JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

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No.6 April 01. 2020

Official Journal of Vas-Cog Japan Society

Review article

Hirofumi Sakurai.
“Frailty and sarcopenia in patients with dementia”

Yoshiki Hase.
“Exploring Interventional Strategies for Vascular Dementia”
Case report

Yosuke Osakada, et al.
“Delayed Serial Microvascular Injury andCognitive Decline After Whole Brain Irradiation”

1

ISSN : 24239372

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Table of Contents

Editorial ………………………………………………………………………………… 3＜ Review article ＞
Frailty and sarcopenia in patients with dementia …………………………… 4
Exploring Interventional Strategies for Vascular Dementia ……………… 12＜ Case report ＞
Delayed Serial Microvascular Injury and Cognitive Decline After
Whole Brain Irradiation ………………………………………………………… 23
10 th Year Anniversary Greetings from Vas-Cog Japan,
the Japanese Society for Vascular Cognitive Impairment …………………… 27
Reports of the Vas-Cog Japan 2019 …………………………………………… 28
Welcome to Vas-Cog Japan 2021 ………………………………………………… 30
Meeting report of Vas-Cog Asia 8 from Manila……………………………… 31

Reports of Vas-Cog Japan Council Meeting …………………………………… 32
A report from the Public Relations Committee ………………………………… 35
As the new leader of board for increasing membership and public relations … 36
As an editor of journal of VASCOG-J …………………………………………… 37
New submission system for Vas-Cog Journal ………………………………… 38
Articles of Association of the Japanese Society for Vascular Cognitive
Impairment ………………………………………………………………………… 40
Vas-Cog Journal Submission Instructions for authors……………………… 42

Vas-Cog Journal Authorship Agreement ………………………………………… 45
Editorʼs Note ……………………………………………………… Inside Back Cover

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Editorial
Shuko Takeda, MD, PhD.
Associate Professor
Department of Clinical Gene Therapy,
School of Medicine, Osaka University
The brand new Vas-Cog Journal

hosted by Profs. Akishita (The University of Tokyo)
and Ikeda (Gunma University). The main theme of the

Vas-Cog Journal, initially launched in 2015 as ameeting, “Cross-talk of Vascular Factors andnewsletter of the Vas-Cog Japan Society, underwent a

Neurodegeneration,” was contributed to by more thanrevamp last year. A brand new style was designed,

200 participants, who discussed a wide range of

given its rise in status as an international academic

popular topics on vascular dementia. The upcoming

journal that accepts peer-reviewed papers in addition

annual meeting, Vas-Cog Japan 2021, will be held on

to regular articles by the editorial board members.

September 11th and 12th in Tokushima. It will be

Vas-Cog Journal now welcomes your submissions ofhosted by Profs. Sata (Tokushima University) andhigh-quality original articles and case reports

Takizawa (Tokai University). The main theme of thisregarding vascular dementia and related diseases. The

meeting will be “Dementia Practice from Vascular andcurrent issue of Vas-Cog Journal (No. 6) presents two

Neurological Medicine,” focusing on the close

sophisticated review articles and an intriguing caserelationship between vascular diseases andreport, both of which were accepted via the newneurodegenerative disorders. Professor Abe at

submission system.

Okayama University reports on the international

A comprehensive review article, co-written by Drs.

meeting of Vas-Cog Asia 8, which was held jointly

Sakurai and Hanyu at Tokyo Medical University,with the Asia-Paciﬁc Stroke Conference 2019 infocuses on the interplay among dementia, frailty, andManila on October 2nd, 2019. Most of the participantssarcopenia, providing new insights into thebelonged to Asian countries, and discussed and sharedmechanisms underlying these age-related diseases.

the current knowledge and future trends of vascular-

Another review article by Dr. Hase from Dr. Kalariaʼs

related cognitive impairment.

Laboratory at Newcastle University, UK, covers a

In this issue of Vas-Cog Journal, Prof. Ikeda ofbroad range of topics on the pathogenesis of vascular

Gunma University summarizes reports from the 11th

dementia, and proposes novel interventional

Board and Council Meeting of the Japanese Society forstrategies against vascular cognitive impairment. In a

Vascular Cognitive Impairment, which was held oncase report from Okayama University, Dr. Osakada

August 3rd, 2019 in Tokyo during the annual meeting

describes an intriguing case of delayed microvascularof Vas-Cog Japan 2019. Additionally, submission

injury and cognitive decline after whole-brain

instructions to Vas-Cog Journal are provided in this

irradiation against a brain tumor. The detailed

issue.

description of this particular case provides useful

Finally, I express my sincere gratitude to theinformation and oﬀers fresh insights regarding thePresident of Vas-Cog Japan (Prof. Morishita of Osaka

possible pathogenesis of irradiation-induced brain

University), the Editor-in-Chief of Vas-Cog Journal

injuries.

(Prof. Shoji), the editorial bord members, andsecretaries for all their eﬀorts toward publishing thisIssue No. 6 of Vas-Cog Journal also reports thethoutlines of the 10 Annual Meeting of Vas-Cog Japan,

issue of the journal. I hope you enjoy the brand newrdwhich was held on August 3 , 2019, in Tokyo, andlook of Vas-Cog Journal.

3

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Frailty and sarcopenia in patients with dementia
Review article

Frailty and sarcopenia in patients with dementia
Hirofumi Sakurai, MD, PhD.；Haruo Hanyu, MD, PhD.
Department of Geriatric Medicine, Tokyo Medical University
Short Title: Frailty and sarcopenia in dementia
Disclosures: The authors declare no conﬂict of interest.
Abstract:
Increasing emphasis has been placed on extending healthy life expectancy. Patients with dementia,
cerebrovascular disease, and frailty due to old age account for 24.8%, 18.4%, and 12.1%, respectively, of people
aged 65 years or more requiring nursing care.
The causes of dementia are numerous, and the most common type is Alzheimerʼs disease (AD), followed by
vascular dementia (VaD), and dementia with Lewy bodies. Lifestyle-related diseases such as diabetes andhypertension are involved in the onset and progression of dementia.
The term “frailty" indicates an intermediate stage between a healthy state and one where an individual will
require nursing care. Frailty involves physical, mental, and psychological decline, and possibly also social factors
such as solitude and ﬁnancial distress.
Sarcopenia, which causes muscle loss, and a decrease in muscular strength and physical function, is the key
factor in physical decline.
Dementia, sarcopenia, and frailty are closely related. The frequency of frailty is higher in patients with AD
than in healthy elderly people. Cerebrovascular disease (CVD), such as lacunes and white matter lesions, iscommon in elderly patients with AD. Frailty is more closely associated with AD + CVD than with AD alone; and it
also shows a stronger association with VaD than with AD.
The close relationship between dementia and frailty/sarcopenia is believed to constitute a vicious cycle.
Key words: Frailty, sarcopenia, Alzheimerʼs disease, cerebrovascular disease (CVD), vascular dementia

Corresponding Author:
Hirofumi Sakurai
Department of Geriatric Medicine, Tokyo Medical University
6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
Tel.: +81-(0)3-3342-6111, Fax: +81-(0)3-3342-2305
E-mail: sakurah@tokyo-med.ac.jp

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Hirofumi Sakurai；Haruo Hanyu
Introduction

dementia, including ﬁndings made at our department

Healthy life expectancy refers to the period during

related to this issue.

which a person is able to live independently without
needing care in their daily life. According to a survey

Frailty

conducted in 2016 by the Ministry of Health, Laborand Welfare of Japan, average life expectancy was

Frailty can be reversed, allowing return to healthy

80.98 years for males and 87.14 years for females,

state (Figure 1)

while healthy life expectancy was 72.14 and 74.79

Frailty has been shown to be associated withyears, respectively.The diﬀerence between average life

increased physical limitations and disability, andexpectancy and healthy life expectancy was 12.35

results in generally poorer health in older people2).

years for women and 8.84 years for men. The results

The term “frailty” is used to denote the intermediateof the same survey also revealed the causes for thestage between a healthy state and one where theneed for nursing care in people aged 65 years or over,individual will require nursing care. This term waswith dementia, cerebrovascular disease (CVD), andﬁrst proposed by the Japan Geriatrics Society in 2014.

frailty due to old age occupying 24.8%, 18.4%, and

It is characterized by an increased susceptibility to1)

12.1% of this particular population, respectively .

stress due to the decrease that occurs in physiological

Recently, increasing emphasis has been placed onreserves with advanced age, with likely outcomes

extending healthy life expectancy, and achieving thisincluding impaired function in daily activities, thegoal will require new eﬀorts to combat dementia,

need for nursing care, and death.

cerebrovascular disorders, and frailty. The causes of

Before reaching a frail state, a healthy individual

dementia are numerous, and the most common type iswill also pass through another distinct stage termed

Alzheimerʼs disease (AD), followed by vascular“pre-frailty”. Both the pre-fail and frail states are notdementia (VaD), and dementia with Lewy bodies

irreversible, however: appropriate intervention and(DLB). Lifestyle-related diseases such as diabetes andsupport, including guidance on exercise and nutrition,

hypertension are involved in the onset andcan result in a return to a healthy state with improved

progression of dementia.

function in daily activities. Therefore, earlyintervention is important3).

Dementia, CVD, and frailty are closely related toeach other. In this article, I would like to give an
overview of the relationship between frailty and

Figure 1

Frailty can be reversed, allowing return to healthy state

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Frailty and sarcopenia in patients with dementia
Frailty has three elements (Figure 2)

Comprehensive geriatric assessment (CGA), which is

Frailty involves a decline not only in an individualʼscommonly used to assess physical impairment in thephysical condition, but also in their mental andelderly, is also useful for assessing frailty.

psychological well-being. This may take the form of a

One study investigated outcomes in individuals

decline in cognitive abilities or depression, forscoring frail in more than 8 out of 25 items included

example. Social factors, such as solitude and ﬁnancial

in a kihon checklist applied in a survey conducted by

distress, must also be taken into account in its

the Ministry of Health, Labor and Welfare of Japan indevelopment.

2010. The results showed that at 1 year later, theSarcopenia is considered to be the key factor in

number of these individuals requiring support/

physical decline with age, resulting in muscle loss, andnursing care was 5 times greater than that in thosea decrease in muscular strength and physicalwho did not, while the number of deaths was 4 times

function.

greater5).

Diagnostic criteria for frailty (Table 1)

Diagnostic criteria for sarcopenia (Figure 3)

Physical frailty was determined according to theSarcopenia is deﬁned according to a set of criteria

revision of the screening test utilized in the Obu Study

developed by the Asian Working Group for Sarcopenia

4)

Health Promotion for the Elderly . The criteria for(AWGS)6). These criteria comprise the following 3

physical frailty were based on the presence orcomponents: low handgrip strength (< 26 kg for men

absence of the following 5 measurable characteristics:

and < 18 kg for women); low gait speed (walking speed

weakness (low grip strength: men < 26 kg, women <of < 0.8 m/sec at the usual space); and low muscle mass

18 kg); slowness (walking speed of < 1.0 m/sec overas assessed according to the skeletal muscle mass index

6m at usual pace); weight loss (2-3kg in 6months);(7.0 kg/m2 for men and 5.7 kg/m2 for women as

low physical activity; and exhaustion. An individual

measured by bioelectrical impedance: BIA ).

meeting 3 or more, 2 or 1, and none of these 5characteristics was deemed to be at the frail, pre-frail,and non-frail stage, respectively.

Physical frailty
䠄Muscle weakness䠅

Mental andpsychological frailty

Social frailty
Solitude and financial distress䠅䠄Dementia anddepression䠅

Figure 2

The three elements of frailty

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Hirofumi Sakurai；Haruo Hanyu
Table 1

Diagnostic criteria for frailty

Evaluation method for frailty: Japanese-Cardiovascular Health Study (J-CHS) criteria

Evaluation criteria
Weight loss

2~3 ㎏ in 6 months

Muscle weakness

Grip strength：men ＜ 26 kg, women ＜ 18 kg

Exhaustion(Last two weeks) I feel tired

Gait speed

Gait speed ＜ 1.0 m/ s
① Do you exercise lightly?

Physical activity② Do you exercise regularly?
Answer “No” for both of the above

Number of applicable items
０ : healthy
1~2：pre-frailty

3 or more：frailty

prevalence of frailty in 140 outpatients with mild-to-

Relationship between AD and frailty
A meta-analysis of studies investigating themoderate AD attending our memory clinic revealed

relationship between AD and frailty revealed that thethat the ratio of frailty to pre-frailty in this group was

prevalence of frailty in patients with mild-to-moderate

68% (frailty, 24%;pre-frailty, 44%)9).

AD was between 11.1% and 50.0% (prevalence,
31.9%; 95% conﬁdence interval; 15.7% to 48.5%)7).

Relationship between AD and sarcopenia (Figure 4)

Moreover, the prevalence of frailty in patients with AD

A cohort study of community-dwelling elderly(31.9%) was higher than that in the general elderly

revealed an association between cognitive function

8)and skeletal muscle mass or motor function10). Muscle(10%) .
One earlier study by our group investigating thestrength has been shown to be associated with mild

No

Yes

Yes

Figure 3

No

Diagnostic criteria for sarcopenia (AWGS2014)

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Frailty and sarcopenia in patients with dementia
cognitive impairment and the development of

Prevalence of frailty status in patients with AD or

11)

Alzheimerʼs dementia . It has been reported thatAD + CVD

brain volume and lean mass are positively correlated

Frailty shows stronger association with AD+CVD

12)

in early AD patients .

than AD alone (Figure 5)

One study by our group investigating the

Cerebrovascular disease, such as lacunes and white

relationship between the severity of AD and thematter lesions, is common in elderly patients withfrequency of sarcopenia demonstrated that theAD.In one study, our group compared the prevalence

frequency of sarcopenia increased with theof physical frailty in patients with AD alone with that

progression of dementia, with the results showing thatin those with AD accompanied by CVD. A total of 82

it was 12% in the healthy elderly (MMSE, 27 points),

outpatients with AD alone (AD group) and 25 with AD

39% in patients with early AD or mild cognitive

accompanied by CVD (AD + CVD group) aged 65 years

impairment (MCI) (MMSE, 25 points), 46% in patientsand older attending our memory clinic were enrolled.

with mild AD (MMSE, 22 points), and 56% in patients

The AD + CVD group showed a signiﬁcantly higher

13)

with moderate AD (MMSE, 17 points) .

frequency of frailty (40%) and pre-frailty (52%) thanA decrease in lower extremity muscle strength andthe AD group (frailty, 16%; pre-frailty, 38%).

walking speed is already observed even in patients

The study also included an evaluation of sarcopenia

with early AD/MCI. One study showed that thisin each group based on the above-mentioned

decrease in strength was not only observed in thecriteria of the AWGS. The AD + CVD group showed alower extremities, but also in the upper extremities insigniﬁcantly higher frequency of sarcopenia (68%)13)

than the AD group (30%)14).

patients with moderate AD , indicating the needfor intervention to be commenced from an early stage

Further work by our group based on MRI and SPECTin the development of AD.

imaging suggested an association between frailty andsmall vessel disease pathology, including periventricular
hyper-intensity, deep white matter hyper-intensity, anddecreased regional cerebral blood ﬂow (rCBF) in theanterior cingulate in patients with AD15).

Figure 4

Sarcopenia and muscle function at various stages of Alzheimerʼs disease

Lower extremity muscle strength and walking speed already show decrease even in patients with early AD/MCI

8

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Hirofumi Sakurai；Haruo Hanyu

Prevalence of frailty ( < 0.001)

16㸣

Frailty40㸣

38㸣
Pre-frailty
52㸣
Non-frailty

Prevalence of sarcopenia ( < 0.01)30㸣Sarcopenia
68㸣

70㸣
Non-sarcopenia

Figure 532㸣

Prevalence of frailty and sarcopenia in AD and AD + CVD

Frailty and sarcopenia show stronger association

with AD and 6.7 times the odds ratio (95% CI: 1.6 towith VaD or DLB than with AD (Figure 6)27.4) in those with vascular dementia18).

In one study, our group investigated frailty andAnother study monitoring 5,480 people in threesarcopenia in patients with AD (24 men and 53

French cities over a period of 7 years found that the

women; mean age, 83.0 ± 5.1 years), VaD (10 men

risk of developing dementia from a status of frailty

and 12 women; mean age, 80.4 ± 5.0 years), or DLB

was 1.22 times the odds ratio in patients with AD(28 men and 20 women; mean age, 81.2 ± 5.5 years)(95% CI: 0.80 to 1.86) and 2.50 times the odds ratiousing a relatively simple screening test (Dr.

in those with VaD (95% CI: 1.01 to 6.19). Frailty thus

16)

SUPERMAN) . Our results showed a correlation

showed a stronger association with VaD than with

between Lewy body dementia or vascular dementia

AD19).

and an increase in dysfunction, such as a reduction in
ADL, falls, and upper and lower limb dysfunction
compared with in AD17).
A cross-sectional study of 654 local residents over
the age of 75 years revealed that the risk ofdeveloping dementia from a state of frailty was 3.2
times the odds ratio (95% CI: 1.7 to 6.2) in patients

9

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Frailty and sarcopenia in patients with dementia

Figure 6

Relationship between frailty and dementia type

Common mechanisms for dementia, sarcopenia, andAcknowledgments

frailty

The authors would like to thank Professor Jeremy

A systematic review investigating the relationship

Williams of the Department of International Medical

between frailty and cognitive impairment identiﬁed a

Communications at Tokyo Medical University for

number of common factors between them, including

editing and reviewing the English of this manuscript.

the presence of Alzheimerʼs pathology, reduced
testosterone, poor nutrition, chronic inﬂammation, therisk of cerebrovascular disease, and depression20).

References

Our group has shown that a greater degree of1.

oxidative damage was found in AD with CVD than in2016 Basic Survey of National Life by Ministry of
Health, Labor and Welfare.

21)

AD alone .

2.

Much work remains to be done on the relationshipFried LP et al. Frailty in older adults: evidence forphenotype. J Gerontol A Biol Sci Med Sci 2001:

between frailty/sarcopenia and cognitive impairment,

56A: M146-M156.

however, and further research is needed.

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Kuzuya M et al. Nihon Rounen Igakukaizassi
2009; 46: 279-285.

Conclusion

4.

Shimada H et al. Combined prevalence of frailty

There is a close correlation between dementia andand mild cognitive impairment in a population offrailty/sarcopenia, with the combination believed toelderly Japanese people. J Am Med Dir Assoc

constitute a vicious cycle. In patients with dementia,

2013; 14: 518-524.

the amount of physical activity decreases due to5.

Satake et al. Validity of the Kihon Checklist for

decreased motivation, and ADL decreases due to theassessing frailty status. Geriatr Gerontol Int 2016;

appearance of muscle weakness and fatigue. On the

16: 709-715.

other hand, it has been reported that ADL is reduced

6.

Chen LK et al. Sarcopenia in Asia: consensus

and the risk of developing dementia is high in frail

report of the Asian Working Group for

elderly people.

sarcopenia. J Am Med Dir Assoc 2014; 15: 95-

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and dementia in the elderly, indicates the importance7.

Kojima G, Liljas A, Iliﬀe S, et al:Prevalence of frailty

of preventive measures, including guidance onin mild to moderate Alzheimerʼs disease: anutrition and exercise, in the elderly, and more

systematic review and meta-analysis. Curr

research needs to be done on this issue.

Alzheimer Res 2017; 14: 1256-1263.
8.

Collard RM, Boter H, Schoevers RA, et al:
Prevalence of frailty in community-dwelling older

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Hirofumi Sakurai；Haruo Hanyu

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J Alzheimers Dis 2019; 67:1201-1208

Namioka N, Hanyu H, Shimizu S, et al: Oxidative

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stress and inflammation are associated with

developed comprehensive geriatric assessment

physical frailty in patients with Alzheimerʼs

initiative “Dr. SUPERMAN” as a convenientdisease.Geriatr Gerontol Int 2017; 17:913-918.

screening test. Geriatr Gerontol Int 2013;

Bums JM et al. Reduced lean mass in early

13:811-812.

Alzheimer disease and its association with brain
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Comprehensive geriatric assessment in elderly

Auyeung TW, Kwok T, Lee J, et al. Functional

patients with dementia. Geriatr Gerontol Int

decline in cognitive impairment-the relationship2015; 15:27-33.
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Kulmala J et al: Association between Frailty and

Neuroepidemiology 2008; 31 :167-173

D e m e n t i a : a p o p u l a t i o n - b a s e d s t u d y.

Boyle PA, Buchman AS, Wilson RS, et al.

Gerontology 2014; 60: 16-21.

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Namioka N, Hanyu H, Hatanaka H, et al.:atrophy. Arch Neurol 2010; 67: 428-433.

between physical and cognitive function.
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Iwamoto T, Hnyu H, Umahara T et al.: Newly

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Avila-Funes JA et al: Is frailty a prodromal stage

Alzheimerʼs disease and the rate of cognitiveof vascular dementia? Results from the Three-decline in community-dwelling older persons.

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Arch Neurol 2009; 66:1339-1344.

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Ogawa Y, Kaneko Y, Hanyu H, et al. Sarcopenia

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Robertson DA, Savva GM, Kenny RA: Frailty andand muscle functions at various stages ofcognitive impairment-a review of the evidence

Alzheimerʼs disease. Front Neurol 2018 Aug 28;

and causal mechanisms. Ageing Res Rev 2013;

9: 710. doi:10, 3389/ fneur.2018.00710

12: 840-851.

Hirose D, Hanyu H, Sakurai H, et al.: Frailty and21.

Hatanaka H, Hanyu H, Hirose D et al. Peripheral

sarcopenia in subjects with Alzheimerʼs diseaseoxidative stress markers in individuals with

with or without cerebrovascular disease. Geriatr

Alzheimerʼs disease with or without

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63: 1472-1474.

Characteristics of frailty status in patients with

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Exploring Interventional Strategies for Vascular Dementia
Review article

Exploring Interventional Strategies for Vascular
Dementia
Yoshiki Hase, MD, PhD；Raj N Kalaria, FRCP, PhD
Neurovascular Research Group, Translational and Clinical Research Institute,
Newcastle University, Newcastle upon Tyne, United Kingdom
Short title :Novel Therapeutic target for Vascular Dementia
Disclosures:
YH and RNK declare no conﬂict of interests concerning this study. Our work is supported by grants from theMedical Research Council (MRC, G0500247), Newcastle Centre for Brain Ageing and Vitality (BBSRC, EPSRC,
ESRC and MRC, LLHW), and Alzheimerʼs Research UK (ARUK, PG2013‒022). Tissue for this study was collectedby the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK MRC (G0400074), by
the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award to the Newcastle
upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimerʼs Society and ART as part of theBrains for Dementia Research Project. YH was supported by SENSHIN Medical Research Foundation, Osaka,
Japan and The Great Britain Sasakawa Foundation, London, United Kingdom.
Abstract:
Vascular dementia (VaD) is regarded as the second most common type of dementia but recent surveys
suggest vascular cognitive impairment (VCI) is even more frequent in most populations worldwide. White
matter hyperintensities (WMHs) detected on brain MRI are the radiological signature of cerebral small vessel
disease (SVD), which is highly characteristic in subcortical ischaemic vascular dementia (SIVD), the mostprevalent subtype of VaD. Vascular risk factors are strongly associated with WMHs and development of poststroke VaD or dementia. The gliovascular unit (GVU) has a critical role in SIVD. Therefore, any component of the
GVU could be a therapeutic target for VaD. When considering pharmacological approaches, more attentions
ought to be paid onto pleiotropic eﬀects of existing drugs. Autonomic dysfunction is highly prevalent in VaD
patients and is a treatable factor to protect GVU from VaD pathologies. As non-pharmacological approaches for
VaD, environmental enrichment (EE) and physical exercise training, particularly limited EE rather than full-time
EE, have been proved to preserve GVU integrity in VaD. Glial responses, especially clasmatodendrosis, would bea novel therapeutic target for VaD. Animal models of VaD are useful to demonstrate pathophysiology, explore
and establish safe and eﬀective treatments. Nevertheless, pathophysiological substrate of VaD is heterogeneous.
Multimodal combination treatments targeting GVU, implementing both pharmacological and nonpharmacological interventions, would be a promising interventional strategy to counter vascular dementia.
Key Words:
Animal model, Chronic cerebral hypoperfusion, Environmental enrichment, Gliovascular unit, Vasculardementia,

Corresponding Author:
Name: Dr. Yoshiki Hase, MD, PhD
Address: Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality,
Newcastle upon Tyne, NE4 5PL, United Kingdom
TEL: +44(0)1912081218
Email: yoshiki.hase@newcastle.ac.uk

12

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yoshiki Hase；Raj N Kalaria
Introduction

baseline, none of them had confirmed to have

Current trends suggest a high burden of

dementia.

Neuroimaging and post-mortem

cerebrovascular disorders worldwide that isinvestigations revealed that more than 75% who

concomitant with increased frequency of vasculardeveloped dementia could be diagnosed to have VaD,

cognitive impairment (VCI). There is no cure for VCI

lacking signiﬁcant Alzheimer type of pathology. Theor for vascular dementia (VaD),

the second moststudy remarkably revealed that the strongest

common type of dementia among the ageing

predictors of dementia after stroke was multiple (twopopulation (1). It is therefore timely that safe andor more) cardiovascular risk factors including

eﬀective interventional strategies, which delay onset,

hypertension, hyperlipidemia and diabetes mellitus.

slow down cognitive decline in patients withThis fact implies that risk to developing dementia

cerebrovascular disorders, or reduce the burden ofafter stroke is strongly related to the presence of

VaD are implemented urgently. Subcortical ischaemic

vascular risk factors and VaD type of pathology. We

vascular dementia (SIVD) is the most prevalentalso found that cognitive processing speed andsubtype of VaD, where elderly exhibit disability andperformance on measures of attention weredeﬁcits in cognitive function over long periods of theirsigniﬁcantly associated with greater white matterremaining lives (2)(3). SIVD is primarily characterised

hyperintensities (WMH) volumes, particularly in theby cerebral small vessel disease (SVD), which isfrontal lobe regions and were worse in those withdescribed by a variety of pathologies including

hypertension (10).

lacunar infarcts, microinfarcts, microbleeds and white

presence of an APOE epsilon4 allele was associatedmatter (WM) lesions (4)(5)(6).

It is thought thatwith greater progression of cognitive decline in stroke

diﬀuse WM changes linked to SIVD largely result fromsurvivors. This also has implications for interventions

a chronic hypoperfusive state or cerebrovascular

aimed at the secondary prevention of dementia ininsufficiency during ageing (7)(8).

stroke patients (11).

While theWe further found that the

However, in clinical settings,

pathological mechanisms that lead to the progression

extensive treatment or control of vascular risk factorsof VCI because of SIVD or post-stroke patients whoin old age is essential to prevent or slow down thedevelop dementia remain unclear, it is urgent to target

progression of VCI and prevent VaD (3).

strategies, which restore or maintain brain perfusion.
In this article, we will review the latest ﬁndings

Small vessel disease (SVD) as an important target

regarding pathogenesis and potential novel

We note that cerebral SVD manifests in several

interventional strategies for VCI and VaD.

cortical and subcortical insults.

However,microvascular abnormalities are key to SVD.
Vascular risk factors (VRFs) and dementia

Microvascular changes including arteriolosclerosis,

It is now abundantly clear that reducing risk of

intimal thickening, ﬁbroid necrosis, hyalinization, andvascular disease reduces risk of cognitive impairment

enlarged perivascular spacing occurring during

or dementia. Several longitudinal studies suggest thatageing but these lesions are at their peak or mostthe strongest predictors for development of dementia

severe in VaD. These changes are also prominent inafter stroke was the presence of cardiovascular risk

post-stroke survivors, who develop dementia (PSD)

factors. In our large longitudinal prospective cohortand those who do not (PSND). While it is diﬃcult toof the Cognitive Function After Stroke (CogFAST)

diﬀerentiate the burden of these lesions between PSD

study (9) in elderly stroke survivors, who

and PSND, it is noteworthy that they both exhibit

predominantly had small infarcts or SVD type ofhigher total vascular pathology scores (12) comparedchanges, we found that during the mean follow-up

to normal ageing control subjects (13).

period of ~4 years, up to 25% of subjects developed

microvascular network, even capillaries are aﬀected

dementia after their ﬁrst episode of stroke.

particularly in the rareﬁed white matter (WM) in bothAt

13With theJAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Exploring Interventional Strategies for Vascular Dementia
PSD and VaD (14). Collapsed and string microvessels,or pharmacological approaches or combination of

microaneurysm-like structures and tortuous vessels

both would ameliorate SVD pathology and contributewere frequently observed in patients with PSD and

to prevent or slow down cognitive decline in patients

VaD. In terms of tissues changes, greater frontal WM

diagnosed with VaD and have features of autonomic

volumes separate post-stroke survivors who develop

dysfunction.

dementia or PSD versus those who remain stable

implicate that ischemic insults or chronic cerebral(PSND). Among post-stroke patients, we also noted

hypoperfusion cause or worsen ageing associated SVD

that the prevalence of microinfarcts was greater inand VaD.

Collectively, these ﬁndings strongly

PSD compared to PSND subjects, suggesting thepresence of cerebral microinfarcts is one of the

Loss of white matter integrity in VaD

predictors of dementia after stroke (9).

White matter hyperintensities (WMH), detected on

There is evidence that SVD pathology may also bebrain magnetic resonance imaging (MRI) of T2-

exacerbated by autonomic dysfunction. Our recent

weighted imaging (T2WI) and fluid-attenuation

study also revealed detrimental eﬀects of autonomic

inversion recovery (FLAIR) imaging, are associateddysfunction on severity of VaD and other dementias

with cognitive dysfunction in patients with SVD,

(13). At least 40% of dementia patients, including VaD

stroke and VaD (18), most probably due to loss ofpatients, exhibit some form of autonomic dysfunction

white matter integrity. In our longitudinal CogFAST

in life (15). The proposed mechanism of autonomic

cohort, volume of WMHs were associated with higher

dysfunction on vascular pathology is that recurrent

mortality rate, shorter time to dementia onset, andepisodic hypotension promotes chronic cerebral

were also an independent predictor of survival tohypoperfusion. This then causes ischaemic damage ordementia (19). These ﬁndings indicate that severity of

rarefaction of the WM, and eventually leads to

WMHs is related to loss of white matter integrity anddisconnection of the WM and impaired cognitive

impairment in functional connectivity within cortical-

function (16). In our study, autonomic dysfunction

subcortical circuits to instigate dementia and reduced

was associated with higher burden of SVD changes,

life expectancy after stroke.

particularly in the deep frontal WM in patients withage-related dementia including VaD (13).

The pathophysiological substrates of WMH are

Weheterogeneous (20). One of the key features of WMHemphasize the importance of screening autonomic

is loss of myelin rather than axonal degeneration. We

function for elderly dementia, especially VaD patients

have previously reported severe myelin loss in thein clinics. The most critical ﬁnding was that in somefrontal white matter of VaD patients compared tocases, autonomic dysfunction is likely ʻasymptomaticʼ

other types of age-related dementias (5), suggesting(17). Thus, there are dementia patients who have nodisruptions of frontal-subcortical circuits are more

apparent clinical symptoms of autonomic dysfunction

profound in VaD compared to other dementias (21).

e.g. repeated falls and syncope.

These individualsThis observation is consistent with ﬁnding from a

could be only proved to have dysautonomia by clinicalstudy showing decreased myelin proteins in the WM

examination.

However, ʻasymptomaticʼ autonomic

in SVD and VaD (22). Loss of oligodendrocytes asdysfunction also has the same adverse eﬀects onanother substrate of WMH (20) is frequently observed

cerebrovascular patholog y as symptomat ic

in SVD and VaD patients (23).

dysautonomia. Therefore, ʻasymptomaticʼ autonomic

Other substrates of WMH are inflammatory

dysfunction is also a risk to develop SVD and WM

changes, evident in form of gliosis including

damage, similar to symptomatic dysautonomia.

astrogliosis, causing gliovascular unit (GVU)

Treatments to improve autonomic dysfunction, evendysfunction and blood brain barrier (BBB) disruption

for preciously detected ʻasymptomatic autonomic(20). The GVU (Figure 1) controls and maintains thedysfunctionʼ cases, implementing lifestyle interventionfunctions of the BBB. The cellular components of the

14

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yoshiki Hase；Raj N Kalaria
GVU in the white matter (WM), consists of endothelial

showed that the opioid analgesic oxycodone

cell, pericyte, astrocyte, microglia andsuppressed detrimental reactive astrogliosis byoligodendrocyte (23).

inhibiting nuclear factor kappa-B (NF- κ B) signaling

In physiological conditions,these cells are interacting each other to maintainin reactive astrocytes (34).

brain homeostasis through BBB. Loss or damage of
microvascular, mural and glial cells caused by

A phenomenal morphological change in astrocytes

ischemic injury or chronic cerebral hypoperfusion

is described as clasmatodendrosis, a cluster ofresults in dysfunction of GVU (24) and increased BBB

damaged astrocytes (clasmatodendrocytes) withpermeability, which may promote diﬀuse WM changes

hypertrophic cell bodies and loss of or retracted

and cognit ive decline (25).

Cilostazol, aprocesses (35). We previously found the presence ofphosphodiesterase type Ⅲ inhibitor, restored BBB

severe clasmatodendrosis in the deep WM of post-

damage in an experimental stroke model in mice (26).

stroke survivors who developed dementia, and also

EE also showed protective eﬀect on BBB in a rat model

had greater WM hyperintensity (WMH) volumes (19).

of chronic cerebral hypoperfusion (27). Therefore,

Similar astrocytopathy was observed in patients withprotection of GVU or its cellular components,

hereditary cerebrovascular disease, cerebral

especially in the WM, would be a key strategy toautosomal dominant arteriopathy with subcorticalpreserve BBB and WM integrity, as well as to prevent

infarcts and leukoencephalopathy (CADASIL) (36).

subsequent strokes and cognitive decline.

CADASIL is also characterized by strategic WMH
detected on brain MRI. Therefore, clasmatodendrosis

Astrogliosis, clasmatodendrosis and disruption ofis one of the key pathophysiological markers of

GVU

progressing WM lesions.

In addition to

Astrocytes, one of the major cellular components ofclasmatodendrosis, abnormal distribution of AQP4,

the GVU, maintain brain homeostasis by interacting

characterised by aggregation of AQP4 at thewith blood vessels via astrocytic end-feet.

periphery of GFAP-positive astrocytes/

Perivascular end-feet of astrocytes have a critical roleclasmatodendrocytes, was evident in post-stroke

to regulate e.g. electrolytes, amino acids and water

survivors who developed dementia with greater WMH

homeostasis in brain (28). The water homeostasis incompared with age-matched normal control subjects

brain is regulated by water channel family aquaporins

(19).

(29).

Aquaporin-4 (AQP4) is present on astrocytic

clasmatodendrosis and AQP4 dislocation in VaD

end-feet surrounding small vessels in brain andpatients is caused by vascular changes, pathologicalexchanging water between vascular lumen and brain

alterations in GVU and BBB disruption.

parenchyma.

These observations strongly implicate that

AQP4 also play a role in pathologic

conditions, e.g. reduce oedema formation after

Animal model of small vessel disease (SVD) andcerebral ischemia (30).

vascular dementia (VaD)

Astrocytes are sensitive to various stimuli and

For the past decades, experimental animal models

transform to reactive cells as activated astrogliosis,

of cerebral hypoperfusion (37), which restrict cerebral

often observed in response to ischaemic insults (31).

blood ﬂow by occluding or narrowing cervical andPrevious reports suggest that reactive astrocytes

cerebral arteries, have been extensively analysed incaused elevated reactive oxygen species (ROS) andmice (38), (39), (40), rats (41), (42), (43), (44), (45),induced cellular inﬂammation (32), which progresses(46), gerbils (47), as well as non-human primates (19),to more widespread brain injury (33).

Therefore,

aiming to elucidate the pathological mechanisms oftargeting of astrocytes which may return reactive

developing SVD and VaD. In addition to these models,

astrocytes to a quiescent phenotype (31) would

bilateral common carotid artery stenosis (BCAS) in

represent a therapeutic target for VaD. Recent reportmice, as a mouse model of chronic cerebral

15

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Exploring Interventional Strategies for Vascular Dementia
hypoperfusion, has been established (48), (49). BCAS

were attenuated by EE more eﬀectively by limited

mouse model exhibited BBB dysfunction (50), changes

exposure to EE (only 3 hours a day) rather than full-in glial cells such as: loss of oligodendrocytes,

time (24 hours a day) exposure to EE.

astrogliosis and microglial proliferation, particularly

especially limited amount of EE and physical exercise

in the WM, as well as hippocampal pathology (51). As

training, appears a safe and eﬀective interventional

BCAS model characterises similar cerebrovascular

strategy for VaD patients with extensive WM

pathologies to human VaD patients, it has been widely

pathology.

used and has been accepted as one of the most usefulThus EE,

Physical activity or exercise has been shown as arodent models of VaD (52), (53), (54).

strategy to slow down cognitive impairment in
humans with VCI (66).

Previous experimental

Bilateral common carotid artery stenosis (BCAS)

evidence a rat mo del of chronic cerebral

mouse model to explore potential treatments andhypoperfusion showed that environment-induced

interventions

physical exercise and cognitive stimulation as well as

The BCAS mouse model has been very useful tosocial interactions, which are incorporated in EE anduncover pleiotropic eﬀects of pharmacological agents,

physical exercise training, exhibit beneﬁcial eﬀects onrole of genes and cell therapy against SVD and VaD.

cognitive dysfunction (27), (67), (68). These studies

For example, BCAS has been utilised to evaluate

reported that EE preserved BBB integrity, increased

efficacies of an anti-platelet agent cilostazol,

brain plasticity, enhanced neurogenesis, and increased

phosphodiesterase type 3 (PDE3) inhibitor (55), (56);synaptogenesis. Furthermore, combination of EE andanti-hypertensive drug: telmisartan, an angiotensin Ⅱ

physical exercise enhanced neurogenesis (69) andtype 1 receptor blocker (57); an antibiotic agent:

upregulation of genetic expressions associated withminocycline, tetracycline (58); an angiogenic peptide:

neurogenesis, synaptic plasticity, neuroprotection andadrenomedullin (59); a gene silencer: silent

intact memory function (70), resulted in preserved

information regulator 2 homolog 1 (SIRT1) (60), (61)cognitive function (71). EE also has been reported toand bone marrow derived mononuclear cells (62). All

have favourable eﬀects on motor function recoveryof these compounds and agents showed protective

after experimental stroke (72), (73).

eﬀects on cerebrovascular pathologies, WM changes

even moderate physical exercise training could be

and cognitive decline induced by BCAS, suggestingsafely and consistently encouraged in man andthese are promising interventional strategies totherefore an effective interventional strategy forameliorate VaD pathologies. Notably, a recent study

patients with SVD, VaD and stroke.

Thus, EE andproved that cilostazol, a phosphodiesterase type 3

Our research group has also successfully replicated(PDE3) inhibitor, slowed down cognitive decline inastrocytopathy, including reactive astrocytes andpatients with mild cognitive impairment (63), and has

clasmatodendrosis with aberrant distribution of AQP4,

been successfully applied for a prospective multi-

similar to VaD patients in the BCAS model (74) as wellcenter clinical trial (64).

as in a non-human primate model of cerebral

Our past studies have also successfully reproduced

hypoperfusion (19). Long-term BCAS in mice caused

WM changes similar to VCI and VaD patients in theastrog liosis, clasmato dendrosis w ith AQP4

long-term version of the BCAS model (65).

dysfunction in the WM.

We

AQP4 dislocation andexplored the effects of differing degrees ofclasmatodendrosis may enhance WM pathology due

environmental enrichment (EE) on WM pathologicalto the disturbance of water homeostasis. We foundchanges.

Long-term BCAS in mice caused WM

that limited regime of EE not only reduced

damage characterised by WM atrophy, WM

astrocytopathy but ameliorated other aspects of GVU

disintegration and loss of oligodendrocytes, resultedfunctions (74).

in cognitive dysfunction. These unfavourable changes

clasmatodendrosis, would be a new aspect to explore

16

Thus, glial responses, especially

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yoshiki Hase；Raj N Kalaria
pathogenesis and establish novel treatment for VaD.

and likely to impact on processes involved in other

This suggests limited exposure to EE preserves BBB

ageing-related dementias.

function via maintenance of GVU integrity.

Wesurmise that long-term BCAS is a relatively reliable

Conﬂict of interest

model of VaD, which accurately replicates several

The authors declare no conﬂict of interestfeatures of the pathophysiology of WM changes asevident in VaD patients. EE, especially limited amountAcknowledgementof EE and physical exercise training, appears a safe

We are grateful to the patients, families, and clinicaland eﬀective interventional strategy to attenuate

house staﬀ for their cooperation in the investigation

unfavourable eﬀects of cerebral hypoperfusion andof this study. We also appreciate the cooperation ofslow down subsequent cognitive decline in VaD.

the Newcastle Brain Tissue Resource (NBTR) directors
and staﬀ in assisting us with this study.

Conclusions

We arethankful to Janet Slade and Arthur Oakley for theWe have reviewed pertinent ﬁndings regarding theexpert technical assistance and for assisting us inpathogenesis of VaD and its potential therapeutic

managing and screening the cohort.

targets. Gliovascular disruption caused by ischemic

thank Neil Hamilton and Sandra Hogg for excellent

insults or chronic cerebral hypoperfusion has beentechnical assistance with respect to the daily care ofsuggested to play critical role to develop VaD

mice and animal husbandry.

pathology in brain.

We specially

Therefore, each component of

GVU would be a therapeutic target for VaD. Firstly,

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cerebral vascular disease. Glia. 2018 Jan

pathogenesis of white matter lesions after

1;66(1):34‒46.
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vasoprotective eﬀects of adrenomedullin on

Nishio K, Ihara M, Yamasaki N, et al. A mouseprevention of cognitive decline after chronicmodel characterizing features of vascular

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Shibata M, Ohtani R, Ihara M, et al. White mattermouse model of chronic cerebral hypoperfusion.
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memory. J Cereb Blood Flow Metab. 2016 Sep

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2012;33(5):1012.e25-1012.e35.

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the rat brain. Acta Neuropathol. 2004

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60.

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Ihara M, Tomimoto H. Lessons from a mouse

information regulator 2 homolog 1 countersmodel characterizing features of vascular

cerebral hypoperfusion injury by deacetylating

cognitive impairment with white matterendothelial nitric oxide synthase. Stroke.

changes. Vol. 2011, Journal of Aging Research.

2014;45(11):3403‒11.

20

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yoshiki Hase；Raj N Kalaria
61.

Hattori Y, Okamoto Y, Nagatsuka K, et al. SIRT1

impairments caused by reduced adultattenuates severe ischemic damage by

neurogenesis. Hippocampus. 2017 Jan

preserving cerebral blood ﬂow. Neuroreport.

1;27(1):36‒51.

2015;26(3):113‒7.
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environmental enrichment on gene expression

effect of bone marrow mononuclear cells

in the brain. Proc Natl Acad Sci U S A. 2000 Nov

against ischemic white matter damage through7;97(23):12880‒4.

augmentation of cerebral blood ﬂow. Stroke.
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71.

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method to improve cognitive function. What can

Ihara M, Nishino M, Taguchi A, et al. Cilostazol

we learn from animal models? Neuroimage.

add-on therapy in patients with mild dementia

2016 May 1;131:42‒7.
72.

Environmental enrichment during the chronic

Saito S, Kojima S, Oishi N, et al. A multicenter,

phase after experimental stroke promotes

randomized, placebo-controlled trial for

functional recovery without synergistic eﬀects

cilostazol in patients with mild cognitiveof EphA4 targeted therapy. Hum Mol Genet

impairment: The COMCID study protocol.

[Internet]. 2019 Dec 9 [cited 2019 Dec

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hypoperfusion. J Cereb Blood Flow Metab. 2018

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21

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Exploring Interventional Strategies for Vascular Dementia

Figure 1. Schematic diagram of major cellular components of the gliovascular unit (GVU).
The GVU comprised of various cellular components, plays a critical role to control andmaintain functions of the blood brain barrier (BBB). Abbreviations;
AQP4, Aquaporin-4; BM, basement membrane.

Figure 2. Outline of multimodal combination therapy for vascular dementia (VaD).
Each component in both pharmacological and non-pharmacological approaches has been proposed
to have protective eﬀects on gliovascular unit (GVU) and eventually counter VaD. Abbreviations; ARB,
angiotensin Ⅱ receptor blocker; BMMNCs, bone marrow derived mononuclear cells; GVU, gliovascular unit;
PDE3 inhibitor, phosphodiesterase type Ⅲ inhibitor; SIRT1, silent information regulator 2 homolog 1;
VaD, vascular dementia.

22

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yosuke Osakada, et al.
Case report

Delayed Serial Microvascular Injury and Cognitive
Decline After Whole Brain Irradiation
Yosuke Osakada, MD；Toru Yamashita, MD, PhD；
Ken Ikegami, MD；Yuko Kawahara, MD, PhD；
Yoshio Omote, MD, PhD；Nozomi Hishikawa, MD, PhD；
Mami Takemoto, MD, PhD；Yasuyuki Ohta, MD, PhD；
Koji Abe, MD, PhD
Department of Neurology, Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University
Short title: Microvascular injury after whole brain irradiation
Conﬂict of interest: The authors state that they have no conﬂicts of interest.
Abstract
An 11-year-old girl underwent craniotomy for suprasellar germinoma. Thereafter, whole brain irradiation (50Gy) was performed. Her cognitive decline progressed from the age of 35. Brain computed tomography indicatedthat calciﬁcation began in the basal ganglia (at the age of 25), followed by the cerebellar dentate nucleus (at theage of 34) and the cerebral cortex (at the age of 43). A late delayed complication of whole brain irradiation
against a brain tumor induced microvascular injury and cognitive decline. The present case showed serial brain
calciﬁcation, which may be related to the progress of microvascular injury after whole brain irradiation.
Corresponding author: Prof. Koji Abe
Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmacy, 2-5-1
Shikata-cho, Okayama 700-8558, Japan.
Tel: +81-86-235-7365; Fax: +81-86-235-7368; E-mail: p5ag1b09@okayama-u.ac.jp

Case

Introduction
Recent advances in brain surgery and drug therapy

An 11-year-old girl was diagnosed as having a1

have improved life prognosis of brain tumor patients .

suprasellar germinoma. After undergoing partial

However, surviving patients sometimes show delayed

craniotomy, whole brain irradiation (50 Gy) was

irradiation-induced brain injury, and its pathology is

performed. After these therapies, the tumor shrank,

still unknown and there are few long-term follow-up

and hormonal supplement therapy was administeredcase reports. Late delayed complication of irradiation

to her as an outpatient. Since her intellectual

therapy against brain tumor induces intracranial

performance and learning ability were lower thancalcification, cerebral infarction, microbleeds andnormal, her last level of education was at the junior2

cognitive decline . Here we report a brain tumor casehigh school level. Later, she started working at the age

with delayed brain injury after whole brain irradiationof 28. At the age of 30, she obtained her driverʼsthat was followed up with a computed tomographylicense. However, disabilities in daily life appeared(CT) scan over 18 years.

through memory loss and reduced attention, andtherefore she stopped working at the age of 35. At the23

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Delayed Serial Microvascular Injury and Cognitive Decline After Whole Brain Irradiation
age of 39, she caused a car accident, andganglia, followed by the cerebellar dentate nucleus

subsequently gave up her driverʼs license at the age ofand the cerebral cortex. Radiation therapy sometimes

41. At the age of 43, she was referred to our hospitalcauses necrosis of small vessels such as arterioles,

because of abnormal brain imaging (Fig. 1).

veins, and capillaries 7, leading to microscopic

Upon admission to our hospital, she showed

vasculitis, ﬁbrosis, hyalinization, and calciﬁcation8.

hypopituitarism, diabetes, hypertension and a non-Thus, the serial calciﬁcation found in the present casealcoholic fatty liver. Her cognitive function declined to

may be related to the progress of microvascular injury

23/30 in the total score of the mini-mental state

after whole brain irradiation over time.

examination (MMSE), but she showed no other

Irradiation-induced brain injury was described inneurological abnormalities. Brain CT revealed bilateral

acute (days to weeks), early delayed (1-6 months), andand symmetrical calciﬁcation of the basal ganglia andlate delayed ( ＞ 6 months) phase9. Acute and early

infarction of the left frontal lobe, at the age of 25 (14delayed injuries such as cerebral edema or transient

years after irradiation). Calciﬁcation appeared in thedemyelination are basically reversible. On the otherdentate nucleus at the age of 34 (23 years after

hand, late delayed brain injury characterized byirradiation) and in the right frontal lobe at the age ofvascular abnormalities, demyelination, and ultimately

40 (29 years after irradiation) (Fig. 2A, arrows). From

white matter necrosis is essentially irreversible andthe age of 40, progressive cerebral atrophy became

progressive, eventually causing cognitive decline2.

evident (Fig. 2A).

Although a previous report showed cognitive decline

At the age of 43 (32 years after irradiation) a

12 years after whole brain irradiation (average age ofwhole-body CT scan did not show any calciﬁed45)1, the present case showed cognitive decline 24

lesions, except for the brain (Fig. 2B). Brain magnetic

years after irradiation (35 years of age).

resonance angiography (MRA) showed a narrowing

In summary, the present case showed serial brain

and irregularity of the middle cerebral artery (Fig. 2C,

calciﬁcation, which may be related to the progress ofarrows), ﬂuid attenuated inversion recovery (FLAIR)

microvascular injury after whole brain irradiation.

showed an old infarction and white matter lesion (Fig.

Cognitive decline was caused by cerebrovascular

2D, arrows), and T2* showed micro bleeds in the leftdisorder in the late stage of radiation-induced latefrontal lobe and cerebellar dentate nucleus (Fig. 2D,

delayed injury.

arrowheads). An electroencephalogram (EEG) had
Acknowledgments

already showed slowing of background activity at theWe appreciate the cooperation of the patient. Thisage of 37 (Fig. 2E).

work was partly supported by the Okayama
Prefecture Intractable Disease Medical Council, aDiscussion
The present case showed characteristic imaging

Grant-in-Aid for Scientiﬁc Research (B) 17H0419619,

ﬁndings such as intracranial calciﬁcation, cerebral(C) 15K0931607, 17H0419619 and 17K1082709,

infarction, microbleeds and cerebral atrophy (Fig. A,

and Grants-in-Aid from the Research Committees (Kaji

3-6

D). Compared to previous reports (Table 1) , theseR, Toba K, and Tsuji S) from the Japan Agency forpathological ﬁndings were followed up with a CT scan

Medical Research and Development (AMED)

over a longer period of time (18 years). As the present

7211700176, 7211700180 and 7211700095.

case had no systemic diseases or vascular risk factorsthat caused calciﬁcation except for well-controlled

Reference

hypertension and diabetes, the present imaging

1.

Douw L, Klein M, Fagel S, et al. Cognitive andﬁndings (Fig. A, C, D) may have been caused by wholeradiological eﬀects of radiotherapy in patientsbrain irradiation.

with low-grade glioma: long-term follow-up. The

In the present case, calciﬁcation began in the basal

Lancet Neurology 2009; 8: 810-818.

24

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Yosuke Osakada, et al.
2.

3.

Greene-Schloesser D, Robbins M, Peiﬀer A, et al.

7.

Radiation-induced brain injury: A review. Front

distribution of vascular endothelial growth factor-

Oncol 2012; 2: 73.

producing cells in clinical radiation necrosis of

Suzuki S, Nishio S, Takata K, et al. Radiation-

the brain: pathological consideration of theirinduced brain calcification: paradoxical highpotential roles. J Neurooncol 2011; 105: 423-

signal intensity in T1 weighted MR images. Acta

431.

Neurochir (Wien) 2000; 142: 801-804.
4.

8.

6.

Pantoni. Cerebral small vessel disease: From

Shobha N, Smith E, Demchuk A, et al. Small vessel

pathogenesis and clinical characteristics toinfarcts and microbleeds associated withtherapeutic challenges. The Lancet Neurology

radiation exposure. Can J Neurol Sci 2009; 36:

2010; 9: 689-701.

376-378.
5.

Nonoguchi N, Miyatake S, Fukumoto M, et al. The

9.

Toﬁlon, Philip J, John R, et al. The Radioresponse

Miura M, Nakajima M, Fujimoto A, et al. Smallof the Central Nervous System: A Dynamic

vessel disease associated with cranial irradiation.

Process. Radiation Research 2000; 153(4): 357-

Rinsho Shinkeigaku 2015; 55: 743-747.

370.

Andrea C, Fuchsia H, Alan N, et al. A CrossSectional Cohort Study of Cerebrovascular
Disease and Late Eﬀects After Radiation Therapy
for Craniopharyngioma. Pediatr Blood Cancer
2016; 63: 786-793.

Table 1: clinical characteristics of patients with radiation-related brain injury
Brain tumornAge ofirradiation(y.o.)

Age of image
evaluation (y.o.)Irradiation dose

Clinical symptom

Image abnormality

LesionSuzuki et al. [2]suprasellar germinoma

3

11

21

63 Gy

mental retardation

calcificationbasal ganglia, brain stem

Nandavar et al. [3]glioma (pons)

137

right facial weakness,dysarthria, righthemiparesis, headache

infarction, thalamic
hemorrhage, microbleeds

basal ganglia, brain stem,
temporal lobe,
periventricularAndrea et al. [4]craniopharyngioma

20

10

cognitive dysfunction

infarction, hemorrhage

basal ganglia, brain stem

Miura et al. [5]suprasellar germinoma

2

17

hemiparesis, dysarthria

infarction, microbleeds

basal ganglia

Present casesuprasellar germinoma

111mental retardation,
cognitive dysfunction

calcification, infarction,
microbleeds, brain atrophybasal ganglia, dentate
nucleus, deep white matter

avg.

avg.

51

avg.

avg.

36

36

avg.

50 Gy

avg.

avg.

25, 34, 37,
40, 43

50 Gy

50 Gy

50 Gy

25

avg.

avg.

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Delayed Serial Microvascular Injury and Cognitive Decline After Whole Brain Irradiation
operation + radiation (total; 50 Gy)
give up driver’s license
junior high school (last level of education)
car accident
stop working
obtain driver’s license
15

11

20

25

30

35

33

37

39

41

(y.o.)
43

EEG

BB
brain calcification
strokebleeding
brain atrophy
cognitive dysfunction
Figure 1: Life history and clinical features
Chronology shows the patientʼs life history after irradiation therapy. A brain CT was performedat the ages of 25, 34, 37, 40 and 43 (arrows), and EEG was performed at the age of 37 (arrowhead).

CT

25 y.o.

34 y.o.

37 y.o.

40 y.o.

43 y.o.

CT

MRA

B
FLAIR

C

L

R

T2*

D

A

E

background activity; 6-8c/z
unipolar, sensitivity 10 ȝVtime constant 0.3 shigh frequency filter 60 Hz

Figure 2
Figure 2:A) A brain CT revealed calciﬁcation of basal ganglia and infarction of the left frontal lobe at the age of 25, cerebellar dentate
nucleus at the age of 34, and of the right frontal lobe at the age of 40.
B) No calciﬁcation was observed in a whole-body CT.
C) MRA showed narrowing and irregularity of bilateral MCA.
D) FLAIR showed an old infarction and white matter lesion (arrows), and T2* showed micro bleeds (arrowheads) in the left
frontal lobe and cerebellar dentate nucleus. E) An EEG showed slowing of background activity.

26

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

10th Year Anniversary Greetings from Vas-Cog Japan,
the Japanese Society for Vascular Cognitive Impairment
Ryuichi Morishita, MD, PhD
President: The Japanese Society for
Vascular Cognitive Impairment
Vas-Cog Japan, in its 10th year after being launched in
2010, has been developing quite considerably. The
society was ﬁrst established under the strong leadershipof former Presidents Prof. Ken Nagata and Pro. Koji Abe,aiming to promote both basic and clinical research on
vascular cognitive impairment and other relateddiseases. I took over the society last year as the thirdpresident from 2018. I would like to express my sincere
gratitude to all members of VasCog Japan for your kindcooperation, assistance, and friendship.
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. Asof March 2020, we have 174 active members from 143
in last year, including 26 directors and 59 councilors,
and the membership is expected to increase in the
future. Furthermore, the ﬁnancial structure has been
going very well year by year. I sincerely thank themembers, councilors, and directors who have supported
this society for all these achievements. As our society has
already met the requirements to be registered as an
academic organization in the Science Council of Japan
with regard to the number of members, membershipmanagement, and publication of journals, the Chairman
for the Promotion of Becoming a Society, Prof. Katsuya
Urakami, has been working on our application forregistration. Under the guidance of Prof. Yoshio Ikeda,
the Chairman of Financial Affairs, we have been
continuing to strengthen the financial structure.
Regarding conflicts of interest, we set up a COI
committee and prepare provisions under the direction of
the Chairman, Prof. Masahiko Suzuki.
We have been publishing an annual newsletter since2014. The newsletter has been widely distributed torelated academic societies in various countries and iswell accepted, thanks to the hard work of former
President Prof. Koji Abe. Due to the eﬀorts of the Chief
Editor of the academic magazine, Prof. Mikio Shoji, it hasdeveloped into Vas-Cog Journal, a joint publication with
Vas-Cog Asia. We will continuously improve the journalʼsstyle and strengthen its content.

The 10th Annual Meeting of Vas-Cog Japan was
successfully held August 3, 2019, at “Sola City
Conference Center” in Tokyo, organized by chairpersons
Prof. Yoshio Ikeda and Prof. Masahiro Akishita. I express
our sincere gratitude, on behalf of all members of VasCog Japan, to the chairpersons for their strong
commitment to the success of the meeting. The 11th
annual meeting Vas-Cog Japan 2021 will be held on
September 11th and 12th, 2021 at Awa Kanko Hotel,
Tokushima, with Prof. Masataka Sata, Department of
Cardiovascular Medicine, Institute of Biomedical
Sciences, Tokushima University Graduate School andProf. Shunya Takizawa, Department of Neurology, Tokai
University School of Medicine, as the chairpersons. Ouraﬃliate VasCog Asia plays an increasingly signiﬁcantrole in the ﬁeld of vascular dementia research. Vas-Cog
Asia 8 was held in Manila on October 2, 2019, jointing
with Asia-Paciﬁc Stroke Conference (APSC). Next VasCog Asia 9 is going to be held in Seoul on September 11(2020) under direction of our President Tsong-Hai Lee(Taipei) and Secretary General Toru Yamashita(Okayama). Next Vas-Cog World will be held in
Newcastle upon Tyne on September 9-12.
We are also pleased to announce that Osaka wasselected to hold the World Expo in 2025, under thetheme “Designing Future Society for Our Lives”. As thegovernment 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 related diseases will be increasingly
important in the aging society.
Vas-Cog Japan, a unique academic society covering awide variety of interdisciplinary fields, such as
cardiology, neurology, and brain surgery, will continue towork on basic and clinical research to elucidate thepathogenesis of vascular dementia and its role in othertypes of dementia and look for more eﬀective treatment
and prevention. We look forward to the participation ofmany of you in our exciting academic society.
March 10, 2020

27

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Reports of the Vas-Cog Japan 2019
Masahiro Akishita MD, PhD
Department of Geriatric Medicine, Faculty of Medicine,
The University of Tokyo
VAS-Cog Japan2019 was held on August 3, 2019 atafter a stroke. After more than two months, thethe Ochanomizu Sola City Conference Center (Tokyo).

training course was approved for the credit for the

The main theme of the meeting was “Crosstalk ofﬁrst time in Vas-Cog meetings. Despite the limited

vascular factors and neurodegeneration”. The newtime for announcement, many of both members andresearch results on AMPA receptors were given by

non-members of the Society participated in theProf. Takuya Takahashi from Yokohama City

session.

University. Two educational lectures were held;

We were pleased with many submissions for The“Diﬀerential diagnosis of Alzheimerʼs disease andYoung Investors Awards (YIA). Dr. Naoki Saji (National

Depression” by Prof. Masasru Mimura, Keio University

Center for Geriatrics and Gerontology), Dr. Naoto

School of Medicine, and “Basic and Clinical Topics ofTakenoshita (Tokyo Medical University), and Dr.

Cerebrovascular Disorders” by Prof. Toshiki Mizuno,

Yorito Hattori (Weill Cornell Medicine) were

Kyoto Prefectural University of Medicine.

nominated. All presentations of the three nominees
were excellent, therefore all three of them were

The joint symposium with the Japanese Society ofawarded at the banquet.

Geriatric Pharmacy (JSGP), “For the Collaboration
between Physicians and Pharmacists in Dementia

Our compact meeting held in one day, provided

Treatment” was held. I, Akishita talked about

many participants with opportunities for discussion.

polypharmacy and drug-based dementia, Prof. Naomi

The enthusiasm lasted till the banquet, where

Kurata (Showa University) gave a lecture on

participants enjoyed food and rice wine from Gumma

medication support and Prof. Yusuke Suzuki (Nagoya

Prefecture and a view of Ochanomizu Nikolai-do

University) talked about inter-o ccupat ional

Cathedral. We would like to thank Prof. Yoshio Ikeda

collaboration in dementia care. About 18 pharmacists

and members of Gumma University for theparticipated in the symposium.

cooperation for the meeting. Thanks to all of you, I

Industrial physician qualiﬁcation renewal training

would like to express my gratitude for the success of(two credits of specialized training) certiﬁed by The

Vas-Cog 2019 and looking forward to seeing you

Japan Medical Association was held to provide

again in the next Vas-Cog Japan meeting in

training for juvenile dementia and returning to work

Tokushima.

28

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Reports of the Vas-Cog Japan 2019
Yoshio Ikeda, MD, PhD
Department of Neurology, Gunma University
Graduate School of Medicine
The 10th annual meeting of the Japanese society for

The special lecture was given by Prof. Takuya

vascular cognitive impairment (Vas-Cog Japan 2019)

Takahashi from Yokohama City University, regardingrd

was held on August 3 , 2019 (Saturday) at thesynaptic plasticity and the AMPA receptor imaging. In

Ochanomizu Sola City Conference Center, Tokyo. We

addition, general presentations (15 platform and 24

would like to express our deep appreciation for yourposter), special symposiums and seminars, and a joint

participation and support. This yearʼs meeting could

symposium with the Japanese society of geriatrichave a big success with a total of 201 participants.

pharmacy, which aims to promote cooperation among

Our society is characterized by academic activities

healthcare professionals, were organized with a lot of

to investigate various vascular factors that are closely

discussions. As a new event introduced into this yearʼs

related to the pathogenesis of dementia. With the aim

meeting, the workshops for the occupational healthof establishing treatments to suppress or improve thephysicians were also conducted.

onset and progression of dementia, we prepared

Finally, we thank all participants for your great

various scientific evens that will be useful forcontributions, and hope to meet you again in the Vas-

participantsʼ future clinical/academic activities.

Cog Japan 2021 meeting.

The main theme of the meeting is “Crosstalk
between vascular factors and neurodegeneration”, inwhich we are focusing on the close relationshipbetween the vascular factors and the pathogenesis
leading to neuronal degeneration causing dementia.

29

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Welcome to Vas-Cog Japan 2021

Department of Cardiovascular Medicine
Institute of Biomedical Sciences
Tokushima University Graduate School

Department of Neurology
Tokai University School of Medicine,

Masataka Sata

Shunya Takizawa

It is our great honor to welcome you to the 11th
annual meeting of the Japanese Society for Vascular
Cognitive Impairment (Vas-Cog Japan 2021). This
yearʼs meeting will be held on September 11th and12th, 2021 at Awa Kanko Hotel, Tokushima. Thisscientiﬁc meeting has been held in August annually.
Because we will have Tokyo Olympic and Paralympic
2021 in the summer of next year, we decided toorganize this meeting in September in Tokushima tosecure transportations and accommodations of theattendees.
Accumulating evidence suggests that life-style
related diseases, such as hypertension, diabetes, anddyslipidemia, are risk factors not only for
cardiovascular diseases but also for dementia. Thus, itwould be fascinating opportunity for the expert
researchers in atherosclerosis and dementia tocommunicate each other to understand recent
advances in both areas. The main theme of themeeting is “Dementia practice from vascular andneurological medicine”. We are focusing on the close
relationship between the vascular diseases and thepathogenesis of neuronal degeneration causing
dementia. The special lectures will be given by Prof.
Takayoshi Shimohata from Gifu University and Prof.
Tomoya Yamashita from Kobe University. Educational
lectures will be given by Prof. Koji Abe from Okayama
University and Prof. Yuishin Izumi from Tokushima
University. We are organizing three symposia“Frontiers in researches in cerebrovascular blood ﬂow
and metabolism related to vascular dementia,”“Dementia and cardiovascular diseases” and“Protective and exacerbating factors in vasculardementia.” We are planning two special symposia
organized by young investigators from vascular andneurological medicine.

The venue is very convenient locating near
Tokushima station. We are expecting many doctors
and researchers on neurology, geriatric medicine,cardiology, metabolic diseases and pharmacology toattend the meeting. Especially, we encourage young
researchers to present at the meeting. At Sept 11th
(Saturday) night, we are planning a reception party,
where you can experience the traditional dance, Awa
dancing. After the meeting, you can enjoy various
delicious foods of Tokushima, such as Awa-beef, Awachicken (Awa-O-Dori), Naruto-red snapper (NarutoDai) and Tokushima-ramen. We are looking forward toseeing you at Vas-Cog Japan 2021 in Tokushima!

30

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Meeting report of Vas-Cog Asia 8 from Manila
Koji Abe, MD, PhD
former Vas-Cog Asia President

I would like to celebrate the great success of Vas-

Vas-Cog Asia society is an independent society with

Cog Asia 8, which was held in Manila on October 2

24 directors from most Asian countries and many

afternoon (2019) always jointing with Asia-Paciﬁc

active members, which is dedicated to elucidate theStroke Conference (APSC) based on the great supports

mechanism of vascular factors in Alzheimerʼs disease

by Professor Maria Cristina San Jose (APSC2019

and related dementia, and to contribute potential

chair) and Professors Jose Navarro and Simeon

therapy for dementia people in Asia. Many vascular

Marasigan (Host of Vas-Cog Asia 8, Manila). Based onrisk factors (VRFs) are related to cognitive decline andthe strong support of Vas-Cog Philippines which justaffective-emotional changes in dementia patientslaunched this February, we welcomed 88 participants

especially in elder or eldering countries in Asia.

from Manila, Japan, Taiwan, Indonesia, China, Hong

Next Vas-Cog Asia 9 is going to be held in Seoul on

Kong, Malaysia, Singapore and India. There were

September 11 (2020) under direction of our President

variety of important presentations in the present

Tsong-Hai Lee (Taipei) and Secretary General Toru

conference. Many basic science, translational

Yamashita (Okayama). Next Vas-Cg World will be held

research, clinical trials and evidence were discussed

in Newcastle upon Tyne on September 9-12. All of you

especially on the aspects of Alzheimerʼs disease (AD),are welcome to actively join these forthcoming Vas-

vascular dementia (VD), behavioral and psychiatricCog meetings to present and discuss on vascularsymptoms of dementia (BPSD), and their importantfactors of all type dementia.

vascular involvement.

KS Tan(Malaysia)

December 5, 2019

Xin
Jang
(China)(China)Jessica(Indonesia)

Ramani(Singapore)

TH LeeMehndiratta
Marasigan
CJ Hu(Taiwan)(India)(Philippines)hilipppinees)
s))
pp
n))
((T
T an)
an
(Taiwan)OngO
Abe
Senanarong
S
Amelia(Indonesia)
Navarro(Japan)(Indonesia)(Thailand)(Philippines)

31

Yamashita(Japan)JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Reports of Vas-Cog Japan Council Meeting
Yoshio Ikeda, MD, PhD
Department of Neurology, Gunma University
Graduate School of Medicine
The 11th board and council meeting of the

5. It is also reported that submission of more

Japanese Society for Vascular Cognitive Impairment

original papers and advertising recruitment should

was held together with 21 board members, 2 auditors

be promoted.

and 27 councilors at the Hall WEST of the* The leader of board for COI, Dr. Masahiko Suzuki,

Ochanomizu Sola City Conference Center, Tokyo, on

reported that the detailed regulations of thethe 3rd of August, 2019. The representative director

Common Guidelines for Conﬂicts of Interest inand committee members reported the topics shown

Clinical Research were established on the 4th of

below and all proceedings were approved byAugust, 2018, and administered on the 1st of April,

members.

2020. Requirement of the registration number of
ethics committee approval was considered for［Membership］

submission of general presentations at the annual

169 regular members (As of July 30, 2019)

meeting.
* The leader of board for ﬁnance, Dr. Yoshio Ikeda,［Report from each committee leader］

reported the necessity to increase the members who* The leader of board for academic organization

paid the annual membership fee. Analysis of thepromotion, Dr. Katsuya Urakami, discussed theﬁnancial balance found that last yearʼs balance hadnecessity to increase the members who paid thea deﬁcit if there is no donation from the last annual

annual membership fee, and to increase a chance tomeeting oﬃce. Both auditors, Drs. Shimamura andpublish an original paper written by Japanese in the

Matsumura reported in the audit report that the

Vas-Cog Journal. It is also discussed that an oﬀer toaccounting was properly conducted.

give a credit for certificate renewal of othersocieties would be desired to increase the number［Plans for future meetings］
thth
1. The 11th Meeting (11 and 12 of September, 2021)

of participants at the annual meeting.

Awa Kanko Hotel in Tokushima* The leader of board for increasing membership andChairmen: Dr. Shunya Takizawa and Dr. Masataka Satapublic relations, Dr. Haruo Hanyu, discussed the

2. Refer to the last page for subsequent schedules.

necessity to increase the number of supporting
members and sponsored companies for banneradvertisement on the homepage of the Vas-Cog［Retirement rule for board members and councilors］

Japan website. Board members were requested to

In order to activate the society, the rule that all

cooperate to distribute a letter of intent to theboard members and councilors have to retire at thepotential sponsored companies.

age of 65 has been established.

* The chief editor of the academic magazine, Dr. Mikio
Shoji, reported that “Submission Instructions for［Report of new board members / councilors］

authors” was published on the homepage of the* indicates board member or councilor.

Vas-Cog Japan website, and all content will be
published in English from the Vas-Cog Journal No.

32

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）[Name list]● Executive Advisor
Hiroshi Mori(Nagaoka Sutoku University)● President● Executive Directors (General Aﬀairs)

Ryuichi Morishita (Osaka University)

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

Kazuma Sugie*(Nara Medical University School of Medicine)

Masafumi Ihara*(National Cerebral and Cardiovascular Center)

Masahiko Suzuki(The Jikei University School of Medicine)

Atsushi Iwata* (The University of Tokyo)

Shunya Takizawa (Tokai University)

Katsuya Urakami (Tottori University)

Hidekazu Tomimoto (Mie University)

Kenjiro Ono*(Showa University School of Medicine)

Yukihito Higashi* (Hiroshima University)

Kazuo Kitagawa(Tokyo Womenʼs Medical University)

Miyuki Matsumura(Institute of Geriatrics
Tokyo Womenʼs Medical University)

Masahiro Akishita (The University of Tokyo)

Etsuro Matsubara (Oita University)

Koichi Kozaki (Kyorin University)

Toshiki Mizuno(Kyoto Prefectural University of Medicine)

Issei Komuro (The University of Tokyo)
Masataka Sata (Tokushima University)

Shokei Mitsuyama (Kumamoto University)

Munehisa Shimamura (Osaka University)

Masaru Mimura (Keio University)

Takayoshi Shimohata*(Gifu University Graduate School of Medicine)

Masaki Mogi* (Ehime University)
Masahito Yamada (Kanazawa University)

Ken Shinmura* (Hyogo College of Medicine)● Auditors

Shuko Takeda* (Osaka University)

Yumi Kameyama* (The University of Tokyo)

33

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）● Councilors
Hitoshi Aizawa (Tokyo Medical University)

Kentarou Deguchi (Okayama City Hospital)

Yasuhiro Aso (Oita University Hospital)

Hiroo Terashi (Tokyo Medical University)

Satoshi Abe (Shimane University Hospital)

Yasuo Terayama (Shonan Keiiku Hospital)

Masaki Ikeda (Gunma University Hospital)

Takashi Tokashiki (Okinawa National Hospital)
Takahiko Tokuda(Kyoto Prefectural University of Medicine)

Nobuyoshi Ishii (Oita University)
Hiroo Ichikawa (Fujigaoka Rehabilitation Hospital)

Kazuaki Nagashima (Gunma University)

Ryoko Imazeki (Tokai University)

Ken Nagata (Yokohama General Hospital)

Jun Iwanami (Ehime University)

Masao Nagayama (IUHW Atami Hospital)

Shinichiro Uchiyama (International University of
Health and Welfare)

Yu Hasegawa(School of Health Sciences at Fukuoka)

Yumiko Uchiyama(Tokyo Womenʼs Medical University)

Haruo Hanyu (Tokyo Medical University)

Takahiko Umahara(Mizuno Memorial Rehabilitation Hospital )Yasuto Higashi (Himeji Central Hospital)

Takao Urabe(Juntendo University Urayasu Hospital)

Toshiya Fukui (Kawasaki Memorial Hospital)

Yasuyuki Ohta (Okayama University)

Masatsugu Horiuchi (Hanwa Daini Senboku Hospital)

Sumito Ogawa (The University of Tokyo)

Kouki Makioka (Gunma University Hospital)

Haruhisa Kato (Tokyo Medical University)
Nobuya Kawabata (Yachiyo Hospital)

Yasuhiro Manabe(National Hospital Organization Okayama
Medical Center)

Noriyuki Kimura (Oita University)

Tohru Minamino (Niigata University)

Hitomi Kurinami (Osaka University)

Takafumi Miyachi (Yanai Medical Center)

Minoru Kouzuki (Tottori University)

Li-Juan Min (Ehime University)

Taro Kojima (The University of Tokyo)

Kazuhiro Muramatsu(Saiseikai Yokohamashi Tobu Hospital)

Nozomi Hishikawa (Okayama University)
Yukio Fujita (Gunma University)

Tatsushi Kamiya (Kamiya Clinic)

Hisatomo Kowa (Kobe University)

Kenichi Meguro (Tohoku University)

Masaki Kondo(Kyoto Prefectural University of Medicine)

Hideki Mochizuki (Osaka University)
Shuhei Yamaguchi(Shimane Prefecture Hospital Bureau)

Kenji Sakai (Kanazawa University Hospital)
Hirofumi Sakurai (Tokyo Medical University)

Takashi Yamazaki (Yokohama General Hospital)

Naoyuki Sato(Center for Development of Advanced Medicine
for Dementia)

Toru Yamashita (Okayama University Hospital)

Masayuki Satoh (Mie University)

Hiroshi Yoshizawa(Tokyo Womenʼs Medical University)

Soichiro Shimizu* (Tokyo Medical University)

Koji Wakayama (The University of Tokyo)

Mikio Shoji (Geriatrics Research Institute Hospital)

Yosuke Wakutani (Kurashiki Heisei Hospital)

Yoshiki Takao (Kurashiki Heisei Hospital)
Daiki Takano (Yokohama General Hospital)
Ayumi Takamura (Tottori University)
Yasushi Takeya (Osaka University)

34

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

A report from the Public Relations Committee
Haruo Hanyu
Department of Geriatric Medicine,Tokyo Medical University
The Increasing Members and Public Relations

In addition, we have three supporting companies,

Committee of the Japanese Society for Vascularincluding Eisai, Nippon Chemiphar, and Japan

Cognitive Impairment (Vas-Cog Japan) has been

Mediphysics. These supporters provide web pages

working to increase the number of general andpublishing advertisement banners. We hope that

supporting members and to announce activities of themany pharmaceutical and related companies will join

Society, such as annual meetings and the like.

our Society.

The members of this Committee consist of the
Chairman (Prof. Haruo Hanyu, Tokyo Medical
University) and four other members (Dr. Yumiko
Uchiyama, Tokyo Womenʼs Medical University
Yachiyo Medical Center; Dr. Masaki Kondo, Kyoto
Prefectural University of Medicine; Dr. Takashi
Yamazaki, Yokohama General Hospital; and Dr. Hiroshi
Yoshizawa, Tokyo Womenʼs Medical University).
The members increase steadily, and there are atpresent 174 active members, including 26 directors
and 59 councilors. Recently, several young
investigators have joined Vas-Cog Japan. Members are
expected to increase in the near future.

35

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

As the new leader of board for increasing
membership and public relations
Kazuo Kitagawa
Department of Neurology.
Tokyo Womenʼs Medical University
It is my honor to work for advertisement of Japanand puts information or poster of our annual meeting

Vas-Cog Society. Main topics of this society isin both domestic and international other conference

involvement of vascular component on cognitive

every year. It is important to let many people who are

decline and dementia. This aspect is very importantinterested in our topics join the society and attend the

because the number of cognitive impairment

meeting of this society. I would like all society

increases as the aging society progresses. People can

executives and members to join the activity of ourcommunicate not only with the same experts but

society.

researchers in other scientiﬁc ﬁeld. Former president
Prof. Abe and current president Prof Morishita haveactivated the level of this society for several years.
Next May, Professor Abe organized the joint meetingof Japan Neurology Society and Japan Vas-Cog Society
as the conference president of the 61st annual
meeting of Japan Neurology Society at Okayama.
Japan Vas-Cog society is expected to be widely known
to all members of Japan Neurology Society andparticipants, over 7000 people, to the conference. The
annual meeting of this society always focus on
attractive topics related to vascular involvement on
cognitive disease. The society publishes a newsletter

36

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

As an editor of journal of VASCOG-J
Toshiki Mizuno
Department of Neurology,
Kyoto Prefectural University of Medicine
It is my honor to work as an editor for VASCOG-J

disease contributes to clinical cognitive impairment as

journal. Vascular dementia (VaD) is a diﬃcult clinicalsubcortical ischemic VaD, small vessel disease also

entity to classify because many processes contributeexaggerates the progress of other neurodegenerative

to cognitive decline. In 2003, Hachinski proposed a

diseases, including Alzheimerʼs disease.

new clinical concept called vascular cognitive
impairment (VCI). I agreed with this concept when I
heard his lecture at VASCOG2003, but I wondered
whether this new concept would be accepted in Japanbecause a corresponding concept, mild cognitive
impairment (MCI), had already been accepted, so the
new concept of VCI might be thought of as aprodromal stage of VaD.
Hachinski explained his concept in detail andFigure 1.

proposed a future direction in an article entitled

Progress toward standardized VCI diagnostic guidelines
in the Vascular Impairment of
Cognition Classiﬁcation Consensus Study.

“Vascular cognitive impairment harmonization
standards” (Stroke 2006;37:2220‒2241). Considering
the progress of imaging, genetics, biochemistry, andpathology, this knowledge should be applied to

Actually, much evidence accumulated aboutprovide a better understanding of VCI as proposed byneurodegenerative diseases is accelerated by ischemic

Hachinski.

events in the brains of elderly patients. Particularly,

About 10 years later, new diagnostic criteria for VCIstudies on emission systems that excrete abnormal

were proposed by the Vascular Impairment ofproteins from the brain have recently been gaining

Cognition Classiﬁcation Consensus Study (VICCCS)

attention. The lymphatic and glymphatic drainage

group, which is composed of international

pathways can be visualized by improving dyes andparticipants ( Alzheimers Dement 2017;13(6):624‒

imaging in vivo, but the main pathway of emission

633). These criteria are divided into mild or major

systems remains controversial. However, previous

type according to the level of cognitive impairment.

studies have revealed that vessel pulsation is

While ordinal VaD is classified as major VCI,

important to eliminate abnormal proteins through thepredementia stage is classiﬁed as mild VCI. Stroke

lymphocytic or venous system.

episode is an important event in the previous criteria

In addition, more genetic, biomarker, inﬂammation,

for VaD. Cases directly related to a stroke event are

and imaging studies are needed to solve the problems

classiﬁed as post-stroke dementia according to theassociated with dementia among the aged in Japan. It

VICCCS. While subcortical ischemic VaD and multi-

is my hope that this journal will continue contributing

infarct (cortical) dementia subtype are categorized

to the progress of dementia studies from a wide range

independently, these pathological changes can existof aspects in the future.

with other neurodegenerative pathologies and are
categorized as mixed dementia. While small vessel

37

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

New submission system for Vas-Cog Journal
Vas-Cog Journal is an official journal of the

Vas-Cog Journal is currently accepting the following

Japanese Society of Vascular Cognitive Impairment. It

manuscript types: original article, review article

was initially launched in 2015 as a newsletter. Vas-

(invited), editorial (invited), and case report. All

Cog Journal changed its style in 2019 and started

original manuscripts will be evaluated by two

accepting submissions from a wide range of scientists

independent reviewers assigned by the Editors. The

and clinicians in addition to the regular articles by themembers of the Editorial Board are listed in “Vas-Cog

editorial board members. High-quality academic

Journal Submission Instructions for Authors” in thispapers on vascular dementia and related disorders areissue as well as on the oﬃcial web site.

welcome, and expected to enhance the scientiﬁc valueof the journal.
Details regarding the new submission system areprovided in “Vas-Cog Journal Submission Instructions
for Authors” in this issue. Please note that at least theﬁrst author and corresponding author should be
members of the Japanese Society of Vascular
Cognitive Impairment. All manuscripts must be
submitted electronically through the online
submission system on the oﬃcial web site of theJapanese Society of Vascular Cognitive Impairment(http://www.jtbw-mice.com/vas-cogj/). The submitting
author should upload the manuscript files inappropriate word and PDF ﬁle formats according to
the instructions provided. After submission via theonline submission system, the contact/submitting
author should complete the “Authorship Agreement”
form with all coauthorsʼ signatures, and email it to the
Editorial Oﬃce (vas-cogj@jtb.com).

38

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

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.

society shall fill in the designated application form,
with the annual membership fee, and shall apply to thesecretariatʼs 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.

(Offices)
Article2
The Societyʼs head office shall be in 2-2 Yamadagaoka,
Suita-city, Osaka 565-0871

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 Memberʼs 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 incorporation and other regulations 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) Business activities such as publication of academic
journals(2) Business activities such as holding annual meetings(Annual meetings shall be financed by theparticipantsʼ entry fees but other organizations may
co-host the meetings. )(3) Business activities such as supporting and awarding
study relating to the medical treatment of vascularcognitive impairment.
(4) Any other business activities for achieving the
purpose provided in the preceding article.

Article11
Regular members and student 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 and39

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

convene the Board of Councilors.
The Representative Director and Board Members shallorganize the Board of Directors, and manage the workof the society.
T he Re p re se nt a t ive Dir ector sha ll r epor t budg etstatements, account settlement, human resources ofBoard Members and any of the other main work of thesociety to the Board of Councilors and the General
Assembly.

Article23
The Representative Director shall hold a Board of
Councilorʼs Meeting temporarily if requested by morethan 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 sʼ f e e s , v a r i o u s s u b s i d e s a n d
donations.

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.

Articles27
Expenses of the society shall be processed by thegeneral fund account and special fund account.

Article18
Officers and Councilors shall serve a term of one fiscal
year. The Representative Director, Executive Director,
Board Members, Auditors and Councilorsʼ terms are twoyears, and they may serve a maximum of two terms in arow.
Officers shall reach the mandatory retirement age on
March 31st of the year in which they become 65 years
old.

Articles28
The general fund account shall record all income andexpenditures excluding the special fund account.
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 membersʼ 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 cietyʼs 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 Chairmanʼs 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
Revised on August 03, 2019

Chapter5.Council
Article22
Annual Meeting, Board of Councilors and General
Assembly shall be held once a year.

40

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Vas-Cog Journal

Submission Instructions for authors

Vas-Cog Journal is an oﬃcial journal of the JapaneseSociety of Vascular cognitive impairment. Original
Articles 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 participantsʼ 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-authorsʼ
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) Complete title of the paper; Abbreviations are
not acceptable in the title.
(2) Name(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) Disclosures; 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 Supplementary
files
4. Abstracts in manuscript types “Original Article ofClinical or Experimental Research” sho u l 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

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

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 ʻIn Pressʼ 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 authorsʼ names should belisted, with “et al.” at the end.
Examples:(1) Ya 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 dAlzheimerʼs Disease. In: Yamagishi S, editor.
Diabetes and Ag ing-related Complicat ions.
Springer, 2018; 101-111(3) Takeda S, Wegmann S, Cho H, et al. Neuronal
uptake and propagation of a rare phosphorylated
high-molecular-weight tau derived from
Alzheimerʼs 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 Authorʼs 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 authorsʼ 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); Bʼs 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:

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

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
Womenʼs 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,

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

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. Authorsʼ disclosures will appear after the “Acknowledgments” section in
the accepted article.
*Multiple pages may also be accepted. Please copy and use this form if it is necessary.
<CAUTION> We do not accept any additional co-authors after the manuscript has been accepted. Please makesure that you add all co-authors in the revision process.

Manuscript title:1)

Authorʼs Print Name:
Signature:2)

Authorʼs Print Name:
Signature:

3)

Date:

Authorʼs Print Name:
Signature:

6)

Date:

Authorʼs Print Name:
Signature:

5)

Date:

Authorʼs Print Name:
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4)

Date:

Date:

Authorʼs Print Name:
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Date:

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

7)

Authorʼs Print Name:
Signature:8)

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9)

Date:

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Sponsers
Eisai Co., Ltd.
Novartis Pharma K.K.
ONO PHARMACEUTICAL CO., LTD.
Osaka Yakken Co.,Ltd.
Otsuka Pharmaceutical Co., Ltd.
Sumitomo Dainippon Pharma Co., Ltd.
Takeda Pharmaceutical Company Limited(in alphabetical order)46

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2020 NO.6）

Editorʼs Note
Mikio Shoji, MD., PhD
Director, Dementia Center,
Geriatrics Research Institute and Hospital

The 6th issue of Vas-Cog Journal reports the outline

Last 5 years, I have been editing the Vas-Cogof the 10th annual meeting, VAS-COG Japan 2019,

journal. Vas-Cog Journal has developed from simple

hosted by Professor Masahiro Akishita and Professor

meeting reports into the one of fully equipped

Yoshio Ikeda on August 3, 2019 in Tokyo, joining

international journals with open contribution rules

about 200 participants. Year by year, participants inand advertisements. From the next issue, editor in

Vas-Cog J annual have been increasing. Besides

chief will be transferred to Dr. Toshiki Mizuno, theclinical doctors and researches, paramedical stuﬀ,

professor, Division of Neurology and Gerontology,

students and companies are joining and boosting up

Kyoto Prefecture University of Medicine.

this meeting successfully. I would like to appreciate

I deeply appreciated for every support by president,

every eﬀort by Vas-Cog J members and be delighted

editorial board members and secretariat, and hopeso much.

these great eﬀorts contribute further advances in thisIn this issue, 2 outstanding review articles, caseﬁeld with the new editor in Chief.

reports and information of related meetings have

God bless us every one! (Charles Dickens 1843)

been carried. Council meeting reports and description
about new submission systems were published.

The past and future annual meeting of Vas-Cog JapanThe 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
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, 2021 (Tokushima) Chairman : Shunya Takizawa and Masataka Sata
The 12th Meeting : August, 2022 (planned) Chairman : Kazuo Kitagawa and Koichi Kozaki
The 13th Meeting : August, 2023 (planned) Chairman : Masahiko Suzuki
The 14th Meeting : August, 2024 (planned) Chairman : Takayoshi Shimohata
The 15th Meeting : August, 2025 (planned) Chairman : Kazuma Sugie- to be continued -53