BM, et al. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol. 2005; 62(7):1047-1051.
10) Swiger KJ, Manalac RJ, Blumenthal RS, et al. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects.
Mayo Clin Proc. 2013; 88(11): 1213-1221.
11) Anstey KJ, von Sanden C, Salim A, et al. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J
Epidemiol. 2007; 166: 367-378.
12) Ravaglia G, Forti P, Lucicesare A, et al. Physical activity and dementia risk in the elderly: findings from a prospective Italian study. Neurology. 2008:
70(19Pt2): 1786-1794.
13) Perez L, et al. Nutrition and vascular dementia. J Nutr Health Aging 2012; 16: 319-324,.
14) Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003; (4):CD004514.
15) Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review andmeta-analysis. Obes Rev. 2008; 9: 204-218.
16) Hui DS, Morley JE, Mikolajczak PC, et al. Atrial fibrillation: a major risk factor for cognitive decline. Am Heart J. 2015; 169: 448-456.

▪ Search formula
PubMed search: June 27, 2015 (Saturday)#1 (“Dementia, Vascular/prevention and control” [Majr] OR (“vascular dementia” [TI] AND prevent* [TI]) OR (vascular cognitive impairment*[TI] AND prevent* [TI])) OR ((“Dementia, Vascular/etiology” [Majr] AND Risk [Mesh]) OR (“vascular dementia” [TI] AND risk [TI]) OR(vascular cognitive impairment* [TI] AND risk [TI]))
Ichushi search: June 27, 2015 (Saturday)#1 ((Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND ((SH = PREVENTION) or Prevention/TI or
Control/TI)) OR ((Dementia-vascular/TH OR vascular dementia/TI OR Vascular cognitive impairment/TI) AND (Risk factor/TH OR Risk
factor /TI OR Risk/TI))

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CQ 14-8What is antithrombotic therapy for vascular dementia (VaD)?
Recommendation
There is little evidence for the use of antithrombotic drugs for primary prevention of dementia. However, appropriate
anticoagulant therapy is desirable for dementia prevention only in patients with atrial fibrillation.
To prevent dementia after noncardiogenic cerebral infarction, consider using antiplatelet drugs.
2C

Comments and evidence
The effectiveness of antiplatelet drugs for dementia is not consistent across several observational studies. In the Aspirin for
Asymptomatic Atherosclerosis (AAA) trial, 3,350 subjects were given aspirin 100 mg or placebo for over 5 years, but nosignificant difference in cognitive function was demonstrated between two groups 1). In another cohort study of 3,809
community-dwelling persons, the odds ratio for cognitive decline after 6 years of aspirin use was 0.97 (95% confidence
interval 0.82-1.15) 2). Therefore, previous studies have not confirmed the usefulness of prescribing antiplatelet drugs at least
for a period of 6 years for primary prevention of dementia. On the other hand, in a study in which 70 patients with multiinfarct dementia were randomized into an aspirin group and a no-aspirin group and followed every year for 3 years, cognitive
function was preserved in the aspirin group. However, study limitations such as lack of placebo control and small sample size
have been pointed out 3). In the South London Stroke Register that analyzed 4,413 patients with ischemic stroke but no atrial
fibrillation, aspirin and dipyridamole combination therapy showed a tendency of protection against cognitive impairment[relative risk, 0.8 (95% confidence interval 0.68 to 1.01)] 4). Thus, although antiplatelet therapy may not be useful for primaryprevention of dementia, this therapy may be considered for prevention of dementia after ischemic stroke.
In the PRoFESS trial, a study was performed in patients with ischemic stroke comparing treatment using aspirin anddipyridamole combination therapy and clopidogrel monotherapy. After a mean follow-up period of 2.4 years, there was nodifference in cognitive decline between two treatment groups 5). Therefore, the effect of combination therapy with antiplatelet
drugs and the class effect (difference in dementia prevention effect by antiplatelet drugs with different mechanisms of action)
for dementia prevention remain unclear.
In the SPS3 trial, patients with symptomatic lacunar infarction were followed for an average of 3 years, and cognitive
function was compared between aspirin monotherapy and combination therapy with two antiplatelet drugs. No dementia
prevention effect was observed for dual antiplatelet therapy 6).
In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is ahereditary vascular dementia, cerebral hemorrhage may develop during the course of disease, and administration of
antiplatelet drugs may increase the risk of cerebral hemorrhage 7). Even in sporadic vascular dementia, it is necessary to pay
attention to bleeding complications when using antiplatelet drugs.
In a 3000-day observational study of 2,693 patients with no history of stroke or dementia who received warfarin for atrial
fibrillation, the groups with poor warfarin control [time in therapeutic range (TTR) <25%, 26-50%, and 51-75%] haddementia hazard ratios of 5.34, 4.10, and 2.57, respectively, compared to the good warfarin control group (TTR >75%) 8). In
patients with atrial fibrillation, appropriate anticoagulant therapy for dementia prevention is desirable.

▪ References
1) Price JF, Stewart MC, Deary IJ, et al; AAA Trialists. Low dose aspirin and cognitive function in middle aged to elderly adults: randomised
controlled trial. BMJ. 2008;337: a1198.
2) Sturmer T, Glynn RJ, Field TS, et al. Aspirin use and cognitive function in the elderly. Am J Epidemiol. 1996; 143(7): 683-691.
3) Meyer JS, Rogers RL, McClintic K, et al. Randomized clinical trial of daily aspirin therapy in multi-infarct dementia. A pilot study. J Am Geriatr
Soc. 1989; 37(6): 549-555.
4) Douiri A, McKevitt C, Emmett ES, et al. Long-term effects of secondary prevention on cognitive function in stroke patients. Circulation. 2013;
128(12): 1341-1348.
5) Diener HC, Sacco RL, Yusuf S, et al; Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Effects of aspirin plus
extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients withischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS)trial: a double-blind, active and placebo-controlled
study. Lancet Neurol. 2008; 7(10): 875-884.
6) Pearce LA, McClure LA, Anderson DC, et al. Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in

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patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. Lancet Neurol. 2014; 13(12): 1177-1185.
7) Rinnoci V, Nannucci S, Valenti R, et al. Cerebral hemorrhages in CADASIL: report of four cases and a brief review. J Neurol Sci. 2013; 330(1.2):
45-51.
8) Victoria Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk ofdementia. Heart Rhythm. 2014; 11(12): 2206-2213.

▪ Search formula
PubMed search: June 28, 2015 (Sunday)#1 (“Dementia, Vascular” [Mesh] OR “vascular dementia” [TI] OR vascular cognitive impairment* [TI]) AND (“Fibrinolytic Agents” [Mesh] OR“Fibrinolytic Agents” [Pharmacological Action] OR “Anticoagulants” [Mesh] OR “Anticoagulants” [Pharmacological Action] OR “Platelet
Aggregation Inhibitors” [Mesh] OR Platelet Aggregation Inhibitors [Pharmacological Action] OR “clopidogrel” [Supplementary Concept]OR
aspirin* [TI] OR clopidogrel [TI] OR cilostazol [TI] OR antiplatelet* [TI] OR warfarin [TI] OR novel oral anticoagulant* [TI] OR NOAC [TI]
OR anticoagulation* [TI])
Ichushi search: June 28, 2015 (Sunday)#1 (Dementia-vascular/TH OR Vascular dementia/TI OR Vascular cognitive impairment/TI) AND (Anti-platelet agent/TH OR Anti-platelet
agent/TI OR Anti-platelet drug/TI OR Aspirin/TI OR Aspirin/TI OR Clopidogrel/TI OR Clopidogrel/TI OR Warfarin/TI OR Warfarin/TI OR“novel oral anticoagulant”/TI OR NOAC/TI OR Platelet aggregation inhibition/TI)

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CQ 14-9

Are there effective drugs for cognitive impairment in vascular dementia (VaD)?
Recommendation
For the treatment of core symptoms of VaD, the cholinesterase inhibitors; namely, donepezil 2B   , galantamine
2B and rivastigmine 2C   ; as well as the N-methyl-D-aspartate (NMDA) receptor antagonist memantine
2B are recommended (off-label).

Comments and evidence
In a double-blind randomized clinical trial conducted in patients with VaD, the donepezil group showed significant
improvement in cognitive function compared to the placebo group. In particular, strong evidence was obtained for shortterm treatment of approximately 24 weeks for mild to moderate VaD. In the future, establishment of evidence for theusefulness of long-term administration is awaited 1). For cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), a hereditary VaD, although administration of donepezil was not effective to improve
cognition overall, usefulness was noted for executive function only 2).
Treatment with galantamine achieved significant improvement in cognitive function compared to the placebo group in a
double-blind randomized clinical trials conducted in VaD patients 3) and in Alzheimer’s disease dementia patients withcerebrovascular disorders 4).
In a double-blind randomized clinical trial in VaD patients, rivastigmine significantly improved some cognitive function
assessment items compared to the placebo group 5).
Treatment with memantine, an NMDA receptor antagonist, resulted in significant improvement in cognitive function
compared to the placebo group in double-blind randomized clinical trials in patients with VaD and in patients with
Alzheimer’s disease dementia and cerebrovascular disease 6, 7).
The above four drugs may be effective to certain extent for VaD, but one cannot exclude the possibility that the observed
effectiveness may be mediated by the effect on coexisting Alzheimer’s dementia.
As for other therapeutic agents, several clinical trials have shown that nicergoline improves cognitive function in VaD. In
Japan, nicergoline is covered by health insurance for “improvement of decreased motivation due to chronic cerebrovasculardisorder associated with sequelae of cerebral infarction”. Amantadine is covered by insurance for sequelae of cerebral infarction,and may be considered for use to improve motivation and initiative in VaD. Ginkgo biloba has been reported to be effective forthe treatment of dementia including VaD in several clinical trials 8). Moreover, risperidone at low doses (mean 0.95 mg/day)
reduces aggression, agitation and psychiatric symptoms associated with VaD 9). Tiapride is covered by health insurance for“improvement of aggressive behaviors, mental agitation, wandering, and delirium associated with sequelae of stroke”.

▪ References
1) Malouf R, Birks J. Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev. 2004; (1): CD004395.
2) Dichgans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial
in CADASIL. Lancet Neurol. 2008; 7(4): 310-318.
3) Auchus AP, Brashear HR, Salloway S, et al. Galantamine treatment of vascular dementia: a randomized trial. Neurology. 2007; 69: 448-458.
4) Craig D, Birks J. Galantamine for vascular cognitive impairment. Cochrane Database Syst Rev. 2006; (1): CD004746.
5) Birks J, McGuinness B, Craig D. Cochrane Database Syst Rev. 2013 May 31; 5: CD004744. doi: 10.1002/14651858. CD004744.pub3.
6) Orgogozo JM, Rigaud AS, Stoer A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized,
placebo-controlled trial(MMM 300). Stroke. 2002; 33: 1834-1839.
7) Wilcock G, Mobius HJ, Stoer A, et al. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia(MMM500). Int Clin Psychopharmacol. 2002; 17: 297-305.
8) von Gunten A, Schlaefke S, Uberla K. Efficacy of Ginkgo biloba extract EGb 761 R in dementia with behavioural and psychological symptoms:a systematic review. World J Biol Psychiatry. 2015: 1-12.
9) Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosisof dementia. J Clin Psychiatry. 2003; 64(2): 134-143.

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▪ Search formula
PubMed search: June 28, 2015 (Sunday)#1 (“Dementia, Vascular/therapy” [Mesh] OR (“vascular dementia” [TI] AND (therapy OR therapeutic* OR treatment*)) OR (vascular cognitive
impairment* [TI] AND (therapy OR therapeutic* OR treatment*))) AND (“Hematologic Agents” [Mesh] OR “Hematologic Agents”[Pharmacological Action])
Ichushi search: June 28, 2015 (Sunday)#1 (Dementia-vascular/TH OR Vascular dementia/TI OR Vascular cognitive impairment/TI) AND Therapeutic use/TH

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CQ 14-10

What is the clinical position of cerebral amyloid angiopathy (CAA)?
Answer(1) Cerebral amyloid angiopathy is related to the development of dementia.
(2) There is no known effective treatment for cerebral amyloid angiopathy, but if hypertension coexists, antihypertensive
therapy is recommended to prevent cerebral hemorrhage.

Comments and evidence
Cerebral amyloid angiopathy is a pathological vascular change, which almost always occurs in Alzheimer’s disease
dementia. However, apart from being a direct cause of bleeding in the brain lobes, symptoms are rarely observed and hence
the condition did not attract much attention. However, image and pathological analyses have clearly demonstrated that
cerebral amyloid angiopathy is associated with various cerebrovascular disorders such as cortical micro-infarcts and cortical
microbleeds 1, 2). Furthermore, report has indicated that it is an independent factor of not only stroke but also dementia 3). Ina systematic review that analyzed the findings of four population-based studies; the Cambridge City over-75s Cohort(CC75C) study, the MRC Cognitive Function and Aging Study (MRC-CFAS), the Honolulu-Asia Aging study, and the
Vantaa 85+ study, CAA was observed in 55% to 59% of patients with dementia but in only 28% to 38% of non-dementia
patients. Severe CAA was observed in 37% to 43% of patients with dementia but only 7 to 24% of non-dementia patients,
with clear differences between the two groups. 3)
In a multicenter randomized study conducted in 6,105 patients with cerebrovascular disease comparing cerebrovascular
events during treatment with antihypertensive medications versus placebo for a mean period of 3.9 years, intracerebral
hemorrhage associated with CAA was observed in a total of 16 patients. Cerebral hemorrhage was reduced by 77% in
patients receiving antihypertensives compared with patients receiving placebo (3 patients in the antihypertensive group, 13
patients in the placebo group) 4). There is no known effective treatment for CAA, but if patients also have hypertension,
antihypertensive therapy is recommended for prevention of intracerebral hemorrhage.
In patients with CAA, acute inflammatory reaction mediated by autoimmune reaction against vascular wall amyloid β
may occur concomitantly, causing acute impairment of consciousness and cognitive deterioration. This condition is called
CAA-related inflammation (CAA-ri) 5). As suggested from the pathological mechanism of CAA-ri, administration of
immunosuppressive drugs such as corticosteroids and cyclophosphamide is effective in the acute phase 6).

▪ References
1) Smith EE, Schneider JA, Wardlaw JM, et al. Cerebral microinfarcts: the invisible lesions. Lancet Neurol. 2012; 11(3): 272-282.
2) Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing andneurodegeneration. Lancet Neurol. 2013; 12(8): 822-838.
3) Keage HA, Carare RO, Friedland RP, et al. Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review. BMC
Neurol. 2009; 9: 3.
4) Arima H, Tzourio C, Anderson C, et al; PROGRESS Collaborative Group. Effects of perindopril-based lowering of blood pressure on intracerebral
hemorrhage related to amyloid angiopathy: the PROGRESS trial. Stroke 2010; 41(2): 394-396.
5) Piazza F, Greenberg SM, Savoiardo M, et al. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications foramyloid-modifying therapies. Ann Neurol. 2013; 73(4): 449-458.
6) Kloppenborg RP, Richard E, Sprengers ME, et al. Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of
evidence for immunosuppressive treatment. J Neuroinflammation. 2010; 7: 18.

▪ Search formula
PubMed search: June 28, 2015 (Sunday)#1 (“Dementia” [Mesh]OR dementia[TI]) AND (“Cerebral Amyloid Angiopathy” [Mesh] OR “cerebral amyloid angiopathy”)
Ichushi search: June 28, 2015 (Sunday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TI) AND (Cerebral amyloid angiopathy/TH OR Cerebral amyloid angiopathy/TI)

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Chapter 15
Prion Disease

CQ 15-1

What are the clinical features of sporadic Creutzfeldt-Jakob disease (CJD)?
AnswerSporadic CJD is the most common form of prion disease, constituting approximately 70% of all cases. Classic cases arecharacterized by a course of rapidly progressive dementia, cerebellar ataxia, pyramidal and extrapyramidal signs, andmyoclonus, progressing to akinetic mutism over weeks.

Comments and evidence
The annual incidence of prion disease in Japan is approximately 1 case per 1 million 1, 2). The mean age at onset is 67.9
years. Typical cases are termed classic CJD, and manifest as rapidly progressive dementia, myoclonus, cerebellar ataxia,
visual disturbances, pyramidal signs and extrapyramidal symptoms, progressing to akinetic mutism in 3 to 6 months on
average. The diagnostic criteria of sporadic CJD have been reported 3, 4).
The analysis of brain samples from patients with sporadic CJD has led to characterization of the protease K-resistant prion
protein (PrP), which is distinguished into type 1 and 2 by Western blot analysis. Combining this typing with the PrP genecodon 129 polymorphism (MM type; homozygous for methionine, MV type; heterozygous for valine, VV type, homozygous
for valine), sporadic CJD is classified into 6 types; MM1, MM2, MV1, MV2, VV1 and, VV2. The MM2 type is further
classified by clinicopathological findings into MM2-cortical and MM2-thalamic types 5). MM1 is the most common typeof sporadic CJD, with a clinical course of the classic type. For details, see references 5 and 6.

▪ References
1) Nozaki I, Hamaguchi T, Sanjo N, et al. Prospective 10-year surveillance of human prion diseases in Japan. Brain. 2010; 133(10): 3043-3057.
2) Nakamaura Y, Ae R, Takumi I, et al. Descriptive epidemiology of prion disease in Japan: 1999-2012. J Epidemiol. 2015; 25(1): 8-14.
3) World Health Organization. WHO Manual for Strengthening Diagnosis and Surveillance of Creutzfeldt-Jakob Disease. Geneva: World HealthOrganization: 1998.
4) Sanjo N, Mizusawa H. Prion disease: The characteristics and diagnostic points in Japan. Clin Neurol. (Rinsho Shinkeigaku) 2010; 50(5): 287-300.
(In Japanese)
5) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases (Research Project for Combating
Intractable Diseases) “Study Group on Prion Disease and Late-onset Virus Infections” (ed.) Clinical Practice Guideline for Prion Disease 2017. (InJapanese)
6) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases “Study Group on Prion Disease andLate-onset Virus Infections” (ed.) Prion Disease and Late-onset Virus Infections. Tokyo: Kanehara Shuppan; 2010. (In Japanese)▪ Search formula
PubMed search: June 29, 2015 (Monday)#1 (“Creutzfeldt-Jakob Syndrome/diagnosis” [Mesh] OR “Creutzfeldt-Jakob Syndrome/epidemiology” [Mesh] OR “Creutzfeldt-Jakob Syndrome/physiopathology” [Mesh] OR Creutzfeldt-Jakob*) AND sporadic
Ichushi search: June 29, 2015 (Monday)#1 (Creutzfeldt-Jakob disease/TH OR Creutzfeldt-Jakob disease/TI OR Creutzfeldt-Jakob disease /TI) AND Sporadic

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Clinical Practice Guideline for Dementia 2017

CQ 15-2

What are the electroencephalographic, cerebrospinal fluid, and MRI findingsof sporadic Creutzfeldt-Jakob disease (CJD)?
AnswerIn typical cases, electroencephalogram (EEG) shows slow and/or irregular waves in the early stage, then periodic sharp
wave complexes (PSWCs) will emerge when myoclonus appears, and is followed by disappearance of PSWCs and flatteningof waves at the end stage. In the cerebrospinal fluid (CSF), the appearance, cell count, and protein level are normal in mostcases, while 14-3-3 protein and total tau protein increase. Abnormal prion proteins in the CSF can be detected by realtime quaking-induced conversion (RT-QuIC) method. Further, hyperintensity is observed in the in cerebral cortex andbasal ganglia (putamen, caudate nuclei) on diffusion-weighted or FLAIR MRI, and in the medial thalamus in some cases.
A

Comments and evidence
In prion disease, the EEG shows slowing and irregularity in the early stage of the disease, then PSWCs emerge at the sametime as myoclonus appears. Finally, PSWCs disappear and the EEG flattens in the end stage 1). Hyperintensity is observed in
the cerebral cortex, basal ganglia (putamen, caudate nuclei), and the thalamus in some cases, on diffusion-weighted or FLAIR
MRI 2, 3). CSF examination typically shows a normal appearance and cell count, and protein levels are normal in most cases;
however 14-3-3 and total tau proteins are increased in the CSF 4). In recent years, the RT-QuIC method has been developed,
which enables the detection of abnormal prion proteins (PrPSc) in the CSF with approximately 70% sensitivity 5, 6).
The Ministry of Health, welfare and Labour Prion Study Group has established a diagnosis support system. Utilization ofthis system is recommended 7, 8).

▪ References
1) Steinhoff BJ, Racker S, Herrendorf G, et al. Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Arch Neurol.
1996; 53(2): 162-166.
2) Meissner B, Kallenberg K, Sanchez-Juan P, et al. MRI lesion profiles in sporadic Creutzfeldt-Jakob disease. Neurology. 2009; 72(23): 1994-2001.
3) Fujita K, Harada M, Sasaki M, et al. Multicentre, multiobserver study of diffusion-weighted and fluid-attenuated inversion recovery MRI for the
diagnosis of sporadic Creutzfeldt-Jakob disease: a reliability and agreement study. BMJ Open. 2012; 2(1): e000649.
4) Nozaki I, Hamaguchi T, Sanjo N, et al. Prospective 10.year surveillance of human prion diseases in Japan. Brain. 2010; 133(10): 3043-3057.
5) Stoeck K, Sanchez-Juan P, Gawinecka J, et al. Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt-Jakob disease and rapid dementias:
a longitudinal multicentre study over 10 years. Brain 2012; 135(Pt 10): 3051-3061.
6) Sano K, Satoh K, Atarashi R, et al. Early detection of abnormal prion protein in genetic human prion diseases now possible using real-time QUIC
assay. PLoS One 2013; 8(1): e54915.
7) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases “Study Group on Prion Disease andLate-onset Virus Infections” (ed.) Prion Disease and Late-onset Virus Infections. Tokyo: Kanehara Shuppan; 2010. (In Japanese)
8) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases (Research Project for Combating
Intractable Diseases) “Study Group on Prion Disease and Late-onset Virus Infections” (ed.) Clinical Practice Guideline for Prion Disease 2017. (InJapanese)▪ Search formula
PubMed search: June 29, 2015 (Monday)#1 ((“Creutzfeldt-Jakob Syndrome/diagnosis” [Majr] OR Creutzfeldt-Jakob*[TI]) AND sporadic) AND (“Electroencephalography” [Mesh] ORelectroencephalography OR “Magnetic Resonance Imaging” [Mesh] OR “magnetic resonance imaging” OR “Cerebrospinal Fluid” [Mesh] OR“cerebrospinal fluid” OR “cerebrospinal fluid” [subheading])
Ichushi search: June 29, 2015 (Monday)#1 ((Creutzfeldt-Jakob disease/TH OR Creutzfeldt-Jakob disease/TI OR Creutzfeldt-Jakob disease/TI) AND Sporadic) AND (Electroencephalography/TH OR Electroencephalogram/TI OR Cerebrospinal fluid/TH OR Cerebrospinal fluid/TI OR MRI/TH OR MRI/TI OR “Magnetic ResonanceImaging”/TI OR Magnetic resonance imaging/TI)

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CQ 15-3

What are the types and features of genetic prion disease in Japan?
Answer
Genetic prion diseases are classified as genetic Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler Scheinker (GSS)
disease, and fatal familial insomnia (FFI). In Japan, genetic prion diseases commonly include V180I (CJD), P102L (GSS),
E200K (CJD), and M232R (CJD) mutations of the prion protein gene (PRNP). CJD with V180I and M232R are foundmore commonly in sporadic cases; therefore, genetic testing is required for diagnosis. Patients with V180I mutation often
have late onset and typically manifest slowly progressive dementia. Patients with P102L mutation have cerebellar ataxia at
onset with slow progression, and patients with E200K mutation show a clinical course similar to classic sporadic CJD. In
recent years, one type with autonomic failure as the main symptom has been reported.

Comments and evidence
In Japan, the common mutations of PRNP include V180I (CJD), P102L (GSS), E200K (CJD), and M232R (CJD). The
frequencies of these mutations differ significantly from those in Europe and America 1, 2). V180I is the most common mutationin Japan and Korea, and M232R and P105L (GSS) mutations are unique to Japan 3, 4). Genetic prion disease is usuallyautosomal dominant, and almost all cases with P105L mutation are familial. However, genetic testing is required for
diagnosis of cases with V180I and M232R mutations because these rarely exhibit a family history.
For details, refer to reference 5.

▪ References
1) Nozaki I, Hamaguchi T, Sanjo N, et al. Prospective 10-year surveillance of human prion diseases in japan. Brain. 2010; 133(10): 3043-3057.
2) Nakamaura Y, Ae R, Takumi I, et al. Descriptive epidemiology of prion disease in Japan: 1999-2012. J Epidemiol. 2015; 25(1): 8-14.
3) Shiga Y, Satoh K, Kitamoto T, et al. Two different clinical phenotypes of Creutzfeldt-Jacob disease with a M232R substitution. J Neurol. 2007;
254(11): 1509-1517.
4) Iwasaki Y, Kizawa M, Hori N, et al. A case of Gerstmann-Straussler-Scheinker syndrome with the P105L prion protein gene mutation presenting
with ataxia and extrapyramidal signs without spastic paraparesis. Clin Neurol Neurosurg. 2009; 111(7): 606-609.
5) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases (Research Project for Combating
Intractable Diseases). Study Group on Prion Disease and Late-onset Virus Infections (ed.) Clinical Practice Guidelines for Prion Disease 2017. (InJapanese)▪ Search formula
PubMed search: June 30, 2015 (Tuesday)#1 (“Prion Diseases/genetics” [Mesh] OR (genetic AND prion disease*) OR (genetic AND gerstmann-straussler-scheinker disease*) OR (genetic
AND “fatal familial insomnia”)) AND (“Japan” [Mesh] OR japan [TIAB])
Ichushi search: June 30, 2015 (Tuesday)#1 (Prion disease/TH OR Prion disease/TI OR Fatal familial insomnia /TI OR Gerstmann-Straussler-Scheinker/TI)AND((SH = Genetics) OR
Genetics/TH OR Hereditary/TI OR Hereditary disease/TH) AND (Japan/TH OR Japan/TI OR This country/TI OR Our country/TI OR Our
country/TI)

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CQ 15-4

What are the types and features of acquired (infectious) prion disease in Japan?
AnswerTwo types of acquired prion diseases have been confirmed in Japan; variant Creutzfeldt-Jakob disease (variant CJD;
vCJD) and dura mater graft-associated CJD. Cases of dura mater graft-associated CJD in Japan constitute over half of allcases worldwide. Surprisingly, some cases showed disease onset over 30 years after dura mater transplantation. Two-thirdsof these cases are the non-plaque type and show a clinical feature similar to classic CJD. One-third of the cases are plaquetype and manifest as relatively slowly progressive ataxia.

Comments and evidence
Acquired prion diseases are classified into Kuru, vCJD, and iatrogenic CJD 1, 2).
Variant CJD exhibits a younger onset compared with the other prion diseases, with a mean age at onset of 29 years.
Patients manifest psychiatric symptoms such as frustration and depression at an early stage; therefore, the disease is often
misdiagnosed as psychiatric diseases. As the disease progresses, cognitive impairment and motor symptoms such as ataxic
gait, gradually emerge. Hyperintensity in the medial-dorsal thalamus (pulvinar sign) is observed on diffusion-weighted
MRI. Periodic sharp wave complexes (PSWCs) on EEG are typically not observed.
In Japan, all cases of acquired CJD, except one case of vCJD, are dura mater grafting-associated CJD, with 154 confirmed
cases (Surveillance Committee, September 2017). The dura mater used in all identifiable cases was cadaveric dura mater
Lyodura® from B. Braun, Germany. The cases in Japan constitute over half of the cases worldwide 3). After Lyodura® was
discontinued (March 1997), the disease has not been found in patients who undergo dura mater grafting. Although theincidence of patients with dura mater grafting-associated CJD has decreased, some cases have presented with disease up to
30 years after surgery 3). Two-thirds of dura mater grafting-associated CJD cases have clinicopathological findings similar toclassic CJD, and one-third of the cases manifest an ataxic gait with relatively slow progression, and no PSWCs is observedon electroencephalogram in the early stage. Pathological examination of the brain shows plaque-like deposition of abnormal
prion protein 4).
For patients with CJD caused by dura mater grafting, the patient/family association has set up a CJD support network(http://www.cjdnet.jp/). Utilization of this network is recommended.

▪ References
1) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases. Study Group on Prion Disease andLate-onset Virus Infections and Study Group Related to Surveillance and Infection Control of Prion Disease. Clinical Practice Guideline for Prion
Disease 2017. (In Japanese)
2) Health Welfare and Labor Sciences Research Grant for Research Project for Combating Intractable Diseases. “Study Group on Prion Disease andLate-onset Virus Infections” (ed.) Prion Disease and Late-onset Virus Infections. Tokyo: Kanehara Shuppan: 2010. (In Japanese)
3) Hamaguchi T, Sakai K, Noguchi.-Shinohara M, et al. Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob diseasein Japan. J Neurol Neurosurg Psychiatry. 2013; 84(10): 1171-1175.
4) Noguchi-Shinohara M, Hamaguchi T, Kitamoto T, et al. Clinical features and diagnosis of dura mater graft associated Creutzfeldt Jakob disease.
Neurology. 2007; 69(4): 360-367.

▪ Search formula
PubMed search: June 30, 2015 (Tuesday)#1 (“Prion Diseases/transmission” [Mesh] OR ((acquired OR transmission* OR “dura mater graft associated” OR infectious OR iatrogenic) AND(“Prion Diseases” [Mesh] OR prion disease*)) OR (variant Creutzfeldt-Jakob disease* OR “variant CJD” OR vCJD OR kuru [TIAB])) AND(“Japan” [Mesh] OR japan [TIAB])
Ichushi search: June 30, 2015 (Tuesday)#1 (Prion disease/TH OR Prion disease/TI OR Creutzfeldt-Jakob disease/TI OR CJD/TI OR Kuru/TI) AND (Acquired/TI OR Acquired/TH OR
Infectious/TI OR Infectious/TH OR Iatrogenic/TI OR ((Dura mater/TH OR Dura mater/TI) AND grafting)) AND (Japan/TH OR Japan/TI
OR This country/TI OR Our country/TI OR Our country/TI)

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CQ 15-5

What are the infection control measures and effective sterilization methods
for prion disease?
Answer
For medical devices that have been used in high-risk procedures for patients known to have prion disease (see Guideline 1)),the currently recommended method is to remove as much as possible the blood and tissue fragments attached to the device, thenimmerse in 3% sodium dodecyl sulfate (SDS) solution and boil at 100°C for 3-4 minutes. After washing manually or in awasher-disinfector, sterilize in a pre-vacuum autoclave at 134°C for 10 minutes.

Comments and evidence
Prion disease can be transmitted not only after disease onset but also during the incubation period via medical devices
that have been in contact with high-risk infectious sites or through blood (for variant CJD). The Japanese guidelines forprevention of prion disease currently recommend disinfection and sterilization methods for surgical instruments that havebeen used in patients with prion disease (http://prion.umin.jp/guideline/cjd_2008all.pdf) 1).

▪ References
1) Health Welfare and Labor Sciences Research Grant; Research Project for Combating Intractable Diseases. Study Group on Prion Disease and Lateonset Virus Infections. Guidelines for Prevention of Prion Disease (2008 edition). 
http://prion.umin.jp/guideline/index.html (In Japanese)▪ Search formula
PubMed search: June 30, 2015 (Tuesday)#1 (“Prion Diseases” [Mesh] OR prion disease* [TI]) AND (“Decontamination” [Mesh] OR “Communicable Disease Control” [Mesh] ORdecontamination OR precaution* OR infection control*)Ichushi search: June 30, 2015 (Tuesday)#1 (Prion disease/TH OR Prion/TI) AND (Infection prevention/TH OR Infection control/TI OR Infection control/TI OR Infection prevention/
TI OR Infection prevention/TI OR Decontamination/TH OR Sterilization/TI OR Disinfection/TI OR Decontamination/TI)

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Chapter 16
Medical Diseases and Others

CQ 16-1

What are the features of cognitive impairment due to vitamin deficiency?
AnswerVitamin B1 deficiency leads to the development of Wernicke encephalopathy, an acute metabolic encephalopathy withmain symptoms of impaired consciousness, eye movement disorder, and motor ataxia. If not responding to treatment,
Wernicke encephalopathy may convert irreversibly to Korsakoff syndrome and manifests symptoms such as disorientation,amnesia, confabulation (storytelling), and lack of disease awareness.
Vitamin B12 deficiency causes memory impairment and psychiatric symptoms, and folate deficiency has been reported
to cause cognitive impairment similar to that of vitamin B12. In recent years, vitamin D deficiency has also been suggested
to cause cognitive impairment.

Comments and evidence
Vitamin B1 deficiency is often caused by alcoholism or an unbalanced diet. As the condition progresses, patients develop
Wernicke encephalopathy with the triad of impaired consciousness, eye movement disorders, and ataxic gait 1). However,
only few cases satisfy all the three main features. Other symptoms such as delirium, weakness, apathy, impaired recognitionof the surrounding situation, and impaired concentration may also be observed; and may even lead to coma and death 2, 3). It
has been reported that Wernicke encephalopathy converts to Korsakoff syndrome in 85% of the cases. In these cases,
memory impairment more severe than recent memory, anterograde amnesia, and confabulation are observed, but procedural
memory is often preserved 3).
Vitamin B6 deficiency can also cause pellagra-like symptoms (see below).
In vitamin B12 deficiency and folic acid deficiency, cognitive impairment may be caused by hyperhomocysteinemia.
In vitamin B12 deficiency, even in the absence of anemia and macrocytosis, cognitive impairments such as slowed thinking,memory impairment, and attention deficit; psychiatric symptoms such as depressive symptoms, delusions, hallucinations,and delirium; and neurological symptoms such as motor, sensational and autonomic symptoms are observed 4).
Although the neuropsychiatric symptoms in folate deficiency are the same as those in vitamin B12 deficiency, it has beenreported that decrease in blood folate level is associated with cognitive impairment 5), but no consensus has been reached.
Niacin (nicotinic acid, nicotinamide) deficiency has been known as pellagra from the past (four “Ds”: dermatitis, diarrhea,
dementia, death) 6).
In recent years, vitamin D deficiency has been found to be quite common in older people. Although a meta-analysis hasreported a relationship between low vitamin D and memory disorder and executive dysfunction 7), there is no consistent
opinion.

▪ References
1) Koyama K. Symptoms of Wernicke’s encephalopathy. Vitamin. 2012; 86(11): 620-624. (In Japanese)
2) Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007; 6(5):442-455.
3) Kopelman MD, Thomson AD, Guerrini I, et al. The Korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol. 2009; 44(2): 148154.
4) Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12 deficiency in elderly patients. J Neuropsychiatry Clin Neurosci. 2012;24(1): 5-15.
5) Michelakos T, Kousoulis AA, Katsiardanis K, et al. Serum folate and B12 levels in association with cognitive impairment among seniors: resultsfrom the VELESTINO study in Greece and meta-analysis. J Aging Health. 2013; 25(4): 589-616.
6) Niwa A. Chapter 3 Diagnosis of dementia, 4 Examinations. Nakajima K (ed.) Dementia Handbook. Tokyo: Igaku Shoin; 2013: 131. (In Japanese)
7) Annweiler C, Montero-Odasso M, Llewellyn DJ, et al. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers
Dis. 2013; 37(1): 147-171.

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▪ Search formula
PubMed search: June 27, 2015 (Saturday), July 21, 2015 (Tuesday)#1 ((“Dementia” [Mesh] OR dementia OR “Cognition Disorders” [Mesh] OR cognition disorder* OR “cognitive impairment”) AND (“Avitaminosis”[Mesh] OR avitaminosis OR “vitamin deficiency”)) OR (((“Thiamine” [Mesh] OR “Vitamin B 1” [TI] OR “Vitamin B1” [TI]) AND (“Korsakoff
Syndrome” [Mesh] OR Wernicke Korsakoff Syndrome* [TI] OR Korsakoff Psychosis* [TI])) OR “Vitamin B 6” [Mesh] OR “Vitamin B 6” [TI]
OR “Vitamin B6” [TI] OR “Vitamin B 6 Deficiency” [Mesh] OR “Vitamin B 12” [Mesh] OR “Vitamin B 12” [TI] OR “Vitamin B12” [TI] OR“Vitamin B 12 Deficiency” [Mesh] “Vitamin D” [Mesh] OR “Vitamin D” [TI] OR “Vitamin D Deficiency” [Mesh] OR “Folic Acid” [Mesh] OR“folic acid” [TI] OR folate [TI]) AND (“Executive Function” [Mesh] OR cognitive function* [TI]) OR ((“Avitaminosis” [Mesh] OR avitaminosis[TI]) AND (“Hyperhomocysteinemia” [Mesh] OR hyperhomocysteinemia* [TI]) AND (“Cognition Disorders” [Mesh] OR “cognition disorder*”[TI] OR “cognitive impairment” [TI] OR “cognition disorder*” OR cognitive impairment” OR “cognitive decline” [TI]))
Ichushi search: June 27, 2015 (Saturday), July 21, 2015 (Tuesday)#1 ((Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive decline/TI) AND (Vitamin
deficiency/TH OR Vitamin deficiency/TI)) OR ((Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive decline/TI) AND(((Thiamine/TH OR Thiamine/TI OR Thiamin/TI OR Vitamin B1/TI OR “Vitamin B1”/TI OR “Vitamin B 1”/TI) AND (Korsakoff syndrome/
TH OR Korsakoff syndrome/TI OR Korsakoff syndrome/TI OR Korsakoff psychosis/TI)) OR “Vitamin B6”/TH OR “Vitamin B6”/TI OR
Vitamin B6/TI OR Vitamin B6 deficiency/TH OR “Vitamin B12”/TH OR “Vitamin B12”/TI OR Vitamin B12/TI OR Vitamin B12 deficiency/
TH OR “Vitamin D”/TH OR “Vitamin D”/TI OR Vitamin D/TI OR Vitamin D deficiency/TH OR “Folic Acid”/TH OR “Folic Acid”/TI OR
Folic acid/TI OR Folic acid deficiency/TH OR ((Vitamin deficiency/TH OR Vitamin deficiency/TI) AND (Hyperhomocysteinemia/TH OR
Hyperhomocysteinemia/TI))))

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CQ 16-2

What are the features of cognitive impairment due to hypothyroidism?
AnswerOvert hypothyroidism causes cognitive impairment and depressive symptoms. Many reports have shown no clear effectof subclinical hypothyroidism on cognitive function, but opinion is divided. In Hashimoto’s encephalopathy, acute
psychiatric symptoms such as impaired consciousness, delirium, and hallucination; cognitive impairment; and chronic
symptoms such as depression and anxiety are observed.
C

Comments and evidence
In overt hypothyroidism, a wide range of cognitive functions are impaired, and impairments of general intelligence,
attention and concentration, memory, perceptual function, language, and executive function are observed. Especially,
memory impairment and verbal memory are consistently reported 1-3). Many studies have concluded that there is an association
between overt hypothyroidism and depressive symptoms.
Subclinical hypothyroidism generally does not cause depressive symptoms, anxiety, or widespread or severe cognitive
impairment, but no consensus has been established 2).
Hashimoto’s disease (chronic thyroiditis) is the most common cause of hypothyroidism. In Hashimoto’s encephalopathy,
cognitive impairment, word-finding difficulty, epileptic seizures, behavioral disorders, myoclonus, gait ataxia, aphasia,
tremor, hyperreflexia, motor deficit, psychotic symptoms, depressive symptoms, confusion, and sleep disorder have beenreported 4). In particular, patients who are positive for anti-N-terminal of α-enolase (NAE) antibody often presents with anacute encephalopathy type, with high frequencies of consciousness disturbance and various psychiatric symptoms andcognitive impairment. In contrast, patients with a chronic course often have depressive symptoms, anxiety, and cerebellar
ataxia.

▪ References
1) Japan Thyroid Association. Guidelines for the Diagnosis of Thyroid Diseases 2013. 
http://www.japanthyroid.jp/en/guidelines.html
2) Samuels MH. Psychiatric and cognitive manifestations of hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2014; 21(5): 377-383.
3) Dugbartey AT. Neurocognitive aspects of hypothyroidism. Arch Intern Med. 1998; 158(13): 1413-1418.
4) de Holanda NC, de Lima DD, Cavalcanti TB, et al. Hashimoto’s encephalopathy: systematic review of the literature and an additional case. J
Neuropsychiatry Clin Neurosci. 2011; 23(4): 384-390.
5) Yoneda M. Hashimoto’s encephalopathy. Japanese Journal of Molecular Psychiatry (Bunshi Seishinigaku) 2013; 13(3): 178-184. (In Japanese)▪ Search formula
PubMed search: June 27, 2015 (Saturday), July 7, 2015 (Tuesday), September 12, 2015 (Saturday)#1 ((“Dementia” [Mesh] OR dementia OR “Cognition Disorders” [Mesh] OR “cognition disorder*” OR “cognitive impairment”) AND(“Hypothyroidism” [Mesh] OR hypothyroid* OR “Hashimoto’s disease” OR “Hashimoto disease”)) OR ((“Executive Function” [Mesh] OR“Cognition” [Mesh] OR cognitive function* OR “Cognition Disorders” [Mesh] OR cognition disorder* OR cognitive disorder* OR cognitive
impairment*) AND (“Hypothyroidism” [Mesh] OR hypothyroid* OR “Hashimoto Disease” [Mesh] OR “hashimoto encephalopathy” OR“hashimoto’s encephalopathy” OR Hashimoto’s disease* OR Hashimoto disease*)) OR (“Thyroid Diseases/diagnosis” [Majr] AND manifestation[TI])
Ichushi search: June 27, 2015 (Saturday)#1 (Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive decline/TI) AND(Hypothyroidism/TH OR Hypothyroidism/TI OR Hashimoto disease/TI)

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CQ 16-3

What are the features of cognitive decline due to neurosyphilis?
AnswerNeurosyphilis is a neurological infection caused by Treponema pallidum, which infiltrates the nervous system after the
initial infection. In late syphilis, which develops more than 15 to 20 years after the initial infection, long-term chronic
meningovasculitis as well as the spread of infiltration and inflammation to the brain parenchyma, cause progressive
paralysis manifesting with dementia, and tabes dorsalis due to damage of the dorsal funiculus and/or dorsal nerve roots.
Dementia symptoms include disorientation, memory disturbance and judgment disability, as well as hallucination,delusion, irritability, and convulsion.

Comments and evidence
After infection occurs via sexual contact or blood transfusion, syphilis can infiltrate the central nervous system and cause
progressive paralysis, mainly manifesting dementia 15-20 years after the initial infection. As a result of long-term chronic
meningovasculitis, bacterial infiltration and/or inflammatory spread to the central nervous system, dementia symptoms inprogressive paralysis are observed as disorientation, memory disturbance, and decline in judgment and calculation capacity,followed by manifestations of anti-social speech and behaviors and abnormal behaviors. Furthermore, patients show
psychiatric symptoms such as hallucination, delusion, and depression. Symptoms are diverse, and it is difficult to distinguishneurosyphilis from other dementias. Clinical diagnosis is made by serum non-treponema tests such as VDRL and RPR,
syphilis-specific antigen test (TPHA), and cerebrospinal fluid examination (TPHA and FTA-Abs in cerebrospinal fluid) 1, 2).
Treatment includes penicillin G (18-24 million units/day) administered by continuous intravenous infusion or intravenous
infusion every 4 hours for 10-14 days. However, some patients show minor improvement with sequelae.
For details, refer to the “Guideline for Diagnosis and Treatment of Sexually Transmitted Diseases” (http://jssti.umin.jp/
pdf/guideline-2011.pdf).

▪ References
1) Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014; 312(18): 1905-1917.
2) Ghanem KG. REVIEW: Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010; 16: e157-e168.

▪ Search formula
PubMed search: June 30, 2015 (Tuesday)#1 (“Neurosyphilis” [Mesh] OR neurosyphilis OR “general paresis” OR “progressive paralysis”) AND (“Dementia” [Mesh] OR dementia[TI] OR“Cognition Disorders” [Mesh] OR “cognition disorder*” OR “cognitive dysfunction”)
Ichushi search: June 30, 2015 (Tuesday)#1 (Syphilis-nerve/TH OR Neurosyphilis/TI)AND(Dementia/TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/
TI OR Cognitive function impairment/TI OR Cognitive decline/TI)

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CQ 16-4

What are the features of cognitive impairment caused by hepatic encephalopathy(HE)?
AnswerIn hepatic encephalopathy (HE), attention, information processing ability, and visuomotor coordination are impaired
from an early stage. Occasionally these symptoms are accompanied by focal neurological signs such as parkinsonism and/or choreic movement.

Comments and evidence
HE is characterized as a group of neuropsychiatric symptoms caused by acute or chronic liver dysfunctions. HE occurs
when the portal venous shunt produces toxic substances such as ammonia produced by hepatocellular injury, and the toxins
enter the systemic circulation without detoxication in the liver 1, 2).
The current trend is to interpret the disease as a continuum and use the following clinical rating: (1) lack of cognitive
impairment (UNIMPAIRED); (2) acute confusional syndrome (unstable); and (3) persistent chronic cognitive impairment(stable). In the continuous approach, patients may move from one situation to another interchangeably 3). Severity is evaluatedcategorically and graded based on the state of consciousness, intellectual function, behavior, and neuromuscular signs into 5
stages (stage 0 to 4) 4).
Acute episodic HE is an acute confusional syndrome that can progress to coma in severe cases. Bilateral symmetrical
hyperintensities in the globus pallidus and ventral midbrain are observed on T1-weighted MRI. In cases of acute exacerbationof chronic hepatitis, bilateral symmetrical hyperintensities have been observed in the thalamus, posterior limb of internal
capsule, and white matter around the lateral ventricle on diffusion-weighted and fluid-attenuated inversion recovery (FLAIR)MRI.
Minimal HE is present in approximately 55% of cirrhosis patients. They show abnormalities on comprehensive
neuropsychological test but not on neurological examination. It is associated with impaired driving skills and a significantly
higher risk of motor vehicle crashes, due to attention and visuomotor coordination deficits.
Even in patients with prolonged chronic cognitive impairment, motor symptoms such as parkinsonism, choreic movements,and myelopathy are observed in the late stages.

▪ References
1) Taniguchi E, Kawaguchi T, Sakata M, et al. Lipid prole is associated with the incidence of cognitive dysfunction in viral cirrhotic patients: a datamining analysis. Hepatol Res. 2013; 43(4): 418-424.
2) Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol.
2010; 16(27): 3347-3357.
3) Cordoba J. New assessment of hepatic encephalopathy. J Hepatol. 2011; 54(5): 1030-1040.
4) Bajaj JS. Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther. 2010; 31(5): 537-547.

▪ Search formula
PubMed search: June 30, 2015 (Tuesday)#1 (“Hepatic Encephalopathy” [Mesh] OR “Liver Diseases/complications” [Mesh] OR “Liver Diseases” [Majr]) OR “hepatic encephalopathy” OR“liver dysfunction” [TI] OR liver disease* [TI]) AND (“Dementia” [Mesh] OR dementia [TI] OR “Cognition Disorders” [Mesh] OR “cognition
disorder*” OR “cognitive dysfunction”)
Ichushi search: June 30, 2015 (Tuesday)#1 (Hepatic encephalopathy/TH OR Hepatic encephalopathy/TI OR hepatic coma/TI OR portal systemic encephalopathy/TI OR portal systemic
encephalopathy/TI OR Liver disease/ TH OR Liver dysfunction/TI OR Abnormal liver function/TI OR Liver dysfunction/TI) AND (Dementia/
TH OR Dementia/TI OR Cognitive impairment/TH OR Cognitive impairment/TI OR Cognitive function impairment/TI OR Cognitive decline/
TI)

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CQ 16-5

What are the features, diagnosis, and treatment strategies for dementia
symptoms of idiopathic normal pressure hydrocephalus (iNPH)?
Answer
Psychomotor speed, attention, working memory, and memory function are the cognitive functions that tend to be
impaired in iNPH and which can be improved by removing cerebrospinal fluid. For diagnosis and treatment strategy,refer to “Clinical Practice Guideline for Idiopathic Normal Pressure Hydrocephalus, 2nd Edition” (2011).
B

Comments and evidence
In patients with iNPH, psychomotor speed decreases, and attention and working memory are impaired even in mild cases.
For diagnosis and treatment policy, refer to the “Clinical Practice Guideline for Idiopathic Normal Pressure Hydrocephalus,
2nd Edition” (2011) 1).

▪ References
1) Japanese Society of Normal Pressure Hydrocephalus, Clinical Practice Guideline for Idiopathic Normal Pressure Hydrocephalus Development
Committee (Ed.) Clinical Practice Guideline for Idiopathic Normal Pressure Hydrocephalus, 2nd edition. Tokyo: Medical Review Co. Ltd.: 2011. 
http://minds.jcqhc.or.jp/n/med/4/med0038/G0000352/0001 (In Japanese)▪ Search formula
PubMed search: May 28, 2015 (Thursday)#1 “Hydrocephalus, Normal Pressure” [Mesh] AND (“idiopathic normal pressure hydrocephalus” OR iNPH)
Ichushi search: May 28, 2015 (Thursday)#1 Hydrocephalus-normal pressure/TH AND (Idiopathic normal pressure hydrocephalus/AL OR “idiopathic normal pressure hydrocephalus”/AL
OR iNPH/AL)

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