JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Editorʼs Note
Director, Dementia Center,
Geriatrics Research Institute and Hospital
The 5th issue of Vas-Cog Journal reports thejournal has been reﬁned and remarkable 2 reviews
and a case report work were carried.

2018, hosted by Professor Katsuya Urakami andappreciated every eﬀort by president, members ofProfessor Etsuro Matsubara on August 4-5, 2018, ineditorial board and secretariat.

Beppu, Oita.

Special lectures, symposium, and 36

deeply appreciate authors: Dr. Ihara, Dr. Takeda, andoral and poster presentations were presented of theDr. Yamashita, who submitted wonderful works formeeting.

As many as participants with 170

this initial issue of renewal academic journal. I hopeattendees joined the meeting. We also introduced

these great eﬀorts contribute further advances in thisthe detail of 10th annual meeting, Vas-Cog Japanﬁeld.

I deeply

And I would also2019 (Tokyo).
In this meeting, committee and attendance had
decided on 2 important issues: Vas-Cog Japan ischange to be the Academic Society and publishes theoﬃcial journal.

Based on this decision, editorial

board made great eﬀorts to publish 5th as the oﬃcial
journal of Vas-Cog Japan. As you can see, Vas-Cog

The 1 st Meeting : August, 2010 (Tokyo) Chairman : Ken Nagata and Toshiya Fukui
The 2nd Meeting : August, 2011 (Tokyo) Chairman : Koji Abe and Shokei Mitsuyama
The 3rd Meeting : August, 2012 (Tokyo) Chairman : Ryuichi Morishita, Yasuo Terayama, and Koji Abe
The 4th Meeting : August, 2013 (Tokyo) Chairman : Mikio Shoji and Haruo Hanyu
The 5th Meeting : August, 2014 (Kyoto) Chairman : Toshiki Mizuno and Hidekazu Tomimoto
The 6th Meeting : August, 2015 (Tokyo) Chairman : Nobuya Kawabata and Shuhei Yamaguchi
The 7th Meeting : August, 2016 (Kanazawa) Chairman : Masatsugu Horiuchi and Masahito Yamada

2019

The past and future annual meeting of Vas-Cog JapanO f f i c i a l J o u r n a l o f Va s - C o g J a p a n S o c i e t―youtline of the 9th annual meeting, VAS-COG Japan

Va s - C o g J o u r n a l―

Mikio Shoji MD, PhD

Vas-Cog Journal
No.5 April 01. 2019

Official Journal of Vas-Cog Japan Society＜ Review article ＞

Masafumi Ihara.
“Neurovascular approach for Alzheimer's disease.”

Shuko Takeda.
“Lifestyle-related diseases and dementia.”

The 8th Meeting : August, 2017 (Tokyo) Chairman :Shinichiro Uchiyama and Issei Komuro
The 9th Meeting : August, 2018 (Beppu) Chairman : Katsuya Urakami and Etsuro Matsubara
The 10th Meeting : August, 2019 (Tokyo) Chairman : Masahiro Akishita and Yoshio Ikeda
The 11th Meeting : September, 2020 (Tokushima) Chairman : Shunya Takizawa and Masataka Sata
The 12th Meeting : August, 2021 (planned) Chairman : Kazuo Kitagawa and Koichi Kozaki
The 13th Meeting : August, 2022 (planned) Chairman : Masahiko Suzuki＜ Case report ＞

Toru Yamashita, et al.
“Heterozygous HTRA1 mutation cases showing SAH.”- to be continued -44

1

ISSN : 24239372

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

37) Authorʼs Print Name:

Table of Contents

Signature:8)

Authorʼs Print Name:
Signature:

Editorial ………………………………………………………………………………… 3＜ Review article ＞
A neurovascular approach to clearing β-amyloid from the brain ………… 4
New insights into the role of lifestyle-related diseases on vascular dementia
and Alzheimerʼs disease ………………………………………………………… 12

9)

Date:

Date:

Authorʼs Print Name:
Signature:

Date:10) Authorʼs Print Name:
Signature:

Date:＜ Case report ＞
A Japanese family of autosomal dominant cerebral small vessel disease withheterozygous HTRA1 mutation showing dementia, gait disturbance andsubarachnoid hemorrhage …………………………………………………… 20
Greetings from Vas-Cog Japan, the Japanese Society for
Vascular Cognitive Impairment ………………………………………………… 27
Reports of the Vas-Cog Japan 2018 …………………………………………… 28
VAS-COG Japan 2018 Report …………………………………………………… 29
Welcome to Vas-Cog Japan 2019 ………………………………………………… 30
Meeting report of Vas-Cog Asia 7 from Jakarta ……………………………… 32
An impression on VAS-COG Asia 2018 ………………………………………… 33
Reports of Vas-Cog Japan Council Meeting …………………………………… 34
Articles of Association of the Japanese Society for Vascular Cognitive
Impairment ………………………………………………………………………… 37
Vas-Cog Journal Submission Instruct ions for authors ……………………… 39
Vas-Cog Journal Authorship Agreement ………………………………………… 42
Editorʼs Note ………………………………………………………………………… 44243 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

EditorialMikio Shoji MD, PhD

Director, Dementia Center,
Geriatrics Research Institute and Hospital
Bon Voyage!

aging and/or cerebral amyloid angiopathy, Aβ
clearance is impaired and accumulation accelerated.

In 2009, Japanese clinical doctors and researchers

Therefore, prevention of vascular degeneration isin the field of vascular dementia have gathered into

also important for AD treatment.   UpToDate review

the Japanese association of Vascular Cognitive

article by Dr. Takeda showed that lifestyle-related

Impairment (Vas-Cog Japan).   Then, we hold annual

diseases induce arteriosclerosis in cerebrovasculature,

meeting every summer for developing researches inwhich leads to vascular dementia, and also affect AD

this fields.   Vas-cog Japan keeps activity and ispathology.   AD-related Aβ peptides have a direct

expanding into the established international society

impact on cerebrovasculature, causing functionalwith about 200 members including basic scientist

and structural damage.   Lifestyle-related diseases

and industrial members.   Since 2015, we publishedand AD synergistically exacerbate the pathogenesis

Vas-Cog Journal as the News letters.   In 2017, Vas-of vascular dementia.   Dr. Yamashita presented an

Cog Japan decided to be the academic associationinteresting case of the Japanese family of autosomal

and to launch the international official journal.  

dominant cerebral small vessel disease with

Based on the details, 5th issue of Vas-Cog journal isheterozygous HTRA1 mutation showing dementia,

apparently renewed and publishes articles.  

gait disturbance and subarachnoid hemorrhage.

In this issue, Dr. Ihara, Dr. Takeda and Dr.

These articles are all elaborative, high-quality, andYamashita published wonderful works in the initialappropriate for this initial issue of renewal academic

issue of this journal and greatly contributed tojournal.  Here, I would deeply appreciate every effort

advance researches of Vascular cognitive dementia.  

by editorial board members and authors.   I hope

Dr. Ihara outlined the mechanisms behind Aβ

these great efforts contribute further advances in thisclearance. When vascular degeneration occurs withfield from now on.

3

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Neurovascular approach for Alzheimer’s disease

Review article

A neurovascular approach to clearing β-amyloid fromthe brain
 Masafumi Ihara, MD, PhD
Department of Neurology, National Cerebral and Cardiovascular Center
Abstract
In the brain, arteries and veins do not run in parallel, and its perfusion system has characteristics not foundin other organs. The presence of a tight blood-brain barrier and lack of authentic lymphatic vessels in theparenchyma means clearance of some waste products, such as β-amyloid (Aβ), is impeded. Aβ is thus cleared
from the brain via at least four clearance pathways including 1) transcytotic delivery, 2) intramuralperiarterial drainage, 3) glymphatic drainage and 4) enzymatic or glial degradation. Failure in any four such
pathways has been implicated in the pathophysiological processes behind Alzheimer's disease. In clinical
trials of Aβ vaccination therapy, vascular Aβ deposition was paradoxically enhanced, with encephalitis
subsequently occurring in a fraction of patients. This serious side effect may be associated with insufficient
clearance of solubilized Aβ through clearance systems in response to immunotherapy. Transcytotic delivery,
intramural periarterial drainage, and glymphatic drainage clearance pathways depend on vascular integrity
and are partly driven by vascular wall motion; therefore arteriosclerosis or perfusion pressure reduction isassumed to increase Aβ accumulation. Strategies activating clearance systems may be helpful in thetreatment of intractable disease through reduction of brain Aβ, therefore aiding development ofneurovascular prevention strategies for Alzheimer’s disease.
Key words: β-amyloid, glymphatic, IPAD, degrading enzyme, transcytosis

Correspondence:
Masafumi Ihara
Department of Neurology
National Cerebral and Cardiovascular Center
5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan
Phone: + 81-6-6835-5137
E-mail; ihara@ncvc.go.jp

4 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Masafumi Ihara
Introduction

transports Aβ from the vascular lumen to the brain

In order to maintain homeostasis and nerve

parenchyma in an opposite direction to transcytosis

function, the brain must manage ionic and amino

and the RAGE inhibitor results in Aβ excretion out ofacid concentrations through three types of strictly

the brain. Despite such theoretical evidence, a phaseregulated barriers: 1) the blood-brain barrier

III trial of the RAGE inhibitor Azeliragon failed to

between the blood and interstitial fluid (ISF), 2) the

demonstrate efficacy (TTP 488) in mild AD patients.

blood-cerebrospinal fluid (CSF) barrier between the(2) Perivascular drainage – clearance through theblood and cerebroventricular CSF, and 3) the blood-

perivascular lymphatic drainage pathway. Here theCSF barrier between the blood and subarachnoid CSF

Aβ-containing ISF flows through the basal[1]. The blood-brain barrier plays a major role,

membrane layer of the blood vessel and is ultimately

occupying 5000 times the area of the blood-CSF

transported to the CSF space and cervical lymph

barrier [2]. Since the presence of these functions is

nodes [7]. This route runs within the vessel wall andessential for controlling ion gradients andhas thus been recently renamed ‘intramural

neurotransmitter concentrations inside and outside

periarterial drainage’ (IPAD) [8]. Since thethe neuron, such systems likely possessed

breakdown of this drainage pathway is related toadvantages from an evolutionary natural selection

cerebral amyloid angiopathy pathology, therapies

viewpoint. However, the development of these tighttargeting such processes have been developed.

barriers has meant ISF containing waste products,

Cilostazol, a vasoactive drug phosphodiesterase III

such as amyloid β (Aβ), cannot easily return to theinhibitor promotes the removal of Aβ from thevascular lumen, leading to Aβ accumulation in thevascular wall in a cerebral amyloid angiopathy model

brain and possibly Alzheimer's disease (AD).

mouse [9]. Thus, an investigator-initiated clinicalHowever, to prevent accumulation of self-

trial, the COMCID study, is currently being conducted

aggregating and misfolded proteins, including Aβ,

in Japan in patients with mild cognitive impairment

several processing mechanisms take place in the[10]. (ClinicalTrials.gov Identifier, NCT02491268)

brain. In this article, we focus on mechanisms behind3) Glymphatic drainage – this conduit system wascerebral clearance and peripheral metabolism of Aβoriginally reported in 1985 as the ‘paravascularand its relationship with dementia causing diseases,

drainage pathway’ [11] but recently renamed due toin particular AD.

the pivotal role of glial cells in the system [12]. CSF
flows into the brain parenchyma through the

I. Clearance mechanisms of Aβ from the brain

Virchow-Robin cavity around the artery and is

Apart from juvenile AD, the main cause of sporadictransported into the parenchyma by the action of

AD in the elderly is thought to be a decrease in Aβaquaporin 4 expressed in the foot processes ofclearance [3].

astrocytes. In the brain parenchyma, the CSF,

The following four representative mechanisms

together with ISF, dissolve Aβ and drain into the(4-d) are thought to play a fundamental role in Aβ

perivenous space [12]. They further drain into

clearance (Figure 1) [4].

cerebral meningeal lymphatic vessels [13]. In Aβ(1) Transcytotic delivery – clearance into the lumen-overexpressing mice, occlusion of the cerebralof blood vessels by transcytosis through transporters

meningeal lymphatic vessels led to Aβ deposition insuch as lipoprotein receptor related protein-1 (LRP-

the lymphatic vessels, as well as the brain

1) [5] and P glycoprotein (also known as ABCB1) [6].

parenchyma, strengthening the importance of theseAβ is transported by transcytosis from the abluminal

systems in Aβ clearance [14].

(brain parenchyma) side to the luminal side. The

4) Enzymatic and glial degradation – this is an Aβ

receptor for advanced glycation end product (RAGE)

degradation pathway through the action of proteases

5JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Neurovascular approach for Alzheimer’s diseasesuch as neprilysin, insulin-degrading enzyme,

arterial pulsation is thought to be the driving force ofplasmin, angiotensin-converting enzyme and glia

IPAD, caused by centrifugal force generated by(astrocytes and microglia) [15]. Recently, it wasreflected waves following pulse waves originating inreported that microglia expressing triggering

the heart.

receptors expressed on myeloid cells 2 (TREM2)

Since Aβ is detected in the middle cerebral arterysurround senile plaques and have a role in protecting

and the basilar artery wall but not in the cervicalneurons from Aβ, consistent with clinical findings

internal carotid artery [22], solutes flowing throughthat a loss-of-function mutation of Trem2 was foundthe IPAD appear to leave the vessel wall at the basein AD [16].

of the brain [7], or via the cerebral meningeal
lymphatics [13], into the local lymph nodes.

II. Drainage pathway of Aβ within vessel wall – IPAD

III. Conditions in which glymphatic pathway works

The presence of IPAD was suggested by Schwalbe
in 1860s, who demonstrated that India ink injected

The glymphatic pathway drainage system is

into the cistern could be detected in the cervicalgaining recognition in scientific literature. However,lymph nodes within 1 minute [17]. Bradbury andin the schematic diagram of the pathway, there are

Cserr et al. subsequently reported 1) tracer injected

no barriers in the Virchow-Robin cavity andinto the cerebral ventricle flowed into the cervicalsubarachnoid space, and CSF freely drains into thelymph node via the lamina cribrosa, 2) tracer

brain parenchyma [13]. This should be reconsideredinjected into the caudate nucleus flowed into theas there is principally no space around arteries of thecervical lymph node unrelated to CSF flow, and

cerebral cortex [8]. Indeed, it is extremely rare to see3) radioisotope-labeled tracer injected into the brain

the Virchow-Robin cavity in the cerebral cortex onparenchyma was observed along the arterial wall

MRI. Also, if ISF-containing Aβ is cleared around theintracranially [18]. In the early 1990s, Weller et al.

vein, it is not clear why cerebral amyloid angiopathy

further showed that 1) India ink injected into theis not observed at this site. In a study injecting

striatum of rats was present in close proximity to thefluorescence Aβ into the CSF space of mice at 6-10

dilated perivascular space, along the middle cerebral

months and 24-30 months of age, Aβ was found inartery branch and the arterial circle of Willis,

the pial-glial basement membrane between the pia

reaching the lamina cribrosa along the olfactory andmatter and astrocytes of the glia limitans, suggesting

ethmoidal arteries, and 2) further through the lamina

that CSF enters the brain along the pial-glial

cribrosa, extending from the nasal lymphatics to thebasement membrane but not through the Virchow-cervical lymph nodes [19].

Robin periarterial space [8]. Nevertheless, one may

As a result of detailed observation by Carare et al.,not entirely exclude the possibility of the glymphatic

the capillary vessels in the brain and the basement

pathway playing a role in pathological conditions or

membrane of the artery wall were shown tothe aging process. Further elucidation of thisconstitute the IPAD, with the route acting as a high-pathway may clarify whether the permeability of the

speed drainage system for ISF [20]. This lymphatic

pia mater increases and the cortical Virchow-Robin

drainage is much faster than the rate at whichcavity enlarges in the pathological conditions,molecules diffuse through the extracellular space andleading to increased contribution of the glymphatic

ISF is almost instantaneously cleared along thepathway in the clearance of waste products includingarterial wall within the brain and meninges, with aAβ.

soluble tracer injected into the brain reaching the

IV. Conditions where IPAD fails

basement membrane of the meningeal blood vessel
within 10 minutes. In a theoretical model [21],Interestingly, IPAD lymphatic drainage aligns with6 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Masafumi Ihara
the site of Aβ deposition in early cerebral amyloid

GOM is also observed in peripheral blood vessels,

angiopathy [23]. Accumulation of Aβ starts from theincluding the skin, the breakdown of such a drainage

smooth muscle cell basement membrane,route may be a phenomenon which can also occur incorresponding to the IPAD pathway. Thus, stagnation

organs other than the brain.

of this pathway may be closely related to cerebral

V. Peripheral metabolism of Aβamyloid angiopathy pathology. Indeed, ISF flow has
been impaired in aged mice, as well as those withAccording to the sink hypothesis, Aβ is withdrawn

cerebral amyloid angiopathy [24]. Furthermore,from the brain parenchyma to the luminal space byartificial constriction of the bilateral common carotid

the action of LRP-1 and P-glycoprotein, which bind toarteries in a cerebral amyloid angiopathy model

serum proteins such as sRAGE, sLRP-1, and ApoE.

mouse results in worsening of the cerebrovascular

More than 60% of Aβ in blood is degraded in theAβ deposition [25]. Therefore, a decrease in vascularliver: hepatocytes take up more than 90%, andpulsation due to aging, arteriosclerosis or Aβphagocytic Kupffer cells less than 2% [28]. Aβ

deposition itself appears to act as an exacerbating

incorporated into hepatocytes is degraded andfactor of cerebral amyloid angiopathy. When dextran

metabolized by proteases, such as neprilysin, insulin-corresponding to the molecular weight of Aβ was

degrading enzyme, plasmin and angiotensin-

injected into the brain and visualized by two-photon

converting enzyme, and finally excreted into the bile

microscopy in real time, the efficiency of dextran(Fig. 2). The medicinal herb Ashwagandha, used In

clearance was shown to be impaired due to vascular

Indian traditional medicine, has been reported to

occlusion and cerebral amyloid angiopathy [26]. The

significantly decrease the amount of Aβ in the brain

glymphatic pathway is promoted by vascular

by increasing the expression of LRP-1 and neprilysin

pulsation by dobutamine [12]. Furthermore, as levelsin the liver in animal experiments, and may thusof neprilysin or LRP-1 decrease, clearance of Aβ is

possess therapeutic properties to promote Aβ

impaired, causing cerebral amyloid angiopathy [4].

withdrawal [29]. Similar to this mechanism,

These Aβ clearance systems function in asolanezumab, an antibody against Aβ, forms acomplimentary manner to prevent accumulation of

complex with Aβ in the blood, resulting in a central-Aβ.

to-peripheral gradient in Aβ concentration,
potentially removing Aβ from the brain parenchyma.

Disease conditions where clearance mechanisms

However, a clinical trial using solanezumab has failed

fail and protein accumulates on the blood vessel wall

to show efficacy against mild AD [30].

may be collectively called protein-elimination failure

Conclusion

arteriopathies (PEFA). Besides Aβ, gelsolin, cystatin C
and transthyretin cause cerebral hemorrhage andThis article has outlined the mechanisms behinddementia in familial cerebral amyloid angiopathy,

Aβ clearance. When vascular degeneration occurs

and especially the latter two proteins accumulate inwith aging and/or cerebral amyloid angiopathy, Aβ

blood vessels of organs other than the brain. Also, inclearance is impaired and accumulation accelerated.

cerebral autosomal dominant arteriopathy with

Therefore, prevention of vascular degeneration is

subcortical infarcts and leukoencephalopathy

also important for AD treatment. In the past,(CADASIL), a hereditary vascular dementia caused by

cerebrovascular disease was generally accepted to be

Notch3 mutation, NOTCH3 produced from vasculardistinct from AD resulting from a neurodegenerativesmooth muscle cells accumulates in the blood vessel

process. However, it is clear that this simple

wall as granular osmiophilic material (GOM) [27],dichotomy needs revision in light of the apparent

which is also thought to be a type of PEFA. Since

vessel-dependent pro cess of Aβ clearance.

7

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Neurovascular approach for Alzheimer’s disease
Therefore, further elucidation of the physiologicallyfunction in neurodegenerative disease. Currand pathologically important Aβ clearance

Pharm Des 2011;17:2771–2777.

mechanism is warranted. AD research, when viewed[7]		Weller RO, Djuanda E, Yow HY, Carare RO.

from a neurodegenerative standpoint, has madeLymphatic drainage of the brain and theconsiderable breakthroughs. However, it is apparent

pathophysiology of neurological disease. Actathat this focus only represents part of the disease

Neuropathol 2009;117:1–14. doi:10.1007/

trajectory, which may explain the lack of efficacy ins00401-008-0457-0 [doi].

recent clinical trials. It is our hope that a more[8]		Albargothy NJ, Johnston DA, MacGregor-Sharp

vascular approach may offer new avenues andM, Weller RO, Verma A, Hawkes CA, et al.

treatments for AD in the near future.

Convective influx/glymphatic system: tracers
injected into the CSF enter and leave the brain

Acknowledgements

along separate periarterial basement

The author would like to thank Dr. Ahmad

membrane pathways. Acta Neuropathol

Khundakar (Teesside University, UK) for his editorial

2018;136:139–152. doi:10.1007/s00401-

assistance.

018-1862-7.
[9]		Maki T, Okamoto Y, Carare RO, Hase Y, Hattori

Disclosures: none

Y, Hawkes CA, et al. Phosphodiesterase III
inhibitor promotes drainage of cerebrovascular

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2004;279:45897–45908. doi:10.1074/jbc.

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Neurovascular approach for Alzheimer’s disease
M407668200.
[29]		Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT,
Hamel E, et al. Withania somnifera reverses
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protein in liver. Proc Natl Acad Sci U S A
2012;109:3510–3515. doi:10.1073/
pnas.1112209109.
[30]		Honig LS, Vellas B, Woodward M, Boada M,
Bullock R, Borrie M, et al. Trial of Solanezumab
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2018;378:321–330.

doi:10.1056/NEJMoa1705971.

10 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Masafumi Ihara

Aβ generated
from neurons④Degradation
pathway by
enzymes andglial cells③Glymphaticdrainage pathway

Senile plaque
●

Vein

Aβ

②Intramural periarterial
drainage pathway

Capillary①Transcytotic
deliverypathway

CSF
cervical lymph nodes
Cortical artery
Leptomeningeal artery

Figure 1. Clearance mechanism of A β (4-d)

Representative pathways of Aβ clearance pathways from the brain include (1) transcytotic delivery, (2) intramuralperiarterial drainage (IPAD), (3) glymphatic drainage and (4) enzymatic or glial degradation. These clearance
mechanisms seem to work in a complimentary manner to prevent the accumulation of Aβ. However, once theequilibrium is disrupted as a result of aging and/or arteriosclerosis accumulation of Aβ may start in the brain.

Brainparenchyma

Aβ
P-gp

LRP-1

Vascularwall
RAGE
Vascular
lumen

Blood
carriers

Delivery by transporters

sRAGE
sLRP-1
GelsolinGM1α2-macroglobulin
ApoE

Hepatic LRP-1
Aβdegrading
enzymes in
the liver

Neprilysin
Insulin-degrading enzyme
Angiotensin-converting enzyme
Plasmin

Biliary system

Figure 2. Peripheral metabolism of A β

According to the sink hypothesis, Aβ is withdrawn from the brain parenchyma to the vascular lumen bytransporters, such as LRP-1 and P glycoprotein (P-gp), and transported by various carriers in the blood. Afterbeing transported to the liver, LRP-1 in hepatocytes incorporate Aβ, which is degraded by Aβ-degrading
enzymes (sRAGE, sLRP-1, gelsolin, GM1, α2-macroglobulin, and ApoE) and excreted into the biliary system.
Therefore, by accelerating such peripheral degradation, the brain-blood equilibrium of Aβ shifts, leading toincreased withdrawal of Aβ from the brain parenchyma into the blood. Since RAGE is involved in the transportof Aβ from the vascular lumen to the brain parenchyma, inhibition of RAGE may result in Aβ clearance.
Abbreviations: ApoE, apolipoprotein E; GM1, ganglioside GM1; LRP-1, low density lipoprotein receptor-related
protein 1; P-gp, P-glycolipid; RAGE, receptor for advanced glycation end product; sLRP-1, soluble low density
lipoprotein receptor-related protein 1

11

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Lifestyle-related diseases and dementia

Review article

New insights into the role of lifestyle-related diseases on
vascular dementia and Alzheimer’s disease Shuko Takeda, MD, PhD.
Department of Clinical Gene Therapy,
Graduate School of Medicine, Osaka University
Abstract
Lifestyle-related diseases, such as diabetes mellitus, hypertension, and dyslipidemia, are known to promote
arteriosclerosis and increase the risk of vascular dementia. Recent epidemiological studies have revealed thatthese lifestyle-related diseases are risk factors not only for vascular dementia but also for Alzheimer’s disease.
Such findings suggest a common molecular pathology between vascular dementia and Alzheimer's disease,which is mediated by biological pathways associated with lifestyle-related diseases, including the reninangiotensin system and insulin signaling. There is a complicated interplay in mutual modifications among
lifestyle-related diseases, vascular dementia, and Alzheimer’s disease. It is important to take the complex andmultifactorial nature of the disease into account when considering the underlying disease mechanisms ofindividual patients with dementia. It is also becoming evident that the molecules related to the pathogenesisof Alzheimer’s disease, such as β-amyloid, have a direct impact on cerebrovascular damages, which could also
be important for understanding the link between vascular dementia and Alzheimer’s disease, and how it isinfluenced by lifestyle-related diseases. Given the rapid growth of the aging population, the treatment
strategy for dementia is necessarily shifting to earlier-stage interventions and prevention. Understanding how
lifestyle-related diseases contribute to the pathogenesis of both vascular dementia and Alzheimer’s disease
could be a key in tackling dementia.
Key words
Vascular dementia, Alzheimer’s disease, lifestyle-related disease, β-amyloid, cerebral amyloid angiopathy

Correspondence to:
Shuko Takeda
Department of Clinical Gene Therapy, School of Medicine, Osaka University
2-2 Yamada-oka, Suita 565-0871, Japan
Tel: 81-6-6210-8351, Fax: 81-6-6210-8354
Email: takeda@cgt.med.osaka-u.ac.jp12 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Shuko Takeda
Introduction

mutually modify their biological mechanisms.

Vascular dementia (VaD) is a general termThis review outlines the relationship among VaD,d e s c r i b i n g a c o g n i t i ve d e c l i n e c a u s e d b y

AD, and lifestyle-related diseases and how lifestyle-cerebrovascular disease (CVD), and it is the second

related diseases affect the pathologic link between

most-frequent form of dementia after Alzheimer's

VaD and AD, focusing on the potential common

disease (AD). The pathogenesis and pathology of VaD

mechanisms.

are extremely diverse. According to the commonly

Relationship between lifestyle-related diseases andused diagnostic criteria of the National Institute ofdementia

Neurological Disorders and Stroke and the
Association Internationale pour la Recherche etLifestyle-related diseases are associated with anl'Enseignement en Neurosciences (NINDS-AIREN),

increased number of dementia cases.4 Hypertension

VaD is divided into: 1) multi-infarct dementia, 2)

is the greatest risk factor for arteriosclerosis—thestrategic single-infarct dementia, 3) small vascular-presence of hypertension in middle and old ages

lesion dementia, 4) low-perfusion VaD, and 5)

raises the relative risk for the development of VaD up

cerebral hemorrhagic VaD. To understand theto approximately 10 times.5 Recent studies haveunderlying disease mechanism and choose an

shown that hypertension in midlife is associated withappropriate medication and therapeutic strategy for

AD development later in life.3 Furthermore, the use ofeach patient with dementia, it is important to noteantihypertensive drugs is shown to reduce thethat VaD is not a single concept.

incidence of dementia, including AD.6-8

VaD and AD are two of the most-common forms of

It has been shown that diabetes mellitus increases

dementia among the elderly and often occur

the risk of CVD through arteriosclerosis, which leads

together. Classically, AD has been distinguishedto the development of VaD in later life.5 Importantly,

from VaD on the basis of having its unique

impaired glucose tolerance, which is a very earlyneuropathological features, senile plaques, andstage of diabetes, is shown to increase the risk ofneurofibrillary tangles instead of the severe

developing VaD, suggesting that early detection andcerebrovascular changes observed in the brain ofintervention of a glucose metabolism abnormality are

VaD. However, a growing body of evidence fromvery important for preventing VaD.9 Multiple studies

clinical and basic studies suggests that they have

have shown that diabetes mellitus significantly raises

1

common molecular mechanisms. Separating them as

the risk of developing AD as well, which provides a

individual diseases, based on their classical concepts,

new insight about biological mechanisms underlying

is not only clinically difficult, but it could also show

AD. 2,10,11 Although the mechanism by which

an extremely inadequate understanding of thehypertension and diabetes mellitus increase

pathogenesis of dementia.

the risk, development of AD is largely unknown,
cerebrovascular alteration mediated by AD-related

Whereas lifestyle-related diseases, such as

amyloid-β (Aβ) may partly account for it.

hypertension, diabetes mellitus, and dyslipidemia,
are well known to induce arteriosclerosis in

Biological link between hypertension and AD

cerebrovasculature and increase the risk ofdeveloping VaD, accumulating evidence suggests that

Recent evidence suggests a biological link between

these factors are also independent risk factors for

hypertension, or alteration of the renin-angiotensin

AD.2,3 This implies a biological interplay among thesesystem (RAS), and AD. The central nervous system ispathological conditions. There seems to be a very

known to have its own RAS mediating physiologicalcomplicated pathologic interaction in the brain,

and pathological brain functions. 12 Most RAS

where VaD, AD, and lifestyle-related diseases

components are present in the central nervous

13

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Lifestyle-related diseases and dementia
system, not only in the cerebrovasculature but also indeposits of Aβ) and neurofibrillary tangle (intracellular

the neuronal and glial cells. Angiotensinogen isaggregates of tau) are major neuropathologicaldetected in the choroid plexus and astrocytes at ahallmarks of AD. Insulin reportedly regulates Aβhigh concentration. Angiotensin II has been

concentration by modulating the enzyme responsible

identified within synaptic vesicles together with afor Aβ production or by modulating Aβ degradation byhigh concentration of angiotensin receptor. Renin

competing with Aβ-degrading enzymes, including

and angiotensin-converting enzymes are widelydistributed throughout the brain.

13

insulin-degrading enzymes.19,20 Insulin is also known

Multiple studies

to affect tau pathology via activation of glycogenhave reported RAS activation in the brain of AD

synthase kinase (GSK)-3β, which is one of the kinases

patients14,15, supporting the idea that RAS could be a

involved in tau phosphorylation. Downregulation ofpotential target for cognitive dysfunction and AD.

insulin signaling leads to hyper-activation of GSK-3β

In this regard, some clinical studies suggest an

and subsequent phosphorylation of tau, resulting inassociation between the use of angiotensin receptor

intracellular aggregation and formation ofblockers (ARB) and a lower incidence of AD.8 Takeda

neurofibrillary tangle.21

et al. have reported a beneficial effect of ARB on AD-

Takeda et al. explored a mechanistic link between

related cognitive impairment, which is independent

diabetes mellitus and AD by establishing uniqueof its blood-pressure-lowering effect. Treatment withdiabetic-AD mouse models.11 The diabetic-AD mice

ARB prevented Aβ-induced vascular dysregulation by

showed an early-onset cognitive impairment

reducing oxidative stress on the cerebrovasculature,compared to the normal AD mouse model. One of theleading to improved cognitive function in AD mice.16

most striking changes in the diabetic-AD mice was

The molecular mechanisms contributing to theimpaired brain-insulin signaling. The diabetic-AD

beneficial effects of RAS modulation may be complex

mice had lower levels of insulin in the brain, and theand pleiotropic.

insulin signaling pathway was severely impaired.
Notably, the diabetic-AD mice showed an

Biological link between diabetes mellitus and AD

accelerated diabetic phenotype compared to normal

The association between diabetes mellitus and AD

diabetic mice, suggesting reciprocal actions between

can partially be explained by cerebrovasculardiabetes mellitus and AD. This reciprocity also

damage due to diabetes, which directly affects

supports the idea that diabetes and AD sharecognitive function. However, findings from clinicalcommon biological mechanisms.

studies imply that the association exists
independently of vascular factors, 10 raising the

Synergistic effect of lifestyle-related diseases on

possibility that diabetic conditions may have a direct

the pathogenesis of dementia

impact on the pathogenesis of AD.

Because lifestyle-related diseases are associated

It is becoming increasingly apparent that insulin iswith both VaD and AD, it is necessary to consider

involved in the neuronal functions in the brain via

that a patient with lifestyle-related diseases ismechanisms that are potentially independent ofpotentially at a high risk for developing both types of

glucoregulatory function. Insulin receptors can bedementia and their pathologic interaction in thedetected in the neurons of the hippocampus andbrain (Fig. 1). Hypertension and diabetes mellitus

cerebral cortex, and a downregulation of insulin andhave synergistic effects on developing CVD throughinsulin-signaling pathway molecules has been shown

arteriosclerosis. Chronic hyperglycemia andin the postmortem brain of AD.17,18

hyperinsulinemia due to diabetes mellitus impair the

Insulin potentially plays a role in the development

vascular endothelial cells through oxidative stressof AD neuropathology. Senile plaque (extracellularand increase inflammatory cytokines.22 Inflammatory14 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Shuko Takeda
cells infiltrating the vascular wall through thefrequently and severely in the brains of those withdamaged endothelial cells cause degeneration of the

AD. CAA is often accompanied by multiple cerebral

vascular wall, leading to the progression of

microbleeds and is also known to contribute to thearteriosclerosis in the cerebral vessels. Cognitive

pathogenesis of VaD.27

function can be impaired when cerebral blood flow

Emerging evidence from clinical and basic

falls below the lower limit of maintaining

research suggests that lifestyle-related diseases may

physiological neuronal activities in the brain.

exacerbate CAA.27 Ellis et al. reported a significant

Reduction of cerebral blood flow can be caused bycorrelation between the severities of CAA andfunctional alteration (decrease in the physiologicalcerebrovascular atherosclerosis in a study ofdilatory capacity of the cerebral artery to maintain

117 autopsy-confirmed AD cases, 28 suggestingenough blood flow and energy for the activated brain

an interplay between AD pathogenesis andarea) or structural changes (narrowing of the blood-atherosclerosis, both of which can be influenced byvessel lumen or thrombus formation) of the blood-

the presence of lifestyle-related diseases. An in vivo

vessel walls, both of which have root cause instudy using an AD animal model with a diabetic

vascular endothelial damage or dysfunction.

condition reported a significant deposition of Aβ in

Hypertension is also tightly associated withthe cerebral vessels of diabetic AD mice, which was

endothelial impairment and cerebrovascularassociated with an increase in the inflammatoryarteriosclerosis; hypertension and diabetes mellitus

responses of the cerebrovasculature, leading to an

have synergistic effects on the risk of development of

exacerbation of the cognitive impairment of the

CVD by up to two- to threefold.23 Studies using AD

mice.11

animal models show that diabetes mellitus andDeposition of Aβ in CAA induces the degeneration

hypertension can increase the production rate of Aβ

of the cerebrovascular walls, such as fibrinoid

in the brain24 or impair the clearance mechanism of

necrosis, microaneurysmal change, and stenosis.

Aβ from the brain,25 both leading to Aβ plaqueProgression of CAA leads to cerebrovascularformation.

breakdown causing hemorrhagic or ischemic lesions

Aβ aggregates are known to accumulate not only

that, in turn, exacerbate cognitive dysfunction.29

in the brain parenchyma but also in the cerebral

Increasing numbers of studies support a direct

26

association between lifestyle-related diseases andAβ has been shown to have vasoconstrictor activity,

CAA. 30 Stricter management of lifestyle-related

blood vessels (cerebral amyloid angiopathy [CAA]).

and it is becoming evident that Aβ accumulationdiseases can be important in a patient withcauses direct damage to the cerebral blood vessels.16

suspected CAA (a patient with multiple cerebral

Recent studies also report that the vascular-

microbleeds on MRI image), especially when withdamaging activity of Aβ becomes more evident in themultiple CVD risk factors in terms of prevention ofpresence of hypertension.

24

This suggests that AD-

cognitive impairment and dementia.

related Aβ plays a role in the development ofhypertension-induced CVD.

Conclusion

CAA, lifestyle-related diseases, and pathogenesis ofdeveloping VaD through arteriosclerotic changes.

Lifestyle-related diseases raise the risk ofdementia

Recent research reveals that: 1) lifestyle-related

CAA may be a key player linking lifestyle-relateddiseases are risk factors not only for VaD but also fordiseases, VaD, and AD. Although CAA can be part of aAD, 2) VaD and AD may have common biologicalnormal aging process, which is observed in themechanisms, and 3) CAA is involved in thebrains of healthy elderly people, it occurs much more

pathogenesis of both VaD and AD. As the number of15

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Lifestyle-related diseases and dementia
dementia cases is expected to increase rapidly with

(1998).

the aging of society, it is becoming more important

7.		Khachaturian, A.S., et al. Antihypertensive

to understand the biological linkage among lifestyle-

medication use and incident Alzheimer disease:related diseases, VaD, and AD (Fig. 3). Better

the Cache County Study. Archives of neurology

understanding of the mechanisms underlying the63, 686-692 (2006).

biological interplay among these pathological

8.		Li, N.C., et al. Use of angiotensin receptor blockers

conditions may contribute to the development of aand risk of dementia in a predominantly malepopulation: prospective cohort analysis. BMJ

new therapeutic strategy for dementia.

(Clinical research ed.) 340, b5465 (2010).

Acknowledgements

9.		Matsuzaki, T., et al. Insulin resistance is associatedwith the pathology of Alzheimer disease: theThis work was supported by JSPS KAKENHI Grant

Hisayama study. Neurology 75, 764-770 (2010).

Number 17H05080 (grant-in-Aid for Young

10.	Ott, A., et al. Diabetes mellitus and the risk of

Scientists (A)).

dementia: The Rotterdam Study. Neurology 53,

Disclosures; ST has no potential conflicts.

1937-1942 (1999).
11.	Takeda, S., et al. Diabetes-accelerated memory

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Lifestyle-related diseases and dementia

Figure 1 Relationship between lifestyle-related diseases, VaD, and AD

Lifestyle-related diseases, such as diabetes mellitus, hypertension, and dyslipidemia, are common risk factors forboth VaD and AD. There is a complex interaction among these pathological conditions. VaD, vascular dementia; AD,
Alzheimer’s disease.

Figure 2 Impact of AD-related A β peptide on cerebrovascular function and cognitive impairment

AD-related Aβ peptide does not only accumulate in the brain parenchyma, forming senile plaques, but also
deposits on cerebral blood vessels developing cerebral amyloid angiopathy. Aβ causes functional or structural
cerebrovascular alterations, resulting in impairment of cognitive function. AD, Alzheimer’s disease; Aβ, β-amyloid.

18 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Shuko Takeda

Figure 3 Lifestyle-related diseases and AD synergistically impair cerebrovascular function and exacerbate VaD

Lifestyle-related diseases induce arteriosclerosis in cerebrovasculature, which leads to VaD. Lifestyle-relateddiseases are also known to affect AD pathology. AD-related Aβ peptides have a direct impact on
cerebrovasculature, causing functional and structural damage. Lifestyle-related diseases and AD synergisticallyexacerbate the pathogenesis of VaD. VaD, vascular dementia; AD, Alzheimer’s disease; Aβ, β-amyloid.

19

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

heterozygous HTRA1 mutation cases showing SAH

Case report

A Japanese family of autosomal dominant cerebral
small vessel disease with heterozygous HTRA1
mutation showing dementia, gait disturbance andsubarachnoid hemorrhage
Toru Yamashita, MD, PhD a; Hiroaki Nozaki, MD, PhD b;
Yosuke Wakutani, MD, PhD c; Koh Tadokoro, MD a; Emi Nomura, MD a;
Yoshiaki Takahashi, MD a; Kota Sato, MD, PhD a;
Nozomi Hishikawa, MD, PhD a; Mami Takemoto, MD, PhD a;
Jingwei Shang, MD, PhD a; Yasuyuki Ohta, MD, PhD a;
Osamu Onodera, MD, PhD b; Koji Abe, MD, PhD aaDepartment of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical
Sciences, Okayama Universityb
Department of Neurology, Brain Research Institute, Niigata Universityc
Department of Neurology, Kurashiki Heisei Hospital

Abbreviations: CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts andleukoencephalopathy; DSWMH, deep and subcortical white matter hyperintensity; FLAIR, fluid-attenuatedinversion recovery; HTRA1, high temperature requirement A serine peptidase 1; MCA, middle cerebral artery;
MMSE, mini-mental state examination; MRI, magnetic resonance imaging; PCR-RFLP, PCR-restriction fragment
length polymorphism; PVH, periventricular hyperintensity; SAH, subarachnoid hemorrhage; SPECT, single
photon emission computed tomography; TGF-β, transforming growth factor-β; TIA, transient ischemic attack;yo, years old.
Abstract
Homozygous mutations of high temperature requirement A serine peptidase 1 (HTRA1 ) gene cause an
autosomal recessive cerebral small vessel disease, namely cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy (CARASIL). Meanwhile, heterozygous mutations of the HTRA1
can also cause an autosomal dominant small vessel disease with a milder clinical phenotype. Here we
described 2 patients in a Japanese family with the same heterozygous HTRA1 mutation (c.496 C>T, p.R166C),
showing a unique clinical history of traumatic subarachnoid hemorrhage (SAH), no alopecia or spondylosis, inaddition to previously similar clinical phenotypes such as cognitive impairment, gait disturbance, andhyperreflexia. The present cases suggest that traumatic SAH may be an important risk of the heterozygous

HTRA1 mutation (c.496 C>T, p.R166C), especially in Asia.
Key words: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy(CARASIL), high temperature requirement A serine peptidase 1 (HTRA1), subarachnoid hemorrhage (SAH).
Corresponding author: Koji Abe
Address: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan
Phone: +81-86-235-7365, Fax: +81-86-235-7368
E-mail: tooy@d1.dion.ne.jp20 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Toru Yamashita, et al.
Introduction

traumatic subarachnoid hemorrhage (SAH) was
detected by head CT scan (Fig. 1d, an arrowhead).

High temperature requirement peptidase A1(HTRA1) is a serine protease, which inhibits  Despite this, he recovered within 3 days withouttransforming growth factor β (TGF-β) signaling

sequela.

pathway1. Homozygous mutations of the HTRA1Patient III-1 is a 56 yo man, the proband of thegene cause a hereditary cerebral small vessel disease

present family, and a nephew of patient II-4. Hischaracterized by leukoencephalopathy, early-onset

mother, who also showed cognitive dysfunction, wasalopecia and lumber spondylosis, and referred to as

diagnosed with Alzheimer`s disease in a local

cerebral autosomal recessive arteriopathy withhospital at 79 yo, and died of aspiration pneumonia

subcortical infarcts and leukoencephalopathy

at 85 yo. At 53 yo, he experienced an acute episode(CARASIL)2, 3. However, recent evidence noted thatof dysarthria and visited a local hospital, where

heterozygous mutations of HTRA1 could also cause

multiple small infarctions were pointed out in the left

small vessel disease with a dominant inheritancemiddle cerebral artery (MCA) territory on a brain

4-6. Here we described 2 patients in a

MRI. Drug treatment with aspirin (100 mg) started,Japanese family with the heterozygous HTRA1

and the above symptom resolved in a week. At 56 yo,mutation (c.496 C>T, p.R166C) showing a unique

he displayed dysarthria once again and newly

patternclinical history of traumatic SAH different fromobtained gait disturbance and cognitive dysfunction.

previous reports.

When he visited our hospital, he did not show

Case Reports

smoker and his blood pressure was normal at

alopecia or lumbar spondylosis. He was a non-Patient II-4 is a 77-year-old (yo) man. When he

125/90 mmHg. His cognitive function was mildly

was 71, he experienced a sudden episode of vertigo

impaired with MMSE score of 26/30, Hasegawa

that disappeared within 2 days. He was aware of gait

dementia scale-revised score of 21/30, frontal

disturbance at 73 yo, which became more severe atassessment battery score of 9/18, and Montreal

75 yo and cognitive function was impaired, but hecognitive assessment score of 23/30. He was

did not show alopecia or lumbar spondylosis. He

depressive with geriatric depression scale of 10/15,

visited a local hospital where old multiple lacunar

and apathetic with apathy score of 23/42, but noinfarctions were detected in brain magnetic

BPSD showing Abe’s BPSD score of 0/44. A

resonance imaging (MRI), and then drug treatmentneurological examination showed dysarthria as wellstarted with clopidogrel (75 mg). He was a non-as hyperreflexia in all extremities, but no evident

smoker and his blood pressure was normal atpathological reflexes nor sensory disturbances in his

117/70 mmHg. His cognitive function was impaired

extremities. Serum analysis showed normal LDL-

to mini-mental state examination (MMSE) score ofcholesterol (128 mg/dl, normal 65-165 mg/dl),

12/30 and Hasegawa dementia scale-revised score of

triglycerides (71 mg/dl, normal 40-234 mg/dl),

7/30. Affective function was also diminished,fasting blood glucose (100 mg/dl, normal 73-109

showing Abe’s BPSD score of 8/44. Neurological

mg/dl), HbA1c (5.7%, normal 4.9-6.0%),

examination showed hyperreflexia and slighthomocysteine (10.3 nmol/ml, normal 3.7-13.5 nmol/

cogwheel rigidity (R>L) in all extremities, but noml), protein C activity (115%, normal 64-146%), andevident pathological reflexes or sensory disturbances

protein S (95%, normal 60-150%). Serum very longin his extremities. A fluid-attenuated inversion

chain free fatty acids were also normal. A

recovery (FLAIR) image of MRI showed

cerebrospinal fluid examination revealed 1

hyperintensity in the periventricular white matter

leucocyte/µl with 100% mononucleosis and normal

with atrophic splenium of corpus callosum (Fig. 1b &glucose (58 mg/dl) but an increased level of protein

1c, an arrow), whereas the tip of the temporal lobe

(78 mg/dl). The MRI (FLAIR) images showed

was spared. At 77 yo, he stumbled and received a

hyperintensity in the deep and periventricular whiteblow to the left side of his head, when a slightmatter with atrophic splenium of corpus callosum

21

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

heterozygous HTRA1 mutation cases showing SAH(Fig. 1f & 1g). Despite no significant stenosis in theand alopecia without spondylosis (Table 1). Althoughmajor artery (Fig. 1e), cerebral blood flow showed

the same heterozygous HTRA1 mutation may cause ahypoperfusion of bilateral frontal lobes, bilateraldifferent clinical spectrum, the present Japaneseparietal lobes, and the left temporal lobe (Fig. 2). Duecases showed a unique clinical history of traumaticto this small vessel disease, cilostazol (100 mg) was

SAH, different from the Greek case (Table 1).

added to aspirin. However, at 58 yo, after he fell and

HTRA1 is a serine protease that represses thehit his head on the floor, CT scan showed a massive

transforming growth factor β (TGF-β) signaling

traumatic SAH (Fig.1h, arrowheads) with rightpathway, whereas mutated HTRA1 cannot repress

subdural hematoma (Fig.1h, arrow). Despite

the production of TGF-β. As a result, overproduced

craniotomy to remove the hematoma, he deceased.  

TGF-β is believed to cause cerebral small vessel disease

For DNA analysis, written informed consent wascharacterized by recurrent ischemic stroke, multiple

obtained from the father and the 2 affected patientslacunar infarctions, and leukoencephalopathy1,3. Inwith approval of the research ethics committee of

patients with a homozygous/heterozygous HTRA1Okayama University (#329) and Niigata University

mutation, cerebral small vessels show pathological(#802). Genomic DNA was extracted from thechanges such as initial thickening with fibronectin,

peripheral blood leukocytes of the father and both

splitting of the elastic lamina and loss of smoothpatients, and Sanger sequence analysis of CSF1R

muscle cells7,8, which has been assumed to induce(exons 12-22) and Notch3 (exons 2-24) were

cerebral ischemia. However, Asian patients, including

performed only in Patient III-1, but were normal.

Taiwanese, Chinese, and Japanese with heterozygous

Then direct sequencing of HTRA1 exons with the

HTRA1 mutations, sometimes showed intracerebral

Sanger method was performed in the father and thehemorrhage9-11, indicating that the HTRA1 mutation

2 affected patients as previously reported6. Bothmay cause vulnerability of cerebral artery. In fact, both

affected patients showed a heterozygous point

Japanese patients in this paper developed traumatic

mutation from C to T coding 496, resulting in

SAH, although use of anti-platelet drugs may also be

substitution of the 166th arginine to cysteine locatedrelated. Hemorrhagic stroke is more common in Asianin exon2 of the HTRA1 gene (c.496 C>T, p.R166C)

people than in Caucasian 12 , so intracerebral(Fig. 3a). The point mutations of c.496 C>T in HTRA1

hemorrhage and traumatic SAH may be a greater and/were confirmed by polymerase chain reaction-

or important risk of heterozygous HTRA1 mutation

restriction fragment length polymorphism (PCR-(c.496 C>T, p.R166C) in Asian patients than in

RFLP) with Hha I, and an uncut PCR product band

Caucasian.

(276 bp) was detected in both patients (Fig. 3b).

Conflicts of interest

Based on the above data, we diagnosed the 2 patientsas having an autosomal dominant cerebral small

The authors disclose no potential conflicts ofvessel disease with heterozygous HTRA1 mutationinterest.

(c.496 C>T, p.R166C).

Acknowledgements

Discussion

This work was partly supported by a Grant-in-Aid

Here we described 2 patients in a Japanese family

for Scientific Research (B) 17H04196, (C) 17K10827

with similar clinical phenotypes such as cognitive

and Challenging Research 15K15527, and by Grants-

impairment, gait disturbance, hyperreflexia, history

in-Aid from the Research Committees (Mizusawa H,of traumatic SAH without alopecia or spondylosis,

Nishizawa M, Sasaki H, and Aoki M) from thecaused by a heterozygous HTRA1 mutation (c.496

Ministry of Health, Labour and Welfare of Japan.

C>T, p.R166C). The same p.R166C mutation waspreviously reported in Greece4, in which a patient ofheterozygous HTRA1 mutation (p.R166C) showedcognitive impairment, gait disturbance, hyperreflexia

22 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Toru Yamashita, et al.
References

7.		Ito J, Nozaki H, Toyoshima Y, et al. Histopathologic

1.		Oka C, Tsujimoto R, Kajikawa M, et al. HtrA1

features of an autopsied patient with cerebral

serine protease inhibits signaling mediated bysmall vessel disease and a heterozygous HTRA1
mutation. Neuropathology 2018; 38: 428-432.

Tgfbeta family proteins. Development 2004;

8.		Oide T, Nakayama H, Yanagawa S, et al. Extensive

131: 1041-1053.
2.		Fukutake T and Hirayama K. Familial young-loss of arterial medial smooth muscle cells andadult-onset arteriosclerotic leukoencephalopathy

mural extracellular matrix in cerebral autosomal

with alopecia and lumbago without arterial

recessive arteriopathy w ith subcort ical

hypertension. Eur Neurol 1995; 35: 69-79.

infarcts and leukoencephalopathy (CARASIL).

Neuropathology 2008; 28: 132-142.

3.		Hara K, Shiga A, Fukutake T, et al. Association of

9.		Kono Y, Nishioka K, Li Y, et al. Heterozygous

HTRA1 mutations and familial ischemic cerebral
small-vessel disease. N Engl J Med 2009; 360:

HTRA1 mutations with mimicking symptoms of

1729-1739.

CARASIL in two families. Clin Neurol Neurosurg
2018; 172: 174-176.

4.		Bougea A, Velonakis G, Spantideas N, et al. The first
Greek case of heterozygous cerebral autosomal

10.	Lee YC, Chung CP, Chao NC, et al. Characterization

recessive arteriopathy with subcortical infarctsof heterozygous HTRA1 mutations in Taiwaneseand leukoencephalopathy: An atypical clinico-patients with cerebral small vessel disease. Strokeradiological presentation. Neuroradiol J 2017;2018; 49: 1593-1601.
11.	Zhang WY, Xie F and Lu PL. Two novel

30: 583-585.
5.		Nozaki H, Kato T, Nihonmatsu M, et al. Distinct

heterozygous HTRA1 mutat ions in two

molecular mechanisms of HTRA1 mutants inpedigrees with cerebral small vessel diseasefamilies. Neurol Sci 2018; 39: 497-501.

manifesting heterozygotes with CARASIL.

12.	Poon MT, Bell SM and Al-Shahi Salman R.

Neurology 2016; 86: 1964-1974.

Epidemiology of intracerebral haemorrhage.

6.		Verdura E, Herve D, Scharrer E, et al. Heterozygous

Front Neurol Neurosci 2015; 37: 1-12.

HTRA1 mutations are associated with autosomal
dominant cerebral small vessel disease. Brain
2015; 138: 2347-2358.

23

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

heterozygous HTRA1 mutation cases showing SAH
Table 1. Characteristics of Patients

Case II-4

Case III-1

Bougea et al. (2017)c.496 C>T(p. R166C)

c.496 C>T(p. R166C)

c.496 C>T(p. R166C)

M

M

M

71

53

29

77

56

31

4

3

2

Hypertension

+

+

+

－

+

－

Smoking

－

+

－

－

－

－

Initial symptom

gait disturbancemigraine

History of TIA or
ischemic stoke

dysarthria and 
dysphasia

+

+

－

+

+

-

+
(12)

±
(26)

+
(24)

+

+

+

Heterozygous HTRA1
mutation
GenderAge at onset, yAge at examination, yDuration of illness, yFamily history

Hyperlipidemia

History of traumatic
SAH
Cognitive
impairment(MMSE)
Gait disturbanceHyperreflexia

+

+

+

－

－

+

－

－

－

－

－

+

PVH

+

+

+

Multiple lacunar infarcts

+

+

+

+

+

+

－

－

－

Alopecia

Spondylosis

Hearing loss

DSWMH

Microbleeds

TIA, transient ischemic attack; SAH, subarachnoid hemorrhage; MMSE, mini-mental state examination; PVH,
periventricular hyperintensity; DSWMH, deep and subcortical white matter hyperintensity.

24 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Toru Yamashita, et al.

Figure 1.

(a) Family tree of the patients. (b, c) FLAIR images of patient II-4 showing white matter hyperintensities withatrophic corpus callosum (an arrow). (d) Head CT of patient II-4 detecting a slight SAH on the surface of the left
temporal lobe (an arrowhead). (e) MR angiography of patient III-1 showing no evident stenosis of the major artery.
(f, g) FLAIR images of patient III-1 pointing out diffuse hyperintensities involving periventricular and deep whitematter with atrophic corpus callosum (an arrow). (h) Head CT of patient III-1 showing a massive SAH (arrowheads)
with right subdural hematoma (an arrow).   

Figure 2.
99m

Tc-ECD-single photon emission computed tomography (SPECT) of patient III-1 shows hypoperfusion of bilateralfrontal lobes, bilateral parietal lobes, and the left temporal lobe.

25

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

heterozygous HTRA1 mutation cases showing SAH

Figure 3.

(a) The 2 patients (II-4 and III-1) carried the same heterozygous point mutation from C to T coding 496(arrowheads), resulting in substitution of the 166th arginine to cysteine located in exon2 of the HTRA1 gene. (b) A
point mutation of c.496 C>T (p.R166C) in HTRA1 , confirmed by PCR-RELP with Hha I. An uncut PCR product band
was found in both patients even after Hha I digestion (an arrowhead).

26

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Greetings from Vas-Cog Japan, the JapaneseSociety for Vascular Cognitive Impairment
 Ryuichi Morishita, MD, PhD
President: The Japanese Society for Vascular Cognitive Impairment
Vas-Cog Japan, in its 9th year after being launchedin 2010, has been developing quite considerably.
The society was first established under the strong
leadership of former Presidents Prof. Ken Nagata andPro. Koji Abe, aiming to promote both basic andclinical research on vascular cognitive impairment
and other related diseases. I took over the society
last year as the third president. I would like toexpress my sincere gratitude to all members of VasCog Japan for your kind cooperation, assistance, andfriendship.
The Vas-Cog Japan society has been steadily
growing, thanks to the efforts of the Chairman for
Increasing Membership and Public Relations, Prof.
Haruo Hanyu. As of March 2019, we have 143 active
members, including 26 directors and 54 councilors,
and the membership is expected to increase in the
future. Furthermore, the financial structure has been
going very well. I sincerely thank the members,
councilors, and directors who have supported thissociety for all these achievements. As our society has
already met the requirements to be registered as an
academic organization in the Science Council ofJapan with regard to the number of members,
membership management, and publication ofjournals, the Chairman for the Promotion of
Becoming a Society, Prof. Katsuya Urakami, has beenworking on our application for registration. Under
the guidance of Prof. Yoshio Ikeda, the Chairman of
Financial Affairs, we have been continuing tostrengthen the financial structure. Regarding
conflicts of interest, we set up a COI committee andprepare provisions under the direction of the
Chairman, Prof. Masahiko Suzuki.
We have been publishing an annual newsletter
since 2014. The newsletter has been widelydistributed to related academic societies in various
countries and is well accepted, thanks to the hard
work of former President Prof. Koji Abe. Due to theefforts of the Chief Editor of the academic magazine,
Prof. Mikio Shoji, it has developed into Vas-Cog

Journal, a joint publication with Vas-Cog Asia. We
will continuously improve the journal’s style andstrengthen its content.
The 9th Annual Meeting of Vas-Cog Japan was
successfully held August 4–5, 2018, at Beppu
Convention Center (B-ConPlaza) in Oita, organized bychairpersons Prof. Katsuya Urakami and Prof. Etsuro
Matsubara. I express our sincere gratitude, on behalfof all members of Vas-Cog Japan, to the chairpersons
for their strong commitment to the success of themeeting. The 10th annual meeting will be held at“Sola City Conference Center” in Tokyo on August 3,
2019, with Prof. Yoshio Ikeda and Prof. Masahiro
Akishita as the chairpersons. We are extremely
excited about the 10 th anniversary meeting andexpecting many of you to attend. Our affiliate VasCog Asia plays an increasingly significant role in thefield of vascular dementia research. The 7th meeting
held in Jakarta on September 6, 2018 was a huge
success with Vas-Cog Asia Director, Prof. Koji Abe.
The 8th annual meeting of Vas-Cog Asia will be heldin Manila on October 3, 2019, in conjunction with
the APSC2019 meeting.
We are pleased to announce that Osaka wasselected to hold the World Expo in 2025, under thetheme “Designing Future Society for Our Lives”. As
the government has set the era of a lifetime at 100
years, the prevention and treatment of dementia is
becoming a top-priority task. Our engagement on
vascular dementia research and other relateddiseases will be increasingly important in the aging
society.
Vas-Cog Japan, a unique academic society covering
a wide variety of interdisciplinary fields, such as
cardiology, neurology, and brain surgery, willcontinue to work on basic and clinical research toelucidate the pathogenesis of vascular dementia andits role in other types of dementia and look for more
effective treatment and prevention. We look forward
to the participation of many of you in our exciting
academic society.
March 10, 201927

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Reports of the Vas-Cog Japan 2018
 Katsuya Urakami, MD, PhD
Section of Environment and Health Science,
Department of Biological Regulation, Faculty of Medicine, Tottori University
The Vas-Cog Japan 2018 was held at the Beppu

dementia-aiming   to nurture young physicians andInternational Convention Center (B-con Plaza),

researchers-” as a theme.   A wonderful lecture wasgiven by Prof. Ouchi, director of Toranomon hospital,

August 4-5, 2018.

and meaningful discussion was held at theJapan faces a super-aging society in which thesymposiums and many presentations.   

number of patients suffering from dementia hassoared.   Nobody doubt that this is the urgent

The Vas-Cog Japan 2018 was the first time that we

problem that should be settled from a socioeconomic

have a two-day meeting, which allows you tostandpoint.  Recently, it becomes clear that life-styleparticipate and visit for a great deal of information

related disease as well as the vascular lesions

regarding vascular cognitive impairments.   As you

occurring afterwards are heavily involved in theknow, Beppu is a hot spring town representing

onset and exacerbation of dementia such as“Onsen-ken Oita”.   After an appropriate stimulation

Alzheimerʼs disease.   This meeting focused on theto the brain at the meeting, we are sure that you

relationship between the vascular pathophysiology

were able to refresh both mind and body with theand the onset of dementia.  Our society also needs todelicious sake and seasonal food as well as a hot

nurture and recruit young physicians andspring.  We are looking forward to seeing you again

researchers having great energy to fight againstin the Vas-Cog Japan 2019 (Tokyo).

dementia.  In the Vas-Cog Japan 2018, we performed“Elucidation of the significance of vascular lesions in28

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

VAS-COG Japan 2018 ReportEtsuro Matsubara, MD, PhD

Department of neurology, Oita University Faculty of Medicine

A host city
The ninth annual meeting of VAS-COG Japan 2018
was held on August 4-5, 2018, in Beppu, Oita.   Thepresident of this meeting was Prof. Katsuya Urakami
from Tottori University and me.   It was our greathonor and pleasure to host the first meeting on theisland of Kyushu.   The two-day meeting is also thefirst trial, which is the touchstone issue for a host
local city like OITA.  I was afraid that young doctors
might hesitate to attend the meeting, but we had as
many as participants with 170 attendees.  
The title of the meeting was on “how to clarify thesignificance of vascular abnormality on dementia”.  
Special lecture, symposium, and 36 oral and poster
presentations were scheduled on the first day of themeeting.   Dr. Ohuchi gave us a special lecture
regarding metabolic syndrome and dementia.  In thefollowing symposium 1 titled with “Vascular lesions
in dementia”, four guest speakers had introduced 4
topics, cardiovascular lesions as a risk factor,
different strategy from a therapeutic viewpoint of
cerebral amyloid angiopathy, glymphatic pathway
and anti-amyloid effect of cilostazol.   We also had

29

poster and oral presentations, including candidates
for young investigator award (YIA).   At the following
welcome party, I am sure that all participants
enjoyed seasonal, fresh foods of OITA, and thereafter
unwound from the fatigue at the “BEPPU ONSEN”.  
On the second day morning, I organized 3-hr
intense brainstorming session under the title“Paradigm shift (pre-emptive therapy): how toreconsider the relationship between AD and vascularabnormality”.  We invited 11 speakers from a varietyof background, and discussed about “community
revitalization and smart aging”, “relationship between
AD pathology and cerebrovascular abnormality”, and“preemptive medicine from a view point ofgeriatrics”.   In the afternoon sessions, two
educat ional lectures fo cused on intest inal
environment and help for a healthy brain-now.  
Current and future vision for the dementia
prevention was also discussed in the symposium 2.  
Finally, we cordially thank all participants andcontributors for the big success of this VAS-COG
JAPAN 2018.

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Welcome to Vas-Cog Japan 2019

Gunma University

The University of Tokyo

Yoshio Ikeda, MD, PhD

Masahiro Akishita, MD, PhD

It is our great pleasure to welcome you to the 10th

neuronal degeneration causing dementia. The special

annual meeting of the Japanese Society for Vascular

lecture will be given by Prof. Takuya Takahashi from

Cognitive Impairment (Vas-Cog Japan 2019). This

Yokohama City University. Other featured lectures orrdyear’s meeting will be held on August 3 , 2019 at

symposia are now under consideration by the

Ochanomizu Sola City Conference Center, Tokyo.

program committees.

Recent studies clarified that the vascular factors

Because the venue for the meeting is convenient tosuch as diabetes mellitus, hypertension, dyslipidemia

access locating nearby Ochanomizu station, we are

were involved in the appearance of not only vascular

expecting many doctors and researchers would joindementia but also Alzheimer’s disease. The main

the meeting. We also would like to encourage young

theme of the meeting is “Crosstalk between vascularinvestigators to present at the meeting. We arefactors and neurodegeneration”, in which we arelooking forward to seeing you at Vas-Cog Japanfocusing on the close relationship between the2019!

vascular factors and the pathogenesis leading to30

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

31

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Meeting report of Vas-Cog Asia 7 from Jakarta


Koji Abe, MD, PhD
Vas-Cog Asia President

I would like to celebrate the great success of Vas-

many active members, which is dedicated to

Cog Asia 7, which was held in Jakarta on September

elucidate the mechanism of vascular factors in

6 afternoon (2018) always jointing with Asia-Pacific

Alzheimer’s disease and related dementia, and to

Stroke Conference (APSC) based on the great

contribute potential therapy for dementia people insupports by Professor Mursyid Bustami (APSC2018

Asia. Many vascular risk factors (VRFs) are related tochair), Professor Yohanna Kusuma (Program chair ofcognitive decline and affective-emotional changes in

APSC2018), and Professor Paulus Anam Ong (Host ofdementia patients especially in elder or eldering

Vas-Cog Asia 7, Jakarta). We had 42 participants

countries in Asia.

from Japan, Indonesia, Taiwan, China, Hong Kong,

Professor Simeon Marasigan announced the Vas-

Malaysia, and India. There were variety of important

Cog Philippines launch on next February 23 (2019)presentations in the present conference. Many basicin Manila, and next Vas-Cog Asia 8 is going to bescience, translational research, clinical trials andheld again in Manila on October 3 (2019) underevidence were discussed especially on the aspects ofdirection of our new President Tsong-Hai Lee

Alzheimer’s disease (AD), vascular dementia (VD),(Taipei) and new Secretary General Toru Yamashita

behavioral and psychiatric symptoms of dementia(Okayama). All of you are welcome to actively join

(BPSD), and their important vascular involvement.

these forthcoming Vas-Cog meetings to present andVas-Cog Asia society is an independent society

discuss on vascular factors of all type dementia.

with 24 directors from most Asian countries and  

Taiwan(Lee)

December 2, 2018

Japan
(Takeda)Indonesia(Made)

Indonesia(Ong)
Indonesia(Silvia)

Thailand(Senanarong)

Japan
(Abe)

32

Philippines
Japan(Marasigan)
India(Uchiyama)(Mehndiratta)

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

An impression on VAS-COG Asia 2018
 Shinichiro Uchiyama, MD, PhD
Professor, Clinical Research Center for Medicine, International University of Health and Welfare
Director, Center for Brain and Cerebral Vessels,Sanno Hospital and Sanno Medical Center
The VAS-COG Asia was held as a joint conference

been widely recognized to share vascular risk factors

with the Asia Pacific Stroke Conference (APSC) 2018

in the background, and thereby relationships

in the Sultan Hotel & Residence Jakarta in the

between dementia and cerebrovascular disease haveafternoon on September 6. This joint conference wasbeen paid more attention than ever. In addition, since

started when I organized APSC 2012 as the Chair indementia and stroke are steeply increasing in Asia,

Tokyo in cooperation with Prof. Koji Abe, and thiswhich occupies 60% of the world population, the role

was the 7th conference following the 6th joint

of VAS-COG Asia will definitely become more

conference with APSC 2017 in Nanjing. The VAS-

important in future. Recent evidence clarified that

COG Asia 2018 was very exciting because of avascular risk factors are associated with not only

variety of presentations of basic and clinical studies

vascular dementia but also any degenerativewith hot discussion, which were titled “promisingdementia including Alzheimer disease. In addition,

biomarkers in vascular dementia”, “vascular andepidemiological studies indicated that vascular risk

beta-amyloid pathogenesis in MCI”, “amyloid genesis

factors are attributable to young and middle-aged

and inflammation in animal model of vasculardementia even more than advance-aged dementia. I

cognitive impairment”, “chronic hypoperfusion

hope many top leaders of dementia research as wellaccelerates Alzheimer’s pathology in AD transgenic

as young physicians and researchers interested inmice”, “mortality risks for vascular dementia in Thai

this field will attend the conference, who will make acohort”, “rapid screening test for cognitive

great contribution to the level up of the VAS-COG

impairment using high-performance eye-tracking

Asia. The APSC 2019 will be held on October 2-5 andtechnology”, and “Abe’s BPSD score (ABS) for post-

the VAS-COG Asia 2019 on October 1 in the

stroke cognitive impairment patients” by young andcharming mega-city Manila, Philippines. Please joinsenior investigators. Dementia and stroke are leading

the Joint Conference of APSC 2019 and VAS-COG

causes of shortening health life span, which have

Asia 2019.

33

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Reports of Vas-Cog Japan Council MeetingYoshio Ikeda, MD, PhD
Gunma University
The 10th board and council meeting for the*	The leader for COI, Dr. Masahiko Suzuki, started toJapanese Society for Vascular Cognitive Impairment

consider detailed regulations based on thewas held together with 16 board members, 2

discussion on the editorial committee.

auditors and 23 councilors in the Reception Hall at*	The leader of board for finance, Dr. Yoshio Ikeda,

Beppu International Convention Center on the 4th ofreported the necessity to increase payments ofAugust, 2018.

annual membership fees although a surplus exists

The representative director and committee

this year. Both auditors, Dr. Shimamura and Dr.

members reported the topics shown below and all

Matsumura reported that the accounting wasproceedings were approved by members.

properly conducted in the audit report.

［Membership］［Plans for future meetings］
rd

1. The 10th Meeting (August 3 , 2019)162 regular members (As of July 31, 2018)

Ochanomizu Sola City in Tokyo［Report from each committee leader］

	Chairmen: Dr. Masahiro Akishita and Dr. Yoshio Ikeda*	The leader of board for society promotion, Dr.

2.	The 11th Meeting (September 12th and 13th, 2020)

Katsuya Urakami, discussed the necessity to

Awa Kanko Hotel in Tokushima

increase payment of annual membership fee.  

Chairmen: Dr. Shunya Takizawa and Dr. Masataka Sada
3. Refer to the last page for subsequent schedules*	The leader of board for increasing membership andpublic relations, Dr. Haruo Hanyu, discussed thenecessity to increase the number of supporting［Report of new board members / councilors］

members and sponsored companies for banner*	on the following pages indicates a new board
member or councilor.

advertisement on the homepage of the Vas-Cog
Japan website.
*	The chief editor of the academic magazine, Dr.
Mikio Shoji, discussed the preparation status for
improving the contents of Vas-Cog Journal No. 5.

34 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）[Name list]● Executive Advisor
Hiroshi Mori
(Osaka City University/Tamiya Hospital)● President● Executive Directors (General Affairs)

Ryuichi Morishita (Osaka University)

Yoshio Ikeda (Gunma University)● Executive Directors
Koji Abe (Okayama University)

Masahiro Akishita (The University of Tokyo)
Shinichiro Uchiyama

Katsuya Urakami (Tottori University)

(International University of Health and Welfare)Nobuya Kawabata (Yachiyo Hospital)

Kazuo Kitagawa (Tokyo Womenʼs Medical University)

Koichi Kozaki (Kyorin University)

Issei Komuro (The University of Tokyo)

Masataka Sata (Tokushima University)

Mikio Shoji (Geriatrics Research Institute and Hospital)

Masahiko SuzukiShunya Takizawa (Tokai University)

(The Jikei University School of Medicine)
Yasuo Terayama (Iwate Medical University)

Hidekazu Tomimoto (Mie University)

Ken NagataHaruo Hanyu (Tokyo Medical University)



 (Research Institute for Brain and Blood Vessels)
Toshiya Fukui (Kawasaki Memorial Hospital)
Etsuro Matsubara (Oita University)

Masatsugu Horiuchi (Ehime University)Toshiki Mizuno
(Kyoto Prefectural University of Medicine)Shokei Mitsuyama (Kumamoto University)

Masaru Mimura (Keio University)

Shuhei Yamaguchi (Shimane University)

Masahito Yamada (Kanazawa University)● Auditors
Munehisa Shimamura (Osaka University)

Miyuki Matsumura(Institute of Geriatrics


35

Tokyo Womenʼs Medical University)

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）● Councilors

Yasuhiro Aso (Oita University Hospital)

Hitoshi Aizawa (Tokyo Medical University)

Masaki Ikeda (Gunma University Hospital)

Satoshi Abe (Shimane University Hospital)

Hiroo Ichikawa (Showa University Fujigaoka Hospital)

Nobuyoshi Ishii (Oita University)

Jun Iwanami (Ehime University)

Masafumi Ihara

Ryoko Imazeki (Tokai University)(National Cerebral and Cardiovascular Center)
Takahiko Umahara (Tokyo Medical University)

Yumiko Uchiyama(Tokyo Womenʼs Medical University)

Yasuyuki Ohta (Okayama University)

Takao Urabe (Juntendo University Urayasu Hospital)

Haruhisa Kato (Tokyo Medical University)

Sumito Ogawa (The University of Tokyo)

Yumi Kameyama (The University of Tokyo Hospital)

Kenjiro Ono (Showa University)

Hitomi Kurinami (Osaka University)

Tatsushi Kamiya (Kamiya Clinic)

Taro Kojima (The University of Tokyo)

Noriyuki Kimura (Oita University)

Masaki Kondo

Minoru Kouzuki (Tottori University)(Kyoto Prefectural University of Medicine)

Hisatomo Kowa (Kobe University)

Hirofumi Sakurai (Tokyo Medical University)
Masayuki Satoh (Mie University)

Kenji Sakai (Kanazawa University Hospital)
Naoyuki Sato

Kazuma Sugie(Center for Development of Advanced Medicine for Dementia)(Nara Medical University School of Medicine)

Takayoshi Shimohata (Gifu University)

Daiki Takano (Yokohama General Hospital)

Yoshiki Takao (Kurashiki Heisei Hospital)

Shuko Takeda (Osaka University)

Ayumi Takamura (Tottori University)

Kentarou Deguchi (Okayama University)

Yasushi Takeya (Osaka University)

Takashi Tokashiki (Okinawa National Hospital) 

Hiroo Terashi (Tokyo Medical University)

Kazuaki Nagashima (Gunma University)

Takahiko Tokuda(Kyoto Prefectural University of Medicine)Yu Hasegawa (Kumamoto University)

Masao Nagayama (IUHW Atami Hospital)

Yukihito Higashi

Yasuto Higashi (Himeji Central Hospital)(Research Institute for Radiation Biology and Medicine)
Yukio Fujita (Gunma University)

Nozomi Hishikawa (Okayama University)

Yasuhiro Manabe

Kouki Makioka (Gunma University Hospital)(National Hospital Organization Okayama Medical Center)
Takafumi Miyachi (Yanai Medical Center)

Toru Minamino (Niigata University)

Kazuhiro Muramatsu

Li-Juan Min (Ehime University)(Tokyo Dental College Ichikawa General Hospital)
Masaki Mogi (Ehime University)

Kenichi Meguro (Tohoku University)

Takashi Yamazaki

Hideki Mochizuki (Osaka University)(Research Institute for Brain and Blood Vessels-Akita)

Toru Yamashita (Okayama University Hospital)

Hiroshi Yoshizawa(Tokyo Womenʼs Medical University)
Yosuke Wakutani (Kurashiki Heisei Hospital)

Kouji Wakayama (The University of Tokyo)

36 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Articles of Association of the Japanese Society for Vascular Cognitive Impairment
Chapter 1.Name(Name)
Article1
The society shall be named Nihon Nokekkan Ninchisho
Gakkai Sokai and shall be written as “the Japanese Society
for Vascular Cognitive Impairment” (abbreviated as
VAS-COG J) in English.
(Offices)
Article2
The Society’s head office shall be in 2-2 Yamadagaoka,
Suita-city, Osaka 565-0871

society shall fill in the designated application form,
with the annual membership fee, and shall apply to thesecretariat’s office.
Article8
Supporting members are individuals or organizations
who agree with the purpose of the society and pay the
supporting membership fees to support activities of thesociety.
Article9
Advisers have an achievements in development related
to vascular lesions and cognitive impairment especiallyand shall be determined by the Board of Directors with
Board Member’s recommendation. Advisers shall be
exempt from the annual membership fee.

Chapter 2.Purpose and Business Activities(Purpose)
Article3
The society is established for development of a new
field of study of cognitive impairment. To this end, thesociety shall study clinical basic research with a wide
field of vision about related matters of vascular lesion
and cognitive impairment in Japan; also shall exchange
informat ion w ith internat ional researchers; shalluncover causes of cognitive impairment andparticipation of vascular lesions, then shall research
the possibilities for drug development.

Article10
Members shall disqualify his/her membership if he /shefalls under any of the following cases:
1.	C a s e s i n w h i c h h e / s h e s u b m i t s a w i t h d r a w a lapplication to the society.
2.	Cases in which he/she has not paid the annual
membership fee for three years, and refuses
demands of payment.
3.	Any other case in which he/she violates the articles
of incorporat ion and other regulat ions or has
damaged the reputation of the society, and Board of
Councilors shall determine his/her dismissal fromthe society.

(Business Activities)
Article4
The society shall engage in the following businessactivities to achieve the purpose provided in thepreceding article:(1)	B usiness activities such as publication of academic
journals(2)	B usiness activities such as holding annual meetings(Annual meetings shall be financed by theparticipants’ entry fees but other organizations may
co-host the meetings. )(3)	B usiness activities such as supporting and awarding
study relating to the medical treatment of vascularcognitive impairment.
(4)	A ny other business activities for achieving the
purpose provided in the preceding article.

Article11
Regular members and stud ent members shall be
accepted an adjournment with notification by the
Representative Director, if they separately establish
fixed conditions.
Chapter4.Officers and Councilors
Article12
The society shall have the following officers.
Board Members :twenty six members
Auditors :two members
Article13
The society shall have Councilors.

Chapter3.Members

Article5
The society shall be comprised of the following types ofmembers:
1. Regular members
2. Student members
3. Supporting members
4. Advisers

Article14
Auditors and additional Board Members outside theBoard Members specified above, shall be determinedaccording to a separate process. Councilors shall also
be determined according to a separate process. The
Chairman shall be selected by a recommendation of theBoard of Directors. Each committee leader shall bechosen by the Representative Director, then approvedby the Board of Directors. The Representative Director,
the Chairman, the Leader of Society Promotion, theLeader of Finance, and the Chief Editor shall bemembers of the Board of Directors.

Article6
Any member shall be distributed academic journals andmay present his/her study in annual meetings,
symposiums and lectures.
Article7
Regular members and student members who agree withthe purpose of the society, are individuals, who shall
pay the annual membership fees separately designatedby the General Assembly. Any applicant who joins the

Article15
The Representative Director shall represent the society,control the performance of the society work and37

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

convene the Board of Councilors.  
The Representative Director and Board Members shallorganize the Board of Directors, and manage the workof the society.
T h e Re p r ese n ta t ive Direc tor shall report bu dgetstatements, account settlement, human resources ofBoard Members and any of the other main work of thesociety to the Board of Councilors and the General
Assembly.

than one-third of the councilors.
Articles24
Meetings of the Board of Directors shall be called by
the Representative Director if necessary. Meetings ofthe Board of Directors require attendance of over twothirds of members, and shall be decided by over half of
the Board Members in attendance. In case a vote is atie, the Representative Director shall determine how toproceed. Individuals nominated by the Representative
Director may attend a Board of Directors Meeting.

Article16
The society shall have a Board for Society Promotion, aBoard of Finance and an Editorial Board.
The Representative Director may establish other boards
with the approval of the Board of Directors. Except incases discussed in Article14, each leader of eachcommittee shall be nominated by the Representative
Director from among the Board Members, then be
approved by the Board of Directors. Members ofcommittees shall be approved by the Board of
Directors, and then the Representative Director shallcommission him/her. Terms for committee members
last four years and maybe renewed indefinitely.

Chapter6.Accounts
Articles25st
The fiscal year of the society shall commence on Apr 1
stof every year and shall end on Mar 31 of the following
year.
  
Articles26
The society shall be financed by annual dues,s u p p o r t i n g m e m b e r s’ f e e s , v a r i o u s s u b s i d e s a n d
donations.
Articles27
Expenses of the society shall be processed by thegeneral fund account and special fund account.

Article17
Auditors shall audit accounting, and shall give advice tothe Board of Directors about managing the society.
Auditors shall not hold any other offices and committee
assignments.

Articles28
The general fund account shall record all income andexpenditures excluding the special fund account.

Article18
Officers and Councilors shall serve a term of one fiscal
year. The Representative Director, Executive Director,
Board Members, Auditors and Councilors’ terms are twoyears, and they may serve a maximum of two terms in arow.

Articles29
The special fund account shall record income andexpenditures to assure a stable financial basis for thesociety. There shall also be provision to record income
and expenditure of funds established for special
purposes.

Article19
If a vacancy o ccurs, the Board of Directors shallappoint new Board Members if necessary, but those
newly appointed members’ terms are bound by theremaining period of their predecessors.

Article30
Establishment of each kind of fund, transfer of funds, anduse of funds shall be approved by the Representative
Director.

Article20
Councilors shall organize the Board of Councilors, anddiscuss issues necessary to the management of thesociety.

【Additional rules】
1.	Any revision of the so ciety’s art icles shall beapproved by the Board of Directors.
2.	The Board Members shall not be paid for theirduties.
3.	The articles of the society shall take effect from the
day following approval by the Board of Directors.
4. The annual member fee shall be ￥5,000.
5. The date of foundation shall be October 01,2014.

Article21
The Chairman shall represent the society in the fiscal
year, and shall carry out their mission as arepresentative of the society.
1.	The Chairman shall be nominated and then confirmedby the Board of Directors.
2.	The Chairman’s term is one year, from the day
following the end of the previous Annual Meeting to
the day the current Annual Meeting finishes.

Established on October 01, 2014
Revised on September 18, 2015
Revised on August 06, 2016
Revised on May 01, 2017
Revised on April 01, 2018

Chapter5.Council
Article22
Annual Meeting, Board of Councilors and General
Assembly shall be held once a year.
Article23
The Representative Director shall hold a Board of
Councilor’s Meeting temporarily if requested by more38 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Vas-Cog Journal

Submission Instructions for authors

Vas-Cog Journal is an official journal of the JapaneseSociety of Vascular cognitive impairment. Original
Art icles deal with either clinical or experimental
investigation of the vascular cognitive impairment. The
journal will also consider the publication of review
articles. Manuscripts must conform to Recommendations
for the Conduct, Reporting, Editing and Publication of
Scholarly Work in Medical Journals (ICMJE
Recommendations) (http:// www.icmje.org/
recommendations/).
Submission of a manuscript to Vas-Cog Journal
implies that the article is original and that no portion(including figures or tables) is under considerationelsewhere or has been previously published in any form
other than as an abstract. Previous publication includes
publishing as a component of symposia, proceedings,
transactions, books (or chapters), articles published by
i nv i t a t i o n s o r r e p o r t s o f a ny k i n d , a s w e l l a s i nelectronic databases of a public nature.
Submission of a manuscript implies that, when
accepted for publication, the authors agree toautomatic transfer of the copyright to the Japanese
So ciety of Vascular Cognit ive Impairment. Every
reproduced figure or table must have permission fromthe copyright holder. Authors should obtain permissionin advance of manuscript submission, and clearly statethat in the figure/table legend. Examples:(1) Adaptedfrom reference no. xx with permission. (2) Reproducedwith permission from xxxx, et al. Neurology 2018; 91:
xx – xx.
When reporting experiments on human subjects,
indicate whether the procedures followed were inaccordance with the ethical standards of the
responsible committee on human experimentation(institutional or regional). The participants’ informed
consent should be obtained and should be indicated in
the text. When reporting experiments on animals,
indicate whether institutional or national guidelines forthe care and use of laboratory animals were followed.
In accordance with the Clinical Trial Registration
Statement from the International Committee of Medical
Journal Editors (http://www.icmje.org/), all clinical
trials published in Vas-Cog Journal should be
registered in a public trials registry at or before theparticipant recruitment. Refer to CONSORT 2010
guidelines (http://www.consort-statement.org/) for
randomized clinical trials, and the STROBE statement(http://www.strobe-statement.org/) for observational
studies (cohort, case-control, or cross-sectional
designs).
Submission of Manuscripts:
At least the first author and corresponding author
should be members of Japanese Society of Vascular
Cognitive Impairment. All manuscripts must be
submitted electronically through online submission
system in the official web site of Japanese Society of
Vascular Cognitive Impairment (http://www.jtbw-mice.
com/vas-cogj/). The submitting author should upload
the manuscript files in appropriate word and PDF fileformats according to the instructions provided. Before
complet ing submission, the submitt ing author isrequired to thoroughly check the PDF file.
Authorship Agreement:
After submission through the online submission
system, the contact/submitting author should complete
the “Authorship Agreement” form (http://www.jtbwmice.com/vas-cogj/kaishi.html) with all co-authors’signatures, and email it to the Editorial Office (vascogj@jtb.com). Because any additional co-authors
cannot be approved after the manuscript has been
accepted, ensure that all co-authors have been properly
listed during the submission process. If additional
authors are included in a revised manuscript, thecontact author of the manuscript is required to provide
another “Authorship Agreement” form signed by theadded authors as well as detailed reasons for theiraddition.
Manuscript Format:
All manuscripts should be written in English (USspelling) and prepared according to the following
specifications.
1.	The main document should be typewritten by wordwith double spacing and include the following in
general: (1) Title page, (2) Abstract, (3) Key words,(4) Text, (5) Acknowledgements, (6) References and(7) Legends for Tables and/or Figures. This word
file should be sent to the office with attachedconverted PDF file of final published style.
2.	Pages should be numbered consecutively in thissequence, beginning with the title page.
3.	The title page must have the following content:(1)	C omplete title of the paper; Abbreviations are
not acceptable in the title.
(2)	N ame(s) of author(s) with highest academicd e g r e e ( s ) ; O n l y M D, P h D, o r B S c c o u l d b e
included.
(3)	Affiliations of all authors at the time of the study;i.e., department and institution(4)	Short title; Up to 50 characters including spaces
can be used.
(5)	D isclosures; Information of all COI, grants,
sources of funding related to the manuscript
should be declared.
(6)	Name and address of the author responsible forcorrespondence(7)	Total word count of the manuscript(8)	Total numbers of Tables, Figures and Supplementaryfiles
4.	Abstracts in manuscript types “Original Article of
C l i ni c a l or E x pe ri me nt a l R e s e a rc h” s houl d b e
structured, and consist of the following 3 headings:
	1: Background: Rationale for study; 2. Method andResults: Brief presentation of methods andpresentation of significant results; Note that bothcategories should be included under the one
heading. 3. Conclusions: Succinct statement of datainterpretation
5.	Units of measurement should be SI units, except forblood pressure, which should be expressed in
mmHg. Do not spell out numbers and standard unitsof measurement except at the beginning ofsentences. Use Arabic numerals and standard

39

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

abbreviations to indicate numbers and units.
6.	References must be numbered consecutively as they
appear in the text and be listed in the same
numerical order at the end of the article. They
should accord with the system used in the Uniform
Requirements for Manuscripts Submitted to
Biomedical Journals. Only published manuscripts
are accepted as references. If a reference is from a
yet-to-be-published book, include ‘In Press’ as wellas the anticipated year of publication. If a referenceis published online only, the “D.O.I” or “URL as wellas the last available date accessed” should be
provided. The titles of referenced journals should be
abbreviated to the style used in Index Medicus(http://www.nlm.nih.gov/tsd/serials/lji.html). All
author names should be listed when referenced
material has 3 or less authors; when it has 4 ormore, only the first 3 authors’ names should belisted, with “et al.” at the end.
Examples:(1)	Y a m a s h i t a T, K a m i y a T, D e g u c h i K , e t a l .
Dissociation and protection of the neurovascular
unit after thrombolysis and reperfusion inischemic rat brain.J Cereb Blood Flow Metab.
2009 (4):715-25.
(2)	T a k e d a S a n d M o r i s h i t a R . D i a b e t e s a n dAlzheimer's Disease. In: Yamagishi S, editor.
Diabetes and Ag ing-related Complicat ions.
Springer, 2018; 101-111(3)	T akeda S, Wegmann S, Cho H, et al. Neuronal
uptake and propagation of a rare phosphorylated
high-molecular-weight tau derived from
Alzheimer's disease brain.Nat Commun. 2015 Oct
13;6:8490. doi: 10.1038/ncomms9490.
7.	All figures in a manuscript are recommended to be
in full color; publication in color requires page
charge of JPY65,000 for one color page (see also“VI. Publication Charges”). For invited articles,
publication in color is cost-free for one page andrequires JPY65,000/one exceeding color page.
Letters and symbols in figures should be clear andof sufficient size to be legible after reduction to thewidth of one column. Specify the size to be printed,
if necessary.
8.	C o n t e n t o f s u p p l e m e n t a r y f i l e s w i l l o n l y b e
published in the online journal. Therefore, if a
supplementary file contains References, they should
be separate from those in the Main Document, andonly refer to the content in the supplementary
file(s). There is a size limit of 5 MB for uploaded
supplementary file(s) per manuscript.

supplementary files, normally occupies 1 journal page.
3. Review Article (Invited)“Review Article” is usually invited one upon requestfrom the Editor-in-Chief, but we will also consider
limited number of non-invited submissions. Total word
count is less than 6,000 words and less than 220 words
for Unstructured Abstract. Number of Table and Figures
are less than 8 and less than 3 supplementary figures.
No limitation of numbers of references.
4. Editorial (Invited)“Editorial” normally occupies no more than 2 journal
pages about subject manuscript should be cited Upon
request from the Editor-in-Chief. Total word count isless than 1,500 words and no abstract, less than 2
Table or figures and less than 15 references.
5. Case Report
Total word count is less than 3,000 words and lessthan 100 words for Unstructured Abstract.  Number ofTable and Figures are less than 4 and 20 references.
Vas-Cog Journal encourage submission by young
researches in this section.
6. Letter to the Editor and Author’s Reply
This is an opinion-letter to a manuscript which has
been published in Vas-Cog Journal. The manuscripts
must not exceed 1,000 words in length and have no
more than 5 co-authors.
Authors who submit or resubmit manuscripts to thejournal are required to have all of their manuscript files
strictly reflect the requirements outlined here. Whenany part does not, we cannot start either the initial orrevision review process. “Total word count” is the total
number of all words appearing in the manuscript files,
except for the text in Table(s) and Figure(s). Note thatlegends for these are included in the “ Total word
count”.
III. Conflict of Interest Disclosure Policy:
The submitting author should complete the online
form in the submission system and have the same
information included in “Disclosures” in the main
document in order to disclose all authors’ relationshipsthat could be perceived as real or apparent conflict(s)of interest. When submitting a manuscript for
publication, all authors are required to disclose any
financial relationship (within the past 12 months) witha biotechnolog y manufacturer, a pharmaceut ical
company, or other commercial entity that has been
involved in the subject matter or materials discussed in
the manuscript. When a manuscript has been acceptedfor publication, all disclosed COI will appear in thearticle.
Example:Disclosures：A (author name) serves as a consultant toZ (entity name); B’s spouse is chairman of Y; C received
a research grant from X; Deceived lecture fees from V;
E holds a patent on U; F has been reimbursed by T for
attending several conferences; G received honoraria for
writing promotional material for S; H has no conflict ofinterest.

II. Manuscript Types:
1. Original article
Total word count is less than 6,000 words and lessthan 220 words for Abstract.   Number of Table andFigures are less than 8 and less than 3 supplementary
figures. No limitation of numbers of references. Three
to 5 Keywords and structured abstract with 3 headings
are other requirements.
2. Images in Vascular Cognitive Impairment
Images in “Vascular Cognitive Impairment” should
contain a novel color image with scientific impact. Notethat we do not accept any case reports. The manuscript
consisted of less than 400 words, 1 figure and 2

IV. Review of Manuscripts:
All original manuscripts are usually evaluated by 2
reviewers assigned by the Editors.
V. Proofs:

40 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Galley proofs of accepted manuscripts will be sent tothe authors for their correction. Changes should be
limited to typographical errors or errors in thepresentation of data. Excessive corrections may berejected by editors and/or be charged to the authors.

2-5-1 Shikata-cho, Okayama 700-8558, Japan
Tel: +81-86-235-7365, Fax: +81-86-235-7368
E-mail: toruyamashita@okayama-u.ac.jp
EDITORIAL ADVISORY BOARD
Ryuichi Morishita (Department of Clinical Gene
Therapy, Osaka University)
Yo s h i o I k e d a ( D e p a r t m e n t o f N e u r o l o g y, G u n m a
University Graduate School of Medicine)
Hiroshi Mori (Osaka City University Medical School,
Tamiya Hospital)
Masahiro Akishita (Department of Geriatric Medicine,
Graduate School of Medicine, The University of Tokyo)
Koji Abe (Department of Neurology Okayama University
Medical School)
Shinichiro Uchiyama (International Univeristy of Healthand Welfare, Center for Brain and Cerebral Vessels,
Sanno Hospital and Sanno Medical Center)
Katsuya Urakami (Section of Environment and Health
Science, Department of Biological Regulation, Faculty of
Medicine, Tottori University)
Nobuya Kawabata (Division of Neurology, Yachiyo
Hospital)Kazuo Kitagawa (Department of Neurology. Tokyo
Women 's Medical University)
Koichi Kozaki (Department of Geriatric Medicine Kyorin
University School of Medicine)
Issei Komuro (Department of Cardiovascular Medicine,
The University of Tokyo Graduate School of Medicine)
Masataka Sata (Department of Cardiovascular Medicine,
Tokushima University Graduate School)
Masahiko Suzuki (Department of Neurology Katsushika
Medical Center The Jikei University School of Medicine)
Shunya Takizawa (Division of Neurology, Department ofInternal Medicine, Tokai University School of Medicine)Ya s u o Te r a y a m a ( I w a t e M e d i c a l U n i v e r s i t y ·Department of Internal Medicine)
Hidekazu Tomimoto (Department of Neurology, Mie
University)
Ken Nagata (Yokohama General Hospital)
Hanyu Haruo (Department of Geriatric Medicine, Tokyo
Medical University)
Toshiya Fukui (Kawasaki Memorial Hospital)
Masatsugu Horiuchi (Department of Molecular
Cardiovascular Biolog y and Pharmacolog y Ehime
University Graduate School of Medicine)
Etsuro Matsubara (Oita University Faculty of Medicine
Department of Neurology)
Toshiki Mizuno (Department of Neurology, Kyoto
Prefectural University of Medicine)
Shokei Mitsuyama (Department of Pharmacology andMolecular Therapeutics, Kumamoto University
Graduate School of Medical Sciences)
Masaru Mimura (Department of Neuropsychiatry, Keio
University School of Medicine)
Shuhei Yamaguchi (Department of Neurology, Facultyof Medicine, Shimane University)
Masahito Yamada (Department of Neurolog y and
Neurobiology of Aging, Kanazawa University Graduate
School of Medical Sciences)

VI. Publication Charges:
Free for publication charge in manuscript submission
rules within total word count, Tables, Figures andReferences. JPY8,000/one exceeding page charge(JPY65,000 for one color page).
VII. Reprints:
Reprints are available in a multiple of 100 copies
when ordered w ith the return of the proofs. The
approximate cost per 100 copies is JPY10,000,
including color pages. Free PDF publication.

EDITORIAL BOARD
Editor-in-Chief
Mikio Shoji
Director, Dementia Center,
Geriatrics Research Institute and Hospital
3-26-8 Otomo-machi, Maebashi, 371-0847, Japan
Tel: 027-253-3311, Fax: 027-252-7575
e-mail: mshoji52@arion.ocn.ne.jp			  m-shoji@ronenbyo.or.jp
Senior Associate Editor
Shuko Takeda
Department of Clinical Gene Therapy,
Graduate School of Medicine, Osaka University
2-2 Yamada-oka, Suita 565-0871, Japan
Tel: +81-6-6210-8351, Fax: +81-6-6210-8354
Email: takeda@cgt.med.osaka-u.ac.jp
Associate Editors
Masayuki Satoh	Department of Dementia Prevention and Therapeutics,
Graduate School of Medicine, Mie University
2-174 Edobashi, Tsu, Mie 514-8507, Japan
Tel/Fax +81-59-230-6031
E-mail: bruckner@clin.medic.mie-u.ac.jp
Hirofumi Sakurai	Department of Geriatric Medicine, Tokyo Medical
University	6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023,
Japan
Tel.: +81 3-3342-6111, Fax: +81 3-3342-2305
E-mail: sakurah@tokyo-med.ac.jp
Masafumi Ihara
Department of Neurology
National Cerebral and Cardiovascular Center
5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan
Phone: +81-6-6835-5137
E-mail: ihara@ncvc.go.jp
Toru Yamashita
Department of Neurology,
Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences,

41

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Vas-Cog Journal
Authorship Agreement
Each author must read and sign the statements on
1. Authorship Responsibility, 2. Copyright, and 3. Disclosure Declaration.
1. Authorship Responsibility.
	Author(s) certify that the manuscript is original and that neither the manuscript nor one with substantiallysimilar content has been previously published or being considered for publication elsewhere in any form otherthan an abstract. Author(s) have read the manuscript and approved its submission to Vas-Cog Journal.
2. Copyright.
	In consideration of the acceptance of the work for publication, the authors agree to transfer all copyrightownership to the Japanese Society for Vascular Cognitive Impairment (Vas-Cog Japan).
3. Disclosure Declaration.
	All relevant financial, personal or professional relationships with other people or organizations must be
disclosed in the online form and main document. Otherwise, the signature indicates author(s) have no
relationships or conflicts to disclose. Authors’ disclosures will appear after the “Acknowledgments” section in
the accepted article.
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42JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

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Table of Contents

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Editorial ………………………………………………………………………………… 3＜ Review article ＞
A neurovascular approach to clearing β-amyloid from the brain ………… 4
New insights into the role of lifestyle-related diseases on vascular dementia
and Alzheimerʼs disease ………………………………………………………… 12

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Date:＜ Case report ＞
A Japanese family of autosomal dominant cerebral small vessel disease withheterozygous HTRA1 mutation showing dementia, gait disturbance andsubarachnoid hemorrhage …………………………………………………… 20
Greetings from Vas-Cog Japan, the Japanese Society for
Vascular Cognitive Impairment ………………………………………………… 27
Reports of the Vas-Cog Japan 2018 …………………………………………… 28
VAS-COG Japan 2018 Report …………………………………………………… 29
Welcome to Vas-Cog Japan 2019 ………………………………………………… 30
Meeting report of Vas-Cog Asia 7 from Jakarta ……………………………… 32
An impression on VAS-COG Asia 2018 ………………………………………… 33
Reports of Vas-Cog Japan Council Meeting …………………………………… 34
Articles of Association of the Japanese Society for Vascular Cognitive
Impairment ………………………………………………………………………… 37
Vas-Cog Journal Submission Instruct ions for authors ……………………… 39
Vas-Cog Journal Authorship Agreement ………………………………………… 42
Editorʼs Note ………………………………………………………………………… 44

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2019 NO.5）

Editorʼs Note
Director, Dementia Center,
Geriatrics Research Institute and Hospital
The 5th issue of Vas-Cog Journal reports thejournal has been reﬁned and remarkable 2 reviews
and a case report work were carried.

2018, hosted by Professor Katsuya Urakami andappreciated every eﬀort by president, members ofProfessor Etsuro Matsubara on August 4-5, 2018, ineditorial board and secretariat.

Beppu, Oita.

Special lectures, symposium, and 36

deeply appreciate authors: Dr. Ihara, Dr. Takeda, andoral and poster presentations were presented of theDr. Yamashita, who submitted wonderful works formeeting.

As many as participants with 170

this initial issue of renewal academic journal. I hopeattendees joined the meeting. We also introduced

these great eﬀorts contribute further advances in thisthe detail of 10th annual meeting, Vas-Cog Japanﬁeld.

I deeply

And I would also2019 (Tokyo).
In this meeting, committee and attendance had
decided on 2 important issues: Vas-Cog Japan ischange to be the Academic Society and publishes theoﬃcial journal.

Based on this decision, editorial

board made great eﬀorts to publish 5th as the oﬃcial
journal of Vas-Cog Japan. As you can see, Vas-Cog

The 1 st Meeting : August, 2010 (Tokyo) Chairman : Ken Nagata and Toshiya Fukui
The 2nd Meeting : August, 2011 (Tokyo) Chairman : Koji Abe and Shokei Mitsuyama
The 3rd Meeting : August, 2012 (Tokyo) Chairman : Ryuichi Morishita, Yasuo Terayama, and Koji Abe
The 4th Meeting : August, 2013 (Tokyo) Chairman : Mikio Shoji and Haruo Hanyu
The 5th Meeting : August, 2014 (Kyoto) Chairman : Toshiki Mizuno and Hidekazu Tomimoto
The 6th Meeting : August, 2015 (Tokyo) Chairman : Nobuya Kawabata and Shuhei Yamaguchi
The 7th Meeting : August, 2016 (Kanazawa) Chairman : Masatsugu Horiuchi and Masahito Yamada

2019

The past and future annual meeting of Vas-Cog JapanO f f i c i a l J o u r n a l o f Va s - C o g J a p a n S o c i e t―youtline of the 9th annual meeting, VAS-COG Japan

Va s - C o g J o u r n a l―

Mikio Shoji MD, PhD

Vas-Cog Journal
No.5 April 01. 2019

Official Journal of Vas-Cog Japan Society＜ Review article ＞

Masafumi Ihara.
“Neurovascular approach for Alzheimer's disease.”

Shuko Takeda.
“Lifestyle-related diseases and dementia.”

The 8th Meeting : August, 2017 (Tokyo) Chairman :Shinichiro Uchiyama and Issei Komuro
The 9th Meeting : August, 2018 (Beppu) Chairman : Katsuya Urakami and Etsuro Matsubara
The 10th Meeting : August, 2019 (Tokyo) Chairman : Masahiro Akishita and Yoshio Ikeda
The 11th Meeting : September, 2020 (Tokushima) Chairman : Shunya Takizawa and Masataka Sata
The 12th Meeting : August, 2021 (planned) Chairman : Kazuo Kitagawa and Koichi Kozaki
The 13th Meeting : August, 2022 (planned) Chairman : Masahiko Suzuki＜ Case report ＞

Toru Yamashita, et al.
“Heterozygous HTRA1 mutation cases showing SAH.”- to be continued -44

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ISSN : 24239372