Introductory remarks

Introductory remarks

Dr. Masanori Fukushima
Japan

Director and Chairman, Translational ResearchInformatics Center (TRI),
Foundation for Biomedical Research andInnovation (FBRI)
Prof. Emeritus, Kyoto University■ Profile
Masanori Fukushima, MD, Ph.D.
With comprehensive experience
spanning over the past 31 years as
a medical oncologist at Aichi Cancer
Center and Kyoto University Hospital,
Dr. Fukushima has engaged in thepractice and dissemination of standard
cancer treatment and reform ofJapan’s medical care system, and isactive to date contributing to building
up the infrastructure of clinical trial,
particularly focusing on translational
research. He is also in charge ofsupervising the national translational
research promotion programs
conducted by the government ofJapan.

Centenarian, another frontier of humankind. It wasa long-cherished dream. Now it is realized Japan istaking a step closer to the super-aging society, dayby day. The reality, it is not always joyful and happy
retirement life we have dreamed of, but sometimes
stressful and painful for many senior citizens. The
main barrier for maintaining long, healthy, active
life is, with no question, the disabilities caused bydementia.
With accelerated aging of the population, social
impact of dementia is increasingly profound inindustrialized society. However, despite remarkableadvances in diagnostic technologies, therapeutic
outcome for dementia has not met the demandof our age, requiring revolution of the current
therapeutic approaches and exploration of novel
technologies. Under such circumstances, we haveplanned the 2nd World Centenarian Initiativeinternational symposium on Mild Cognitive
Impairment and Alzheimer’s disease, with a special
focus on the early detection and intervention
strategy to modify disease processes.
In order to accelerate such movement, thisinternational conference is an invaluable opportunity
to share the state-of-the-art approaches and future
directions for prevention of the Alzheimer’s disease
among the distinguished scientists from the world.
Japan carries the most aging society in the world,with more than 50 thousand centenarians. We
should keep in mind that we need to tackle andovercome this unprecedented challenge, committing
to delay, prevent, and ultimately cure this disease.

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-3

4

Session Chairs

Session Chairs

Keynote address

Dr. Masanori Fukushima
Director and Chairman, Translational ResearchInformatics Center,
Foundation for Biomedical Research and Innovation

Session I

Session II

Session III

Session IV

Clinicopathology of AD

Dr. Masafumi Ihara

Dr. Ding Ding

Chief Physician, Department of Stroke andCerebrovascular Diseases
National Cerebral and Cardiovascular Center, Japan

Associate Professor, Department of Neurology,
Huashan Hospital, Fudan University
WHO Collaborating Center for Research and Training
in Neurosciences, Shanghai, China

Approaches for risk assessment of AD

Dr. Rachelle S. Doody

Dr. Jae-Hong Lee

Professor, Baylor College of Medicine, USA

Professor, Department of Neurology, Asan Medical
Center, Seoul, Korea

Approaches for early detection of AD

Dr. Bin Zhou

Dr. Hiroshi Mori

Translational Research Informatics Center,
Foundation for Biomedical Research and Innovation

Professor Emeritus, Department of Clinical
Neuroscience, Osaka City University Medical School,
Professor in Dept. of Clinical Neuroscience andadvisor, Tamiya Hospital, Japan

Clinical trials for prevention and treatment of AD

Dr. Gen Sobue

Dr. Hidenao Fukuyama

Distinguished Professor, Nagoya University
Graduate School of Medicine, Nagoya, Japan

Professor and Director, Human Brain ResearchCenter, Kyoto University, Japan

General discussion

Dr. Bin Zhou

Dr. Rachelle S. Doody

Translational Research Informatics Center,
Foundation for Biomedical Research and Innovation

Professor, Baylor College of Medicine, USA

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

5Keynote address

New Orange Plan and Dementia Prevention in Japan

Dr. Koji MiuraJapan

Director-General, Health and Welfare Bureau for the Elderly, Ministry of Health, Labour, and Welfare,Japan■ Abstract
Japan is aging faster than the rest of the world. It could be
represented as a super aging society. In 2012, the Japanese
population of over 65 years old was 24.1%. This figure means oneout of four of the Japanese population is elderly. In addition to thissituation, a recent estimation showed that 4.62 million people over
65, approximately 15% of the elderly population, are with dementia.
The estimation also showed the number of people with MCI (Mild■ ProfileCognitive Impairment) is 4.00 million or 13% of the elderly population.

Koji Miura, M.D., M.P.H., and Ph. D.

with dementia or experiencing preliminary stages of dementia. The

He started his carrier at the Ministryof Health and Welfare in 1983. His
carrier at Ministry includes Directorof the Health for the Elderly Divisionof the Health and Welfare Bureau for
the Elderly, Director of the Health
Sciences Division of the Minister’s
Secretariat, and the Director General for the Technical Affairs of
the Minister`s Secretariat.

These figures reveal that one in four persons over 65 are living
prevalence of dementia is expected to continue to rise as society
continues to age. A new estimation conducted by Dr. Ninomiya
of Kyusyu University revealed that the number of persons withdementia will be approximately 7.00 million in 2025. It means that one
in five persons over 65 will be with dementia compared to current
one in seven. Today, dementia has become one of the “common”
diseases.
Last November, MHLW held the ‘Global Dementia Legacy EventJapan’ in Tokyo with the theme of ‘New Care and Prevention Models.’
At this event, the Prime Minister declared to start formulating a
new action plan for dementia. In response to this statement, MHLW
formulated the new plan ‘Comprehensive Strategy to Accelerate

Since July 2014, he has been in the

Dementia Measures (New Orange Plan).’current position.

In this plan, seven pillars are set to accelerate dementia measures
such as,1: Raising awareness and promoting understanding of
dementia, 2:Providing health care and long-term care services
in a timely and appropriate manner as the stages of dementia
progress, 3:Strengthening the measures for early onset dementia,
4:Supporting those looking after people with dementia, 5:Creating
age and dementia-friendly community, 6:Promoting research anddevelopment and disseminating the results of prevention, diagnosis,
cure, rehabilitation model, and care model for dementia, 7:Prioritizing
the standpoint of persons with dementia and their families.
In this speech, I would like to introduce the "New Orange Plan" toreview the aim of the plan and some specific measures for persons
with dementia including a viewpoint of dementia prevention.

6

New Orange Plan and Dementia Prevention in Japan

Keynote address■ Presentation slides
Abstract
Strong Political Leadership

P.M. Abe

H.M. Shiozaki“Comprehensive
Strategy to Accelerate
Dementia Measures（New Orange Plan)”

Age and Dementia Friendly
Community

Prevalence Projection
Prevalence in 2025

“Integrated
Community Care

7,000,000￥

System”

Dementia Supporters Program

One in Seven in 2012→
One in five in 2025

Dementia Care and Risk
Reduction(of aged over 65)“Next-gen Dementia Cohort”“Information andCommunication Technology““Robotics”“6.1 million participants(March, 2015) ⇒8 million
participants (FY 2017)”

Number of Persons with Dementia

19%: if the rate of eachgeneration is stable.

20.6%: if the rate

“Universal Health Coverage”“Long-Term Care Insurance”

Public Health Systemincreases along with theincrease of diabetes mellitus.

2

3

1

Strong Political
Leadership

History⃝ 1987:Reports by “MHW Headquarters for the Promotion of Dementia Elderly Measures”••

2

Promotion of “Wards for dementia elderly”
Establishment of “Day-Service Center for Dementia”⃝ 1994:Reports by “The Committee for Dementia Elderly Measures ”•

Establishment of “Group Home for Dementia”
2000
Enactment of “Long-Term Care Insurance Act”
2004
Change of the Japanese terminology for “Dementia”

Shinzo Abe, Prime Minister on November 6th at Global Dementia Legacy
Event Japan⃝ 2005:Launch of “ten-year conception of raising awareness and community development for
dementia”••

Launch of “Training of Dementia Support Doctors”
Launch of “Dementia Supporters Training Program”‹Three foundational pillars of the new plan›①integrated community care system & early
diagnosis and intervention②comprehensive plan to foster dementiafriendly communities③Prioritize the standpoint of persons withdementia and their families⃝ 2008:Reports by “Emergency Project for Improvement of Medical Care and Quality of Life
for Persons with Dementia”••

Prevalence survey of dementia
Promotion of Medical Center for Dementia⃝ 2012:Reports of “Direction of Future Dementia Measures ”•

Development of Dementia Care Pathway“Five-Year Plan for promotion of Dementia Measures (Orange Plan)”•

Development of “Initial Phase Intensive Support Team”⃝ 2015:“Comprehensive Strategy to Accelerate Dementia Measures (New Orange Plan)”“Now, I am asking the Minister of Health,Labour and Welfare to formulate a new action
plan for dementia”“The new plan will involve collaboration acrossgovernment to implement the strategy in aholistic way to support the lives of people withdementia.”

Yasuhisa Shiozaki, Minister of Health, Labour and Welfare, on
November 6th at Global Dementia Legacy Event Japan

4

5

3

4

Comprehensive Strategy to Accelerate Dementia Measures（New Orange Plan）

Comprehensive Strategy to Accelerate Dementia Measures（New Orange Plan）~To Realize Age and Dementia-Friendly Community~~To Realize Age and Dementia-Friendly Community~• One-fourth of aged 65 and over is either persons with dementia or those in its
preliminary stages. In 2012, one in seven, 4.62 million, is persons with dementia.
It is supposed to be one in five, around 7 million in 2025.
• We should look to provide support so that persons with dementia can live wellwith dementia, recognizing that they are not merely persons to be provided withcare.

Seven Pillars①Raising awareness and promoting understanding of dementia②Providing health care and long-term care services in a timely andappropriate manner as the stages of dementia progress③Strengthening the measures for early onset dementia④Supporting those looking after people with dementia⑤Creating age and dementia-friendly community⑥Promoting research and development and disseminating the results,
of prevention, diagnosis, cure, rehabilitation model, and care modelfor dementia⑦Prioritizing the standpoint of persons with dementia and theirfamilies

Bacic Cocept

Realization of a society where persons with dementia can live with dignity in apleasant and familiar environment as how they hope to be as long as possible.
• Formulated by MHLW in collaboration with Cabinet Secretariat, Cabinet Office,
NPA, FSA, CAA, MIC, MOJ, MEXT, MAFF, METI, and MLIT
• Targets at 2025 when the baby boomers turn 75 years and older• Prioritizing the standpoint of persons with dementia and their families(MHLW: Ministry of Health, Labour and Welfare, Consumer Affairs Agency;, NPA: National Police Agency;, FSA: Financial Services Agency;,
MIC: Ministry of Internal Affairs and Communications;, MEXT: Ministry of Education, Culture, Sports, Science and Technology;, MAFF: Ministry6
of Agriculture, Forestry, and Fisheries,; METI: Ministry of Economy, Trade and Industry;, MLIT: Ministry of Land Infrastructure and Transport)

7

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

67

Session I : Clinicopathology of AD

Pathological aspects of amyloid burden in AD

Dr. Hiroshi MoriJapan

Professor Emeritus, Department of Clinical Neuroscience, Osaka City University Medical School,
Professor in Dept. of Clinical Neuroscience and advisor, Tamiya Hospital, Japan■ Abstract
The most critical malfunction of Alzheimer’s disease (AD) is theloss of memory that may come from brain atrophy and neuronal
dysfunction. Such cognitive dysfunctions frequently referred to as
dementia have been considered due to amyloid burden like senile
plaques or amyloid angiopathy. Amyloid burden is certainly importantbecause its occurrence is highly specific to AD, Down syndrome andnormal ageing. APP (the abbreviation of amyloid precursor protein)■ Profilelocated on chromosome 21 is the only gene to produce Abeta protein

Hiroshi Mori was born in 1950. He

mutations of the APP gene are segregated with familial cases withreceived a B.S. degree in Biology and
M.S. degree in Biochemistry, both from
Osaka University, Japan, in 1974 and1976, respectively. He also received
a doctorate in Biochemistry from
University of Tokyo, Graduate Schoolof Science, Biochemistry, in 1979.
He was appointed as an Associate
Pr o f essor a t F u k u i Pref ec t u ra l
College, Fukui, a Research Associate
at Harvard Medical School, Brigham& Women’s Hospital, Boston, U.S.A,
a Chief Resea rc her i n Dept . o f
Neurophysiology, Tokyo Institute ofGerontology, an Associate Professor in
Dept. of Neuropathology, University ofTokyo Medical School, Head of Dept.
of Molecular Biology, Tokyo Instituteof Psychiatry, and Professor in Dept. of
Neuroscience, Osaka City University,
Medical School, Osaka, Japan in 1998.
He is a professor emeritus of Osaka
City University, and is appointed
as Professor in Dept. of Clinical
Neuroscience and advisor of Tamiya
Hospital since 2015.
8

to constitute amyloid and triplicated in Down syndrome. CriticallyAD, and found to up-regulate Abeta (particularly Abeta1-42 species),
furthermore model mice to overexpress APP with FAD mutation
reproduced the neuropathology of senile plaques as well as leaning
failure and so on. Despite these strong suggestive evidence, clinical
trials of neither AN1792 nor Bapineuzumab resulted in little cure
whereas reduced amyloid burden. In contrast to fibrous amyloid
structure as seen in senile plaques, it proved that Abeta protein
potently forms a soluble form as the Abeta oligomer that is thename for a condition that Abeta protein self-aggregates more than
2 molecules. The Abeta oligomer is particularly significant because
it is observed only in model mice (Lesne S et al, (2006) Nature) and
induces synaptic LTP disturbance (Lambert MP et al, (1998) PNAS;Walsh DM et al, (2002) Nature). Thus synaptic abnormality becomesthe central issue to understand AD symptoms and pathology (Terry
RD et al, (1991) Ann Neurol; Selkoe DJ (2002) Science). In late years
it is almost established as the causal molecule of Alzheimer's disease
under the new hypothesis of "Abeta oligomer hypothesis”, which is
replacing "Abeta amyloid hypothesis".
We had a chance to analyze patients with the early-onset familial
AD. They showed clinically AD but their pedigree seems to inherit
the disease in a different fashion from the conventional autosomal
hereditary diseases. Under the agreement of family members, themolecular mechanism was examined and proved to be that thisOsaka mutation is the first human evidence to support that Abeta
oligomer is the sole culprit to induce AD in the absence of amyloid
burden. (Supported in part by Grants-in-Aids by the Alzheimer's
Association (IIRG-09-132098) and by JST, CREST, MEXT of Japan,
also by Research on Dementia from the Ministry of Health, Labourand Welfare, Japan.)Pathological aspects of amyloid burden in AD■ Presentation slides

Disclosure

Pathological aspects of AD

collaborating and supporting companies:
Japanese Mediphysics Co. (Tokyo, Japan)
Teijin Co. (Tokyo, Japan)

Acknowledgment

Hiroshi Moria, b)
Department of Clinical Neuroscience, Osaka City University
Medical School,a) Tamiya Hospital, Nagaoka, Niigatab)

1

Session I

Supported in part by Grants-in-Aids by the Alzheimer's
Association (IIRG-09-132098) and by JST, CREST, MEXT of
Japan, also by Research on Dementia from the Ministry of
Health, Labour and Welfare, Japan.

2A oligomer model mice
Strain: B6C3F1 (C57BL/6N x C3H/HeN)
Promoter: Mouse prion promoter (the kind gift from Dr. Borchelt, D)
Transgene: Human APP695 cDNA with the Osaka mutation (E693

NonTg

WT

E22

Tg2576(IHC with 001, 24 mo）

E22

NL (Swedish)

G (Flemish)Tg2576hAPP

I (London)
Q (Dutch) N (Iowa)
K (Italian)
G (Arctic)(Osaka; deletion mutation)

actin(PiB-PET, 24 mo）

Tomiyama T et al. (2010) J Neurosci 30:4845-56,
Maeda J et al. (2011) J Neurosci (in press)

Tomiyama T et al. (2008) Ann Neurol 63: 377–87.

3

LTP

4

PET imagesof the patient bearing the Osaka mutation (E22)

Water mazeA oligomer

2003.1.31
FDG

2006.10.25

Redox malfunction (mitochondria)

FDG

PIB
Nishitsuji K. Et al. (2009) Am J Pathol 174: 957–69.
Tomiyama T et al. (2010) J Neurosci 30:4845-56,
Umeda T et al. (2011) J Neurosci Res 89: 1031–42.

Shimada H. et al. (2011) Dement Geriat Cog Dis (in press)

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

69Session I : Clinicopathology of AD

Clinicopathological Correlation in Alzheimer's Disease

Dr. Raj N Kalaria

United Kingdom

Professor, Institute of Neuroscience, NIHR Biomedical Research Centre, Newcastle University,
Camus for Ageing and Vitality, United Kingdom■ Abstract
The neuropathological hallmarks of Alzheimer disease (AD) comprise amyloid
plaques, cerebral amyloid angiopathy and neurofibrillary tangles. AD pathology
is also associated with reactive cell or glial responses, and neuronal and synaptic
loss. A definite diagnosis of AD can only be made at autopsy. Postmortem studies
have enabled the staging of the progression of both amyloid and tangle pathologies
with the consequent development of diagnostic criteria, which are used widely.
Clinicopathological correlation studies have also been crucial to generate hypotheses■ Profileabout the pathophysiology of the disease, by establishing that there is a continuum

Professor Dr Raj Kalaria is Director of theoccurs primarily before the onset of cognitive deficits, while neurofibrillary tangles,

Neurovascular Research Group in the Instituteof Neuroscience, Campus for Ageing Vitality,
at the old Newcastle General Hospital site anda Professor of Pathology (Cerebrovascular
Diseases) at Newcastle University. He qualified
from King’s College, University of London andthe Royal College of Pathologists. His interests
include the interface between Alzheimer
disease (AD) and vascular dementia (VaD), PostStroke Dementia and Small Vessel Diseases of
the Brain. He also works on the prevalence
and risk factors of AD and VaD in indigenous
populations of developing countries. Prof Kalaria
serves as section/associate editor on the editorial
boards of European Neurology, Neuropathology
and Applied Neurobiology, Current Alzheimer
Research, Clinical Neurology, Brain and
Behaviour Function and NeuroReport. He hasserved on the Executive and Scientific Boards of
the British Neuroscience Association, Alzheimer’s
Research Trust (UK), International Brain
Research Organisation (IBRO, Paris) and Fogarty
International Centre (NIH). He is currently theliaison officer for IBRO-WFN and SecretaryGeneral of the International Society for Vascular
Behavioural and Cognitive Disorders (VasCog).
10

between ‘normal’ ageing and AD type of dementia, and that amyloid plaque accretion
neuron loss, and particularly synaptic loss, parallel the progression of cognitive
decline. Clearly, failing clearance mechanisms during ageing is another factor in the
progression. In recent studies, however, both neuritic plaques and neurofibrillarytangles independently predicted Clinical Dementia Rating scores. Severe small
vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also
independently associated with the degree of cognitive impairment. Thus, plaques
and tangles independently appear to contribute to cognitive impairment and that
concurrent vascular disease strongly correlates with cognitive dysfunction evenin a sample selected to represent the AD pathological continuum. The substantial
clinical and pathological overlap between AD and vascular dementia (VaD) with anincreasing burden of mixed pathology in the very old suggests an interaction between
vascular and neurodegenerative processes. While significant small vessel disease or
microvascular changes are found in many elderly persons, either alone or in association
with neurodegenerative changes, it is abundantly clear that the combination of vascularpathology and neurodegenerative changes are additive at each level of pathology
lowering the threshold for development of dementia. Considering recent large
sample studies could AD, therefore result from two different lobar processes suchthat vascular factors or disease affects the frontal lobe whereas neurodegenerative
pathologies largely propagate from the temporal lobe? There is some evidence toindicate that the respective pathological conditions, when they co-occur, are operating
simultaneously through cellular or metabolic alterations in different brain regions
and potentially represent independent pathways to AD progression. However, it isproblematic to consider the frontal and temporoparietal lobes separately. It may bethat these perceived separate processes are linked through other unforeseen factors.
The dual pathologies (vascular and neurodegenerative) possibly still have synergistic
effects on cognition through the widely accepted cortico-cortical disconnection.
Our work is supported by the Dunhill Medical Trust (UK), Alzheimer’s Research UK(ARUK) and the Medical Research Council (UK).

Clinicopathological Correlation in Alzheimer’s Disease■ Presentation slides
Common causes of dementia

Dementia with Lewy Bodies (15-20%)• Lewy bodies• Lewy neurites(α synuclein)

FrontoTemporal
Dementias(15-20%)DLB

VaD• Neurofibrillary Tangles (NFTs)• Amyloid β deposits• Cerebral Amyloid Angiopathy

Mixed
AD&DLB

Mixed
Mixed
VaD&DLB AD&DLB
& VaD

Mixed
AD&VaD

Cognition and Brain Pathology
during Ageing

Alzheimer’s Disease (50-60%)•

More than one
pathology becomes
additive in driving
cognitive decline•

Vascular pathology
may exacerbate or
trigger development of
AD pathology

AD

Vascular Dementia (25-30%)

1

Brain amyloid plaques with Ageing

Session I• Large Vessel Disease ischemic stroke  Multi-infarct dementia (delayed?)• Small Vessel Disease  chronic hypoxia/ischaemia,  SVD dementia, Biswanger’s disease2

Staging and Natural
history of cerebrovascularpathology

Cortical accumulation of NPs•

Semiquantitative scoring of CVL

Nelson PT et al, JNEN, 2012

3

4

Vascular and Neurodegenerative
pathways to Dementia

Age-related vascular changes and AD pathology
Vascular changes
may influence
Alzheimer lesion
burden: evidence
from animalstudies
Scheme showing
how CBV factors
may affect amyloid
β processing andclearance

In later stages of disease, the two pathologies converge to cause full-spectrum
dementia (even in AD). Other unknown factors might also play a part.

Kalaria R et al, 2012

Kalaria RN & Ihara M, 2013

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

611

Session II : Approaches for risk assessment of AD

Japan community-based study for identifying risk factors of Alzheimer's disease

Dr. Takashi AsadaJapan

Specially-Appointed Professor, Tokyo Medical and Dental University, Japan■ Abstract
A number of studies on the risk factors for dementia in general and
Alzheimer’s disease in particular have been published in the last two
decades. Such risk factors can be divided into three major categories:
gene level; medical level, and life-style level. Regarding the life-style
related factors, researchers have paid attention to exercise, rest
including sleep, and nutrition. Here we examine and introduce thestudies from Japan dealing nutrition and associated factors, because■ Profile
Education

March 1981 Graduated from Tokyo Medical and Dental University,

the strategy to prevent or delay the onset of dementia. Recently, theevidence for combined effects, such as multinutrient approaches, or a

Tokyo Japan.

healthy dietary pattern, such as the Mediterranean diet, is growing.

December 1993 Received Medical Doctor, Yamanashi Medical

Although such approaches appears to be practical and useful, several

University, Yamanashi Japan.

Research and Professional StateClinical, epidemiological study on dementia: prevention, cognitive training
Professor of Department of Neuropsychiatry, Institute of Clinical
Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba city, Ibaraki,305-8575 Japan
1981-1982

Clinical fellowship at Rojyo Hospital, Ishikawa, Japan,

1982	Clinical fellowship at Tokyo Medical and Dental
University, Tokyo, Japan
1982-1983

Clinical fellowship at Kofu Municipal Hospital, Kofu, Japan

1983-1988	Department of Neuropsychiatry, Yamanashi Medical
College (research associate), Yamanashi, Japan
1988-1989	Department of Geriatrics (research associate), Radcliff
Infirmary, Oxford University, UK
1989-1995	Department of Neuropsychiatry (lecturer), Yamanashi
Medical College, Yamanashi, Japan
1995-1999

Division of Old Age Psychiatry (chief), Musashi Hospital,
National Center for Neurology and Psychiatry, Tokyo, Japan

2000-2001

D ivision of Rehabilitation (director), Musashi Hospital,
National Center for Neurology and Psychiatry, Tokyo, Japan

2001-2015	Department of Neuropsychiatry (professor), Institute ofClinical Medicine, Tsukuba city, Ibaraki, Japan
2015-present	Tokyo Medical and Dental University (specially-appointed
professor)

Professional Society Memberships

Japanese Society of Biological Psychiatry director
Japanese Psychogeriatric Society Vice president
Japanese Society of Dementia director
Japanese Society of Neroropsycjhiatry director
International College of Geriatric Psychoneuropharmacology director

Major Research Topics:

Nation-wide prevalence study of dementia in Japan12

nutrition is an important modifiable risk factor that plays a role inJapanese researches on nutritional effects have focused on the role ofindividual nutrients and bioactive components.
These include milk, green tea, fish oil and so on. We first examine
these studies and discuss possible mechanisms between the nutrientsand development of dementia. On the other hand, some studies
reported that a combination use of supplements might reduce the riskof dementia. We make refer to the possible explanations for the effectby the researchers.
Needless to say, tooth is very important for taking nutrients, and it isvery interesting that a recent study reported an association between
tooth loss and the development of mild memory impairment in theelderly. Dental aspects associated with nutrient as a risk factor for
dementia is also discussed.

Japan community-based study for identifying risk factors of Alzheimer’s disease■ Presentation slides

Valley of death from basic research
to knowledge of dementia prevention

Protective Factors

Cognitive engagement, Physical activity

Diet,
Alcohol
Antihypertensives,
NSAIDsHigh education

Aging

Genetic factors

Socioeconomic
factors

Hypertension,
Vascular factor,
Lifestyle, Depression,
Traumatic brain injury,
Occupation

Risk Factors
Age

1

NIH Statement on
Preventing Alzheimer’s Disease and Cognitive Decline

2

Attention to Nutrition and Diet

• Control of diabetes• Improvement of high blood pressure andelevated blood cholesterol level• Preferable body weight management• Social and cognitive engagement• Participation in physical activity• Healthy diet including high fruits andvegetables• Smoking cessation• Control of depression

Nutritional and Dietary factors and Onset of AD

Neuronal
death

Aβ42
Aggregation

Session II

APOE4
Aging
Oxidative stress
Cerebral inflammation
Cerebrovascular disease

AD

Nutrition and Diet
Antioxidant
HomosysteinHigh calorie diet
Fat
Carbohydrate
Alcohol
Mediterranean diet3

4

Evidence of Association With Cognitive Decline
Association With Cognitive Decline

Study Type and Factor
Nutritional
B vitamins and folate

× ？

Vitamins C and E and β-carotene

×

Ginkgo biloba

×ω-3 Fatty acids

×

Medications

×

Statins×（？）

Antihypertensives
NSAIDs×

Gonadal steroids

×

Cholinesterase inhibitors

×

Social, economic, or behavioral
Physical activity○

Cognitive engagement△～○○：decreased risk

△ ：slightly decreased risk

×：no association

Plassman BL et al

Ann Intern Med. 2010;153:182-193

Table 2- modified(？ ：controversial)

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

613Session II : Approaches for risk assessment of AD

Community-based prevention of dementia in Japan

Dr. Takao Suzuki

Japan

Director, Research Institute of Aging and Development,
Professor, Graduate School, J.F. Oberlin University, Tokyo.
Secretary of President, National Center for Geriatrics and Gerontology, Japan■ Abstract
In Japan, the population is aging at an accelerated rate, withincreasing life expectancy and decreasing birth rate; the total
population is declining while the older population ratio keeps
increasing with prolonged life expectancy, especially that of the old-old
aged 75-84 and the oldest-old aged over 85. As the risk of developing
MCI and dementia increases with age, the prevalence of MCI anddementia increases in parallel with the enlargement and deepening of■ Profilethe aging society. In 2010, the prevalence of dementia and MCI was

Takao Suzuki, MD. PhD

17%) and 13% (3.80 million, 95% CI: 10-16%), respectively, and since

Director of the Research Institute ofAging and Development, and Professor of
Graduate School, J.F. Oberlin University,
Tokyo.
Designated Secretary of President,

then, the prevalence is ever-increasing. We should face up to thereality that the social burden on the productive-age population exerts
a considerable impact on the national economy. Accordingly, thefight against dementia is now the most challenging issue in Japan,
and strategies for dementia prevention should be regarded as one of
the national proprieties of healthcare policies in terms of the national

National Center for Geriatrics andeconomy as well as individuals’ health.

Gerontology, Obu, Aichi.

Thus, the Japanese National Center for Geriatrics and Gerontology

He was born in 1951 and graduated from
Sapporo Medical University (MD) in 1976
and Graduate School of the University

launched a project to promote community-based research, including
the development of an effective screening system for high-risk groups
and intervention for dementia prevention. In the presentation, I would
like to introduces the project, the Obu Study of Health Promotionof Tokyo (PhD) in 1982. After serving as

for the Elderly, with the following strategic triad: 1) Identification of

Associate Professor at Sapporo Medical

the target population by population screening; we regarded patients

University, he worked as General
Manager (1990-2000) and Deputy Director(2000-2009) Metropolitan Institute ofGerontology (TMIG). He served as
Director in the Research Institute,with MCI as the target population, and developed a screening test
battery to identify MCI in a population screening setting. 2) Scientificverification of community-based intervention; we developed aninterventional method combining exercise and cognitive training(“cognicise”). In practical settings, “cognicise” is programmed into
multicomponent exercise intervention, which was reported to have

National Center for Geriatrics andbenefits of cognitive improvement and reduction of brain atrophy

Gerontology (NCGG) from 2009-2015. Hebased on randomized controlled trials. 3) Standardization of thehas been still working as a Designated
Secretary of President in NCGG and also
working as a Professor in the Graduate
School and Director of the ResearchInstitute of Aging and Development in
the J.F. Oberlin University.
14

estimated to be 15% (4.39 million, 95% confidence interval (CI): 12-

methods of population screening and community-based intervention
for evidence-based policy making and widespread implementation.
Dementia prevention, or at least delaying the onset of dementia and/or stopping/slowing the progression of dementia, should benefit thewhole society as well as individuals. It is our continuing challenge toimprove the screening system and community-based intervention for
dementia prevention through accumulation of evidence.

Community-based prevention of dementia in Japan■ Presentation slides

Major Flow of Preventing Dementia

Japanese Elderly People Today
Young‐old (65‐74 yrs.)
Very healthy
Very active
Good social tie and network
Hoping to work as possible

1 Screening

Old‐old (75 + yrs.)
Geriatric Syndrome
Long‐term care state
Frail & Sarcopenia
Dementia (Cognitive function↓）

2

3 Intervention

Neuroimaging

Exercise or Education Classes

FDG PET

MRI
Cognitive Assessments

Cognitive
Assessment Tool

Music Classes

NCGG-FAT

NIRS
ch−2

0.06

ch−3

0.02

−0.03

90
0
−0.02

ch−6

90

−0.01

−0.02

0

0.06

−0.01
−0.02
−0.03

ch−9

90

90

−0.02

−0.02
0.03

0

90

0.01
0

ch−13

0.03

ch−12

ch−16

−0.01
0.02

−0.02

0.02
0

−0.03

90 0.01

0.02

0

ch−15

0.01
90

0.01

−0.01

0

−0.02

0
0

0
−0.01

0

0.02
0

ch−14

0.02

0
−0.01

0.01

−0.01
−0.02

90 0.02
0

0

ch−11

0.02
0.01

0

0.04
0

ch−10

0.03
0.02

−0.01

0.01
90

90 0.02
0

0

0.01
0

0.02

0

0.04
0.03
0

0.01

0

ch−8

0.02

ch−7

−0.01
−0.02

0

0.04
90 0.02−0.02

Questionnaire

ch−4

0.04

−0.04
−0.05

0

0.03

0

−0.01
−0.02
−0.03

0

−0.03
−0.04

ch−5

0.01

0

ch−1

0.01

−0.01
−0.02

−0.03

90

0

90

−0.02

−0.01
0

90

−0.02

0

90

−0.04

0

90

Physical Assessments

1

2

Multicomponent Exercise (“Cogni-cise”) Program for
MCI

Comparison of brain atrophy
Suzuki T, et al., PLoS ONE 2013
Baseline

Exercise withlearning-task

脳萎縮領域の割合 (健忘型MCI高齢者)

Session II

Task 3Stretch andmuscle strength(%)

Exercise

Task 1After 6-month

10
9.5
9
8.5

Task 4

Aerobic exercise

Behavior
modification
technique

8

運動教室群

7.5
7

Control

Task 2

6.5

健康講座群

6
5.5
1
介入前

2.0

2
介入後

6.0

3

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

415

Session II : Approaches for risk assessment of AD

Prevalence and progression of mild cognitive impairment :the Shanghai Aging Study
Dr. Ding Ding

People's Republic of China

Associate Professor, Department of Neurology, Huashan Hospital, Fudan University
WHO Collaborating Center for Research and Training in Neurosciences, China■ Abstract
The Shanghai Aging Study is the first prospective community-based
cohort study of cognitive impairment in China, with a comparable
study design, procedures, and diagnostic criteria for dementia andmild cognitive impairment (MCI) to most previous cohort studies indeveloped countries. This prospective cohort is used to enumerate
the prevalence, incidence and risk factors for dementia and MCI
among residents aged ≥60 in an urban community of Shanghai,■ Profile

China. Participants received clinical evaluations including physical

Ding Ding, MD, MPH, PhD.

neurologic examinations, and neuropsychological testing. Urine andDr.Ding is an associate professor andneuro-epidemiologist at the Institute of
Neurology, Fudan University Huashan
Hospital, WHO collaborating center for
research and training in neurosciences,
Shanghai, China. Before joining theInstitute in early 2002, she was alecturer of epidemiology in the Schoolof Public Health of Fudan University.
She has research experience inblood samples were collected, aliquoted, and stored. DNA was extracted
for Apolipoprotein (APOE) genotyping. Diagnoses of dementia and MCI
were made using standard criteria via consensus diagnosis.
The baseline survey was conducted during Jan 2010 to Sep 2011.
Among 3,141 participants aged ≥60, we diagnosed 156 (5.0%, 95%
CI 4.3-5.8%) participants with dementia. The prevalence rates of
Alzheimer's disease and vascular dementia were 3.6% (95% CI 3.0-4.3%)
and 0.8% (95% CI 0.5-1.1%). Among 2,985 nondemented individuals, 601
were diagnosed with MCI, resulting in a prevalence of 20.1% for total
MCI, 13.2% for amnestic MCI (aMCI), and 7.0% for non-amnestic MCI(naMCI). The proportions of MCI subtypes were: aMCI single domain

epidemiology, biostatistics, and health(SD), 38.9%; aMCI multiple domains (MD), 26.5%; naMCI-SD, 25.0%; andeconomics of neurological diseases,

naMCI-MD, 9.6%. The prevalence of aMCI-MD increased rapidly withsuch as Alzheimer’s disease, epilepsy,
Parkinson’s disease, stroke, multiple
sclerosis, etc. She has been Co-PI
and PI on several China government
and NIH-funded grants, especiallyage in women APOE ε4 carriers (from 60 to 69 years to ≥80 years,
3.1%–33.3%, P <0.001).
From Jan to Dec 2014, we completed a follow up study to observe theprognosis of MCI cases defined at the baseline from the community.
After averagely 3.5 years, 82 (23%) progressed to dementia, and 101

for community-based epidemiological(28%) converted to cognitive normal. The annual progressing rate fromsurvey and risk factors of epilepsy

aMCI to dementia was 7.6% (95% CI 5.9-9.7%), while that from naMCI

and dementia. She also has experienceof clinical trials. She was awarded the
Bruce S. Schoenberg InternationalAward in Neuro-epidemiology ofAmerican Academy of Neurology in
2006.

16

measurements, demographic and lifestyle questionnaires, physical andto dementia was 4.5% (95%CI 2.8-6.9%). The annual convertion ratefrom aMCI to cognitive normal was 9.3% (95% CI 7.4-11.5%), while thatfrom naMCI to cognitive normal was 5.6% (95%CI 3.7-8.3%).
Our findings suggest that 20% of Chinese elderly are affected by
MCI. Further prospective studies are needed to examine other risk/
protective factors to the prognosis of MCI.

Prevalence and progression of mild cognitive impairment : the Shanghai Aging Study■ Presentation slides

Shanghai Aging Study (SAS)Early diagnosis and treatment of Alzheimer’s disease in Shanghai: prevalence
survey of Alzheimer’s disease and mild cognitive impairment
Supported by Shanghai Science and Technology Committee
2009-2012

Prevalence and progression of mild cognitive impairment
the Shanghai Aging Study

Objectives:* to establish a community-based study cohort of general population of elderly

Ding Ding, Qianhua Zhao, Qihao Guo, Haijiao Meng, Bei Wang, Yan
Zhou, Lirong Yu, Li Zheng, Zhen Hong* to identify the MCI (all types) and dementia (all types) cases in 5,000
community residence aged 60 and over.
* to identify the prognosis of MCI by follow-up

Department of Neurology, Huashan Hospital, Fudan University,
WHO Collaborating Center for Research and Training in Neurosciences
Shanghai, China* to identify the related factors of the prognosis of MCI

1

2

Session II

Prevalence of dementia and MCI by agegroup

3

4

Discussion
 A strong participation rate is achievable from recruitment ofcommunity-based elders in urban Shanghai.
 Collection of detailed diet, risk factor, medical and family history, andclinical, neuropsychological data, as well as acquisition of blood,urine and MRI is highly feasible.
 MRI contribution to the accurate diagnosis
 Memory complain for MCI diagnosis
 Underestimated prevalence (younger age, higher education
population sample)
 Risk factors/protective factors need cohort study to confirm

5

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

617Session III : Approaches for early detection of AD

How imaging and biofluid biomarkers are used for clinical trials :The Alzheimer's Disease Neuroimaging Initiative (ADNI).
Dr. Michael W. Weiner

United States of America

Professor, Medicine, Radiology, Psychiatry and Neurology, University of California San Francisco.

■ Abstract
The goal of ADNI (see ADNI-info.org) is to standardize and validate
MRI and PET imaging and blood/CSF biomarkers for Alzheimer’s
treatment trials. We studied: MCI (n= 850); AD (n= 350); Normal
Controls (n= 350) and 150 controls with cognitive complaints with:clinical visits, neuropsychological assessments, MRI (structural,
perfusion, diffusion-tensor and fMRI), FDG PET, amyloid PET(Florbetapir) blood and urine, and CSF (abeta, tau, ptau and other■ Profileanalytes) and whole genome sequencing. Many patients diagnosed

Michael W. Weiner, M.D.

plaques. About 30% of cognitively normal elders do have high levels

with dementia due to AD do not have high levels of brain amyloidof plaques, and the presence of plaques is a risk factor for cognitive

EDUCATION
The Johns Hopkins University, Baltimore, Maryland

B.A. 1961

SUNY Upstate Medical Center, Syracuse, New York

M.D. 1965

PROFESSIONAL EMPLOYMENT:
Assistant Professor of Medicine, University of Wisconsin, School of
Medicine

1971-1974

Assistant Professor of Medicine, Stanford University, School of
Medicine

1974-1980

Associate Professor of Medicine in Residence, University of California,
San Francisco

1980-1990

Director, Center for Imaging of Neurodegenerative Diseases San
Francisco Veterans Administration Medical Center

2004-2013

Professor of Medicine, Radiology, Psychiatry and Neurology Universityof California, San Francisco

1990-present

Michael Weiner, MD, is a Professor in Residence in Radiology
and Biomedical Imaging, Medicine, Psychiatry, and Neurology
at the University of California, San Francisco. He is Principal
Investigator of the Alzheimer's Disease Neuroimaging
Initiative, which is the largest observational study in the worldconcerning Alzheimer's Disease. He is the former Director of
the Center for Imaging of Neurodegenerative Diseases (CIND)
at the San Francisco Veterans Affairs Medical Center. He
has also launched The Brain Initiative, which is a web-based
registry for recruiting, screening, and longitudinally monitoring
subjects for neuroscience studies of all types. Dr. Weiner has
750 published articles and he has written 70 book chapters.

18

decline. Similar ADNI-like projects are underway in Australia, Japan,
Europe, China, Taiwan, and Korea leading to the “World Wide ADNI
network.” and the Parkinson’s Progressive Markers Initiative (PPMI). All ADNI data is available to all scientists in the world, on USC/LONI/ADNI, without embargo. Blood and CSF samples can berequested. ADNI methods are now widely used in clinical treatment
trials, and have led to the development of the “new” research criteria.
Over 650 papers have been published on ADNI data and all scientists
are encouraged to explore this rich data set and publish results. It
is expected that ADNI will substantially contribute to identifying
effective diagnostic techniques and treatments to slow progression
and prevent AD.

How imaging and biofluid biomarkers are used for clinical trials : The Alzheimer's Disease Neuroimaging Initiative (ADNI).

■ Presentation slides

2

3

4

5

6

Session III

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

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Session III : Approaches for early detection of AD

Brain imaging on Alzheimer's diseaseDr. Hidenao Fukuyama

Japan

Professor and Director, Human Brain Research Center, Kyoto University, Japan■ Abstract
The beginning of the studies on Alzheimer's brain imaging was in
the early 1980s. This was plausible due to Glucose metabolic ratemeasurement of the brain by Sokollof and Phelps's studies by Positron
Emission Tomography (PET). They found the remarkable reductionof glucose metabolism in the temporal and parietal lobes, which
was astonishing finding because all of the pathology researchers on
Alzheimer's disease believed whole brain would be damaged diffusely■ Profileby Alzheimer's pathology. Later, Precuneus and Posterior cingulate

Hidenao Fukuyama, M.D., Ph.D.

process.

Dr. Hidenao Fukuyama is now at the position of
the Professor and director, Human Brain
Research Center, Kyoto University Graduate
School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto, Japan.
Graduated March 1975 with the degree of Bachelor of
Medicine.
Received a Ph.D. in March 1983 from Kyoto
University
Received a license of Medical Doctor on May 27, 1975.
Served as a lecture, Depa rtment of
Neurology, Faculty of Medicine, Kyoto
University until June 15, 1995, and as an
associate professor, Department of Brain
Pathophysilogy, Faculty of Medicine, Kyoto
University. Affiliated the Professor of thedepartment of Functional Brain Imaging on
January 1st, 2001. Appointed as the directorof the Human Brain Research Center, Kyoto
University Graduate School of Medicine, on
April 1st, 2003.
Main works has been directed to the imaging of
Neurological disorders, in particular, cerebrovasculardisorders and dementia such as Alzheimer's disease.
Recent MRI researches collaborating with Denis Le
Bihan (Neurospin, Paris) is the leading project for new
field of functional MRI using diffusion MRI, whichappeared in recent journals such as PNAS.
20

cortex were easily damaged in the very first stage of the disease
In addition to Glucose metabolism as well as cerebral blood flow, newpathological process in the brain of Alzheimer's disease was disclosed
using PK11195, which can reveal the activated microglia and indicatesthe mild inflammation in the brain, where the most damaged area
was seen to be in the inflammatory condition.
Recent advances of biogenetic research on the senile plaque andAlzheimer's tangle made feasible the imaging of amyloid (componentof plaque) and recently tau protein (component of tangle). Those
images were available by pathological specimens 20 years ago, but atpresent, we can see them in vivo human brain.
Our study on glucose metabolism and cerebral blood flow by PET,
the most damaged area such as in parietal lobe, indicated theischemic condition and disturbed transport from blood vessels to thebrain parenchyma. This is the result due to the amyloid depositionor primary pathological process of Alzheimer's disease is not clear.
Those will be the supportive evidence for Ihara's hypothesis on
Alzheimer's disease mechanism.
Legends
Amyloid imaging (right upper panel) by courtesy of Dr. K. Ishii (Tokyo
Metropolitan institute of Gerontology)
Tau imaging (right lower panel) by Dr. K.Kudo (Tohoku University)

Brain imaging on Alzheimer's disease■ Presentation slides
PIB in control subjects
Aβ蓄積

CBF

高

CMRglu

低

CMRO2

OEF

1

タウイメージング

PIBによるAlzheimer、MCIの診断
NormalAlzheimer’s

Amnestic MCI

MMSE 28

MMSE 20MMSE 27

2

4

Session III

3

Diffuse Lewy Body Disease

Diffuse cortical damage produces CMRGlc reduction similar to Alzheimer’s disease ?

5

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

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Session III : Approaches for early detection of AD

Novel Imaging biomarker for early detection of AD

Dr. Gen Sobue

Japan

Distinguished Professor, Nagoya University Graduate School of Medicine, Japan■ Abstract
Brain protein aging is the greatest and most fundamental factor of
dementia. In Alzheimer’s disease (AD), Aβ and Tau protein shows theloss of physiological functions, failure of mutual interaction with functional
molecule, accumulation of acquired pathogenicity, and propagated inneural cells. This is expected to be a functional molecular basis of neuraldegeneration, which causes the breakdown of neural circuits and results inthe presence of dementia. However, it is not fully clarified the process of■ Profilebrain protein aging and the mechanism of neural circuit breakdown. Thus,

Gen Sobue, MD, PhD

neural circuit breakdown are important in order to develop reliable imaging

Distinguished Professor, Nagoya University
Graduate School of Medicine, Nagoya, JapanEDUCATION：
Nagoya University School of Medicine, JAPANMD 1975 Medicine
Nagoya University Graduate School of Medicine, JAPANMD, PhD 1981 Medicine (Neurology)

EMPLOYMENT :Lecturer, Aichi Medical University, Aichi, JAPAN(1981-1991)
Resea rch , Fel low Un iversit y of Pen nsylva n ia ,Pennsylvania, USA (1982-1983)
Assistant Professor, University of Pennsylvania,

visualization of brain protein aging and clarification of the mechanisms ofbiomarker for very early diagnosis of AD and breakthrough treatment.
PBB3 and THK-5351 are new tau PET tracers developed in Japan. Bothtracers do not bind Aβ and can visualize the abnormal tau deposition
consistent with the autoradiography findings of AD brain sections accessedby tau antibodies. PBB3 study showed that tau deposition was more closely
associated with cognitive dysfunction than Aβ. Interestingly, aged healthy
subjects as well MCI subjects showed intermediate uptake of PBB3 or
THK-5351 independent of Aβ deposition. AD has been believed to be
associated with a cascade of pathological events involving the formationof amyloid-based neuritic plaques, tau-based neurofibrillary tangles, andfunctional neuronal changes. However, tau imaging may bring some othernew paradigm shift in AD pathogenesis.
As for visualization of brain network, we observed several intriguing

Pennsylvania, USA (1983-1984)

findings in normal aging and MCI subjects. We have investigated the change

Associate Professor, Aichi Medical University,of brain network in 1,000 healthy control subjects using resting-state MRI,

Nagoya, Japan (1991-1995)

diffusion tensor MRI, 3D MPRAGE, and magnetoencephalography. Based

Professor, Nagoya University School of Medicine,on preliminary analysis with aged 200 healthy subjects, brain atrophy will

Nagoya, Japan (1995-2000)

be observed in mainly limbic and premotor area with aging. Diffusion tract

Professor, Nagoya University Graduate School of
Medicine, Nagoya, Japan (2000-2015)
Associate Dean, Nagoya University Graduate Schoolof Medicine, Nagoya, Japan (2007-2008)
Dea n, Nagoya University School of Medicine /Nagoya University Graduate School of Medicine,
Nagoya, Japan (2009-2012)

AWARD:
Toshihiko Tokizane Memorial Award, 2005
Chunichi Culture Award, 2007

imaging showed anatomical network disruption surrounding the lateral
ventricle. However, resting state functional MRI showed that increase ofresting connectivity across multiple cortical areas were more frequently
observed than the decrease of those. These results may be a compensatory
phenomenon of functional brain networks against the progression of brain
atrophy and disruption of anatomical brain networks with aging brain.
Furthermore, several networks showed significant correlation with scoresof cognitive function test. Interestingly, a number of these networks wereoriginated from specific anatomical lesions. Thus, collapse of these "hub"lesions which may play an important role for maintaining the cognitive
function will be closely associated with the development of dementia.

22

Novel Imaging biomarker for early detection of AD■ Presentation slides

To elucidate the relationship between brain protein aging andmicro/macro brain network disruption is crucial.

THK-5117/5105 and PBB3 are novel PET tracers for imaging[11C]PBB3 tau(タウ)pathology in AD

Brain protein aging and disruption of macro brain network– molecularmechanism and visualization
Aging

Dysfunction

ProdromalRNA, microstructure, micro
network abnormalities?

Oligomer? Disruptionof compensation?

[18F]THK-5105 PET images

Dementia

Amyloid and multiple protein deposition?
Macro network abnormalities？

Brain protein aging and disruption of micro brain network– molecularmechanism and target
NormalRNA/structure change（Brain 2014）

Propagation/Infection

Oligomer/AmyloidP[11C]PBB3 PET images

Ub

Dysfunction

Synaptic failure

Neuronal loss

（Neuron 2013）

1

Resting networks have a tendency to increase theirconnectivity with other lesions with age

PBB3 deposition is significantly correlated with cognitive dysfunction
Medial temporal lobe
SUVR

2

Representative restingstate networks

r2=0.867
p < 0.01

Regions showed significant increased connectivity
with green areas with age
Regions showed significant decreased connectivity
with green areas with age

Precuneus Network

SUVR

Precuneus
r2=0.773
p < 0.05

Higher Visual Network

SUVR: Standardized uptake value ratio（Neuron 2013）

4

Session III

3

MCI can show not only decreased connectivity but
increase connectivity with resting network on MRI
Increased connectivity

Yellow and red：increase of connectivity
Blue：decrease of connectivity
1

4

16

3

Anterior salience
Auditory 8
Basal Ganglia11
Dorsal DMNHigh Visual25
27
Language34
LECN402

1

Posterior Salience
Precuneus52
Primary Visual56
58
RECN
64
Sensorimotor70

0Decreased connectivity-1

Ventral DMN

80-2

Visuospatial

80

90

Visuospatial

52 5658 64 70

Ventral DMN

LECN

34 40

Precuneus
Primary Visual
RECN
Sensorimotor

2527

Posterior Salience

8 11 16

Dorsal DMNHigh Visual
Language1

Anterior salience
Auditory
Basal Ganglia

90

p < 0.05

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

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Session III : Approaches for early detection of AD

Imaging of A β -linked brain milieu disruption

Dr. Yasuomi Ouchi

Japan

Professor, Department of Biofunctional Imaging, Medical Photonics Research Center,
Hamamatsu University School of Medicine, Japan■ Abstract
β-Amyloid protein (Aβ) is a center of culprits responsible for
A lzheimer’s disease (A D), which has been propelling ma ny
researchers to develop sensitive biomarkers to detect it earlier andeffective drugs that act specifically on Aβ generation or deposition.
As many pieces of literature indicate that Aβ deposition is no longer
healthy in the brain, our recent study has proven it by showing that

■ Profile
Yasuomi Ouchi, M.D., Ph.D.
Title:	Professor

Affiliation:	Department of Biofunctional Imaging,	Medical Photonics Research Center	Hamamatsu University School of Medicine

people deteriorates normal responses in default mode network
activity and hence impair working memory performance.
In addition to Aβ-related breakdown of brain functions, Aβ-induced
inflammation is also pathophysiologically important. Supported bymany animal reports about activation of microglia playing a majorrole in neuroinflammation in the AD brain, in vivo imaging of
microglia activation clearly shows their activation occurring even in

Academic and work experience

the preclinical AD period. In this talk, we introduce a couple of data

1982-1988 	Kyoto University, School of Medicine

on microglial activation that can be illustrated by positron emission

1991-1995	Kyoto University, School of Medicine,

tomography (PET) with the first, widely-used TSPO tracer [11C]

Graduate School (Neurological Science)

PK11195 and the second generation TSPO tracer [11C]DPA713, which

1995-2007	Hamamatsu Medical Center, Positronare considered as promising biomarkers for the activation detection.

Medical Center, Neurology, Chief

Interestingly, the accumulation of Aβ ([11C]PIB uptake) in early-

1997-2000	H awa i i Q ueen’s Med ic a l C enter,middle staged AD patients was negatively correlated with microglial

Collaborative researcher

activation, suggesting that a generation of soluble Aβ monomer or

2004-present	H a m a m a t s u M e d i c a l P h o t o n i c soligomer activates microglia more than deposition of a fibril form ofFoundation, DirectorAβ.

2007-present	Hamamatsu University School of Medicine,

Abnormalities of the neurotransmitter system are also considered	Medical Photonics Research Center,

as important pathophysiological changes in the AD brain, letProfessor
Bibliography (recent)
1. Nozaki T, Ouchi Y, et al. Effect of subthalamic nucleus
stimulation during exercise on the mesolimbocorital
dopaminergic region in Parkinson’s disease: A PET
Study. J Cereb Blood Flow Metab. 33：415-421, 2013
2. Suzuki K, Ouchi Y, et al. Microglial activation inyoung adults with autism spectrum disorder. JAMA
Psychiatry. 70:49-58, 2013
3. O kada H, Ouchi Y, et al. Alterations in α4β2
nicotinic receptors in cognitive decline in Alzheimer’s
etiopathology. Brain. 136：3004-17, 201324

the greater degree of Aβ deposition in cognitively normal elderly

alone metabolic and circulatory disturbances as shown elsewhere.
Considering the cholinergic system, for instance, nicotinic receptors(nAChRs) currently attract AD researchers in that modification ofnAChRs may lead to promising approach of AD treatment. We are
now targeting at α4β2 and α7 nAChRs to be depicted by in vivo
molecular imaging for the purpose of clarifying Aβ-related abnormal
nAChRs that are responsible for cognitive dysfunction in AD.
The presentation today is thus a mixture of our recent PET findings
on AD pathophyisiology that has been viewed from the peripheryof main proteins such as Aβ and tau. Prevention of AD should be
preceded by clarification of any pathological events in the AD brain
using the state-of-the-art technology, which then helps monitor the
posttreatment condition of the brain milieu of the disease.

Imaging of A β -linked brain milieu disruption■ Presentation slides

2

3

4

5

6

Session III

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

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Session IV : Clinical trials for prevention and treatment of AD

Strategies for prevention of AD : Clinical Trials Considerations

Dr. Rachelle S. Doody

United States of America

Professor, Baylor College of Medicine, USA■ Abstract
Alzheimer’s disease is a neurodegenerative process that becomes
clinically manifest when there is failure of brain processes. The
pathophysiologic process itself and the processes that sustain
the general condition of the brain are all targets for potential
treatments.

It is likely that interventions effective in the pre-clinical stages of AD will not have the same degree of effectiveness,or will be ineffective once the clinical symptoms have started to■ Profileprogress. Strategies for treatments under consideration to prevent

Rachelle S. Doody, M.D., Ph.D.

genetics; neurotransmitter-based treatments modeled on current

Dr. Doody is the Effie Marie Cain Chair in Alzheimer’s Disease Research and Professor of Neurology at
Baylor College of Medicine where she also directs the
Alzheimer’s Disease and Memory Disorders Center. She
received a B.A. from Rice University in 1978, and M.D.
(with honors) from Baylor College of Medicine in 1983.
After completing internship and residency at the RoyalVictoria Hospital and Montreal Neurologic Institute inMontreal and at Baylor College of Medicine, she wasboard certified in Neurology in 1988. Dr. Doody thenreceived a Ph.D. in Cognitive Anthropology from Rice
University, where she studied the brain and language.
Since joining the faculty at Baylor, Dr. Doody has
pursued research interests in cognitive behaviors,
including dementia (loss of thinking and memory
abilities) and aphasia (disturbed speech and language
secondary to brain dysfunction). She has published over
175 original articles which deal with the diagnosis,
progression, or treatment of Alzheimer’s Disease andrelated disorders. She has received multiple research
grants, including a Zenith Award from the National
Alzheimer’s Assocation, and conducted numerous
clinical trials of Alzheimer’s Disease therapies. She
regularly presents her research data at national andinternational scientific forums. Current researchinterests include studies to understand and model the
progression of Alzheimer’s Disease, studies of clinicalheterogeneity, and research and development of new
medications to treat Alzheimer's Disease.

26

AD come from: epidemiological data regarding population risk;
effective AD therapies; metabolic treatments; regenerative therapies;
inflammatory modulators; APO E modifying drugs; and drugs that
attempt to interfere with plaque and tangle formation.

Recentdata about the biomarker changes in pre-clinical disease afford an
additional approach to defining populations at risk for prevention
trials. While some public health interventions, such as diet andexercise, are low risk and may be justified based upon current
epidemiology, more potent and potentially risky approaches arebeing studied in populations who are at risk based upon genetics(API Columbian Study, Dominantly Inherited AD Network or DIAN,
API E4 Homozygote Study) or biomarkers (Anti-amyloid therapy in
Asymptomatic AD or A4 Study and TOMMORROW study. The API
and A4 trials are using anti-amyloid drugs, while the TOMMORROW
study uses a low dose of pioglitazone). Several studies are also
underway in prodromal AD or Mild Cognitive Impairment due to AD,
including drugs that affect neurotransmitters, monoclonal antibodies
targeting beta amyloid, intranasal insulin, dietary modulation, physicaland mental exercise, and transcranial magnetic stimulation. Clinical
trials must select treatments based upon a solid rationale, and thentailor the population and trial design to the treatment approach.

Strategies for prevention of AD : Clinical Trials Considerations■ Presentation slides

Is there one pathway for AD
treatment?
Initiating Event
TheoryStrategies for Antidementia Drugs

 Drugs/nutraceuticals suggested by risk Neurotransmitter
Neurotransmitter--based therapies
 Metabolic/Neuroprotective/Regenerative

Brain Failure Theory

drugs and therapies

 Interaction between
 Amyloid accumulation

through increased
synthesis or decreased
clearance

susceptibilities, habits,
and the biology of aging

 Tau modulating drugs
 Glial/inflammation modulating drugs
 APO E modifying drugs
 Amyloid modulating drugs

 Protein accumulations

including AβAβ and Τau andother brain changes

1

2

Possible Fates for MCI in
Clinical Trials

Clinical Trials Issues

 Remain a separate clinical entity
 Pending a second primary measure to use
along with cognition eg Patient Reported
Outcome What population
population?
?
 What treatment?
 What effects of treatment?

 Merge with prepre-dementia in some trials
on the basis of shared biomarkers

 Merge with mild AD in some trials on thebasis of shared symptoms

3

4Conclusions: Rationale for AD
treatments

Conclusions: Prevention
Populations

 Can target a specific pathway in the Prevention trials can be done in groups

pathophysiology

at risk for AD

 Can target other causes of brain failure Risk/benefit ratio needs to beappropriate for the group in whom thetreatment will be tested

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2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

Session IV Mutation carriers E4 or other genetic risk positive Biomarker defined risk
 Epidemiologically defined risk

627

Session IV : Clinical trials for prevention and treatment of AD

Practical points in conducting clinical trials on Alzheimer's disease

Dr. Jae-Hong Lee

Republic of Korea

Professor, Department of Neurology, Asan Medical Center, Korea■ Abstract
At Asan Medical Center, the largest hospital in Korea, we haveconducted 12 global clinical trials for Alzheimer’s therapy in thepast 5 years. Among those are monoclonal antibodies to Abeta,
tau aggregation inhibitor, BACE-1 inhibitor, serotonin receptor
antagonist, alpha-7 nicotinic acetylcholine receptor agonist, and soforth. Half of them are phase I or II clinical studies. We have now
become a regular customer of multinational sponsors. There are■ Profilesome challenges we face: 1) we are still underestimated and hardly

Jae-Hong Lee, M.D.

obviate the chance of reflecting regional concerns/issues in the study

PRESENT ACADEMIC & HOSPITAL APPOINTMENTS:- Professor of Neurology
Asan Medical Center, Univ. of Ulsan College of Medicine- Executive of Foreign Affairs, Korean Dementia Association- President-elect, Korean Dementia Association

EDUCATION:
1980-1986	M.D. degree from Seoul National University,

College of Medicine, Seoul, Korea
1991-1993	Master’s degree from Seoul National University,
Graduate School, Seoul, Korea
1993-1995	Ph.D. degree from Korea University, Graduate
School, Seoul, Korea

allowed to get involved in drawing up a protocol of any study, which
protocol. 2) Phase I and II studies require PK/PD data collection, ECG
monitoring, and long observation time, which makes the utilization ofa clinical research center imperative. 3) People still lack the sense ofcommitment to contributing to medical advancement by participating
in a clinical trial. Rather, they tend to have suspicion of clinical trials
experimenting on them.
Alzheimer’s drug trials are characterized by long-term followup, involvement of elderly individuals, and a modest drug effect.
Conducting a trial for AD therapy is indeed a high-maintenancejob. As for the investigators, there are also challenges including thefrequent change of staff members during the study, communication
problem among the great number of staff, and partnership with
CRO. These problems should be addressed to move forward witha successful clinical trial. We need to have a voice and try to let

CAREER:
1989-1992	Residency of Neurology at Seoul National
University Hospital
1992-1994	Clinical Fellow of Neurology, Asan Medical
Center, Univ. of Ulsan College of Medicine

the sponsor know about the concerns we have and the situations
local sites deal with in advance of the initiation of any clinical trials.
We find researchers network important. It enables spreading thestandard of practice and sharing experience and knowledge among

1994-1997	Instructor of Neurology, Asan Medical Center,the members. We need to pay more attention to investigator-

Univ. of Ulsan College of Medicine

initiated trials (IIT). Given the limitations of randomized clinical trials

1998-1999	Visiting Scholar (Clinical Research Associate),sponsored by pharma companies, studies focusing on real world

Alzheimer's Disease Research Center, UC San Diego

problems and something out of protocol-driven care are required to

1997-2001	Assistant Professor of Neurology, Asan Medical

provide evidence-based decision making in clinical practice. Issues ofCenter, Univ. of Ulsan College of Medicine
2001-2006	Associate Professor of Neurology, Asan Medical
Center, Univ. of Ulsan College of Medicine

indemnification or litigation should be addressed fully prior to clinical
trials so that investigators feel protected and concentrate on them.
Some of the useful tips on conducting good clinical trials: good

2007-Present	Professor of Neurology, Asan Medical Center,

teamwork, adherence to GCP guideline, regular refresher course

Univ. of Ulsan College of Medicine

on it, good communication on multiple levels, and, last but not least,
investigator’s enthusiasm and commitment to clinical trials.

28

Practical points in conducting clinical trials on Alzheimer's disease■ Presentation slides

Multi-Center, RCTInternational multi-center drug trials

 Rationale Basic designs
 Participants Intervention
 Blinding Outcomes Adherence Follow-up

12 trials at AMC NR

2010-2015
 Phase I clinical trial: 2
 Phase II clinical trial: 3 (+ domestic 2)
 Phase III clinical trial: 4 (+ domestic 1)

1

Problems or Challenges – patient
enrollment & monitoring

2

Alzheimer’s drug trials: characteristics

 Resistant about taking an investigational drug

 Long-term follow up: the importance of rapport

 Screening failure Elderly individuals: comorbidity & polypharmacy

 Variable faithfulness to carrying on the study Modest drug effect Adverse events notification

 High-maintenance job!
3

4

Moving forward

Conducting good clinical trials

 Researcher network – important!

 Good teamwork

 Spread the standard of practice Adherence to GCP guideline

 Share experience & knowledge

 Regular refresher course

Session IV

 Independent IIT study Good communication on multiple levels
 Investigator’s enthusiasm and commitment
5

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

629

Session IV : Clinical trials for prevention and treatment of AD

Strategy to tackle MCI : a drug repositioning approach

Dr. Masafumi Ihara

Japan

Chief Physician, Department of Stroke and Cerebrovascular Diseases
National Cerebral and Cardiovascular Center, Japan■ Abstract
The concept of mild cognitive impairment (MCI) was first introduced
for the purpose of identifying individuals in an intermediate state
between no cognitive impairment and Alzheimer’s disease (AD).
Recently, the heterogeneity of MCI has attracted attention as it has
become clear that other diseases, such as cerebrovascular disease
can also cause mild cognitive deficits, prompting a redefinition of
MCI. Heterogeneity of MCI has been confirmed by neuropathological■ Profile

examinations. Most MCI patients not only possess amyloid plaques

Dr Masafumi Ihara, MD, PhD, FACP, issuch as arteriosclerosis and cerebral amyloid angiopathy (CAA).

a Chief Physician in the Department of
Stroke and Cerebrovascular Diseases,
National Cerebral and CardiovascularCenter (NCVC), Osaka, Japan. He graduatedfrom Kyoto University School of Medicine
in 1995. His clinical training was at Kyoto
University Hospital in 1995 and at NishiKobe Medical Center in 1995-1999. In 1999
he entered Kyoto University Graduate
School of Medicine and completed a PhD in
Neuroscience in 2003.
Dr Ihara received his neuropathologicaltraining under Prof. Kalaria in Newcastle
University during 2006-2008. Since
returning to Japan in 2008, Dr Ihara has
led a neurovascular research group in
Kyoto University (2008-2012), Instituteof Biomedical Research and Innovation(2012-2013) and NCVC (2013-). His major
research and clinical interests are theneurochemistry, molecular biology, andtreatment of stroke and dementia. He has
published over 100 peer-reviewed papers
regarding clinical and basic research on
stroke and vascular cognitive impairment.
30

and neurofibrillary tau tangles, but also cerebral vascular pathology
CAA induces cerebral infarcts or hemorrhage of varying size andtype, attributing to further cognitive impairment. Sporadic AD and
CAA has been suggested to be the consequence of Aβ elimination
failure, mainly caused by disturbance of the perivascular drainage
system. Since severe CAA is an independent risk factor for dementia,
facilitation of Aβ clearance has been suggested as a potential
treatment of AD and MCI.
We have recently shown by retrospective analysis that patients withmild cognitive impairment receiving an antiplatelet and vasodilating
drug cilostazol, a selective inhibitor of phosphodiesterase 3, exhibit
significantly reduced cognitive decline (Ihara M, et al. PLOS ONE
2014). In addition, we have found that cilostazol protects against
the disruption of the neurovascular unit and facilitates the arterial
pulsation-driven perivascular drainage of Aβ in AD/CAA (Maki T,
et al. Ann Clin Transl Neurol 2014). Based on these lines of evidence,
we have started an investigator-initiated, prospective, randomized,
placebo-controlled, double-blind, multicenter trial using cilostazolfor patients with MCI. As cilostazol is used for peripheral arterydisease worldwide and for secondary stroke prevention in Japan, theavailability of its pharmacokinetic, toxicology, and safety profiles isan obvious advantage. Such drug repositioning approach has several
benefits over the traditional de novo drug discovery approach,including reduced development costs and shorter time to approval
and launch. Drug repositioning would be an attractive strategy thatshould be more actively pursued for MCI.

Strategy to tackle MCI : a drug repositioning approach■ Presentation slides

Phosphodiesterase inhibitors

Preclinicalstudy

Promotion of Aβ clearance by cilostazol

Cerebrovascularreserve （5%CO2）

Aβ in thehippocampus

Clearance efficiency ofstereotaxically injected Aβ1-40

Cognitive function

Control

Control

Tg-SwDI mouse
x

20
10
0

Control Cilostazol

4

3

(μm)

80
60

3500

2

40

3000

1
0

%alternation behavior*

30(alternation behavior）

4000

Maximal distance

PDE3 inhibitor: Cilostazol
PDE5 inhibitor: Sildenafil (Viagra®)
Nonspecific PDE inhibitor: Caffeine40

Y maze%area of Abeta% increase in CBF

CREB (cAMP-related element binding) ↑-> Memory/plasticity↑

2922 μm

Cilostazol

Cilostazol

3507 μm

2500

20

2000

Control Cilostazol

Control Cilostazol0

Control Cilostazol

Maki T, et al. Ann Clin Transl Neurol 2014

1

Cilostazol promotes perivasculardrainage of Aβ

Suppression of cognitive decline bycilostazol: a retrospective analysis

Aβ production
by neurons

Enzymatic/glial
Degradation

2

Glia

Total
Senile plaqueTranscytotic
Delivery

Capillary
Cortical artery

1

0

-1

-2

Vasoactive
cilostazol

No cilostazol

N=2279.8yrCerebral amyloid
angiopathy
partially to CSF

Cilostazol＊ N=70p<0.05 76.3yr

Normal(MMSE ＞26）MCI
(MMSE 22–26）

Dementia(22＞ MMSE ）

2

-1

2

2

N=4
74.5yrN=981.3yr1

0

N=2073.9yr

0

-2

-4

1

0

-1

-2

N=9
80.7yr＊ N=31p<0.05 76.6yr

N=19
78.5yr

Leptomeningeal
arteryModified from Herzig MC, et al. Brain Pathol 2006
Saito S and Ihara M. Front Aging Neurosci 2014

Taguchi A, et al. Psychogeriatrics 2013

3

Plan of an investigator-led
clinical trial (Phase II)

Δorientation fortime/year

Δorientation forplace/year

Δdelayed recall/year

Donepezil only
N=36; mean 78.4 years
Donepezil + Cilostazol
N=34；mean, 77.2 years

p=0.022p=0.003

Subjects:
moderate-to-severe dementia（MMSE ≦21）
No effects of cilostazol on cognitive decline

p=0.017p=0.045

Ihara M, et al. PLoS One 2014

Subjects：MCI(55-84 years old)
24 months F/U

Investigational Therapy
Cilostazol 50mg B.I.D. p.o.
Comparative Treatment
Placebo B.I.D. p.o.
12 multi-center“Drug repositioning”

Primary endpoint Change in MMSE
Secondary endpoints
 Time to Conversion from
MCI to “All-cause Dementia”
 Neuropsychological exam(e.g. ADAS-cog, CDR-SB,
ADCS-MCI-ADL, WMS)
 Changes in Hippocampal
volume (MRI)

Session IV

ΔMMSE/year

RANDOMIZATIONSuppression of cognitive decline bycilostazol add-on thrapy:
a retrospective analysis
Subjects:
mild dementia(MMSE 22-26）

4

Exploratory endpoint Free and cued selective
reminding test

2012/11/24

5

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

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Session IV : Clinical trials for prevention and treatment of AD

Current and potential status of clinical trials for MCI and dementia in Asia

Dr. Christopher Chen

Republic of Singapore

Director, Memory Aging and Cognition Centre, National University of Singapore■ Abstract
Asian countries possess several advantages for clinical trials : Largepatient pools, a high incidence of particular diseases, rapid economic
development, high pharmaceutical growth rates, well trained
clinicians, an increasing pool of trials personnel and potentially swift
enrollment.
It is therefore not surprising that an increasing number of important■ Profilepivotal trials have a significant Asian component. These include in the

Dr. Christopher Chen is a Senior ClinicianScientist at the National Medical ResearchCouncil of Singapore, Associate Professor at
the Department of Pharmacology, Faculty of
Medicine, National University of Singapore,and Director of the Memory Aging andCognition Centre, National University
Healthcare System.

FISS-tris, ESPRIT and PERFORM. This development is driven by

He read for the Medical and Natural Science
Tripos at Fitzwilliam College, Cambridge
University, graduating in Physiology &Psychology in 1982. His clinical training
was at the University of Oxford from where
he graduated in 1985. In 1990, he waselected the Janssen Junior Research Fellow
at Worcester College, Oxford University
and was a Visiting Research Fellow at theInstitute of Neurology, London.
Currently he is Chair of the International
Society for Vascular Behavioural andCognitive Disorders Executive Committee,
Secretary-General of the Asian Society
A g a i n s t D e m e nt i a ; m e m b e r o f t h e
International Stroke Society Board of
Directors and the Constitutional Committeeof the World Federation of Neurology.

32

stroke field the Chinese Acute Stroke Trial, PROGRESS, IMAGES,
the realization that there may be ethnic or genetic influences ontherapeutic response and is aided by regulatory developments suchas the ICH / GCP as well as the WTO.
By contrast, few dementia clinical trials have significant Asianparticipation despite the huge public health challenge posed bydementia for rapidly aging Asian societies. This is due to several
factors including lack of well developed research environments
leading to a poor receptivity towards clinical trials among patients/
participants as well as clinicians; a lack of regulatory bodies/
standards; a perception that instruments are not validated oravailable in local languages; lack of specialised assessors such as
experienced psychometricians and high attrition due to non-medical
reasons.
The way forward includes harmonisation of clinical trial procedures,development of standardised validated measures, training of clinician
investigators in the design, conduct and ethical oversight of trials so
as to allow truly multinational leadership. Asian researchers should
thereby be able to contribute towards global efforts on improving
treatment for dementia. Moreover, there must be a focus on trials
addressing risk factors unique to Asian populations as well as thoseseeking accessible and affordable treatments for Asian diseasephenotypes.

Current and potential status of clinical trials for MCI and dementia in Asia

■ Presentation slides

Current and potential status ofclinical trials for MCI and dementia
in Asia

CLINICAL TRIALS IN ASIA
Large patient poolsHigh incidence of particular diseases
 Rapid economic development
Specific Challenges & Barriers in Asia



DR CHRISTOPHER CHEN

High pharmaceutical growth rate

MEMORY AGING & COGNITION CENTRE
NATIONAL UNIVERSITY OF SINGAPORE

Well trained clinicians

SENIOR CLINICIAN SCIENTISTNATIONAL MEDICAL RESEARCH COUNCIL

Swift enrollment



Increasing pool of CRAs, trials personnel

1

CLINICAL TRIALS IN ASIA












CLINICAL TRIALS IN ASIA

Increasing number of important / pivotal trials with significant Asiancomponent Major contribution of Asian sites in several major areas

including stroke

Chinese Acute Stroke Trial
PROGRESSIMAGES
FISS--tris
FISS
ESPRITPERFORM
ROCKET--AF
ROCKET Relatively minor contribution to trials in Alzheimer’s

Disease and other dementias despite growing epidemic ofdementia in Asia
 Diagnostic Challenges

Ethnic / genetic influences on therapeutic response
Regulatory developments2

 Cultural Barriers

 Bureaucratic Barriers

ICH / GCP
WTO

3

4

CHALLENGES FOR
DEMENTIA DIAGNOSISIN ASIA

CLINICAL TRIAL DESIGN Hypothesis

 “burning question” relevant to field Good science Language barriers

 Biologically plausible

 Cultural barriers

 Clinical Uncertainty

Session IV Educational limitations

 A window of ethical opportunity

 Applicability of Western

instruments

5

2nd World Centenarian Initiative International Symposium on Alzheimer's Disease Prevention Strategy -In Search of the Road to New Horizon-

633