 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Vas-Cog Journal
No.9 April 01. 2023

Oﬃcial Journal of Vas-Cog Japan Society
1ISSN : 24239372

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Table of Contents

Editorial ��������������������������������������

4＜ Special Lecture ＞ T he relationship between amyloid-β accumulation and cerebrovascular disease in 
Alzheimer’s disease: role of amyloid positron emission tomography ����������

5＜ Review article ＞ C ellular and Molecular Neuropathology of Cerebral Small Vessel Disease and 
Dementia ������������������������������������

9＜ Young Investigator Award ＞ T he deleterious effects of Alzheimer's disease pathology on skeletal muscle ������ 23＜ Case report ＞ A case of Moyamoya disease with Graves’ disease presenting clinical and radiologicalimprovement only after treatment for hyperthyroidism ��������������� 30
Greetings from the President of the Japanese Society for Vascular Cognitive Impairment ������������������������������������ 35
Reports of the Vas-Cog Japan 2022 ������������������������� 36
Welcome to Vas-Cog Japan 2023
Theme: Innovation in vascular cognitive impairment research ������������� 37
Meeting report of Vas-Cog Asia 11 from Kaohsiung ������������������ 38
Reports of Vas-Cog Japan Council Meeting ���������������������� 39
Sponsors  ������������������������������������� 40
Editor’s Note/
The past and future annual meeting of Vas-Cog Japan ���������� Inside Back Cover

3

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Editorial
Toshiki Mizuno, MD, PhD

Professor of Neurology, Kyoto Prefectural University of Medicine
between Alzheimer's disease and cerebral blood vessels. In

We are entering an era of fundamental change in theparticular, it needs to be clarified whether the drainage systemtreatment of Alzheimer's disease. Following FDA approval of

from the brain and its pathways are impaired by ageing andAducanumab in the US in 2021 and Lecanemab in 2023, thePMDA is currently investigating these drugs for approval inatherosclerosis. Previous findings in hereditary Alzheimer's

disease biomarkers, and also blood and spinal fluid tests, could

and therapies have been developed using genetically modified

disease have emphasized the gain of toxic function of Abeta,

Japan. If these drugs are approved, PET tests for Alzheimer's

models based on this hypothesis. However, the development ofalso be covered by insurance. For prescribing these antibody

animal models and therapies based on the role of thedrugs, the Japanese government may require performance of
these tests to diagnose Alzheimer's disease accurately. Testing

degradation and efflux systems in Alzheimer's disease

onset of ARIA during treatment .  In Japan, free access to healthJapan Society would like to further support the progress ofoccurring in human ageing has only just begun. The VAS-COG

will also be needed to manage patients safely by detecting the

research towards the development of treatments for this age-care is available, which means that many dementia patients

related loss of function.

seeking new drugs may be seen, so changes to the healthcare

system will certainly be required. In addition, it will benecessary to consider how much these therapies will contributeto society. We  should consider these issues now that antibody
therapies for Alzheimer's disease are available,. On the other

hand, these antibody therapies are currently not effective in all

patients with Alzheimer's disease. The antibody therapy has

only been tested in patients in the early stages and may belimited, e.g. with risk factors such as APOE4 . We need to know
how to select patients for antibody therapy and how to informpatients and families of possible risk and benefit. Medically, as

noted with ARIA, further research is needed into the link4 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Hiroo Kasahara et al.

Special Lecture (review article)

The relationship between amyloid-β accumulation andcerebrovascular disease in Alzheimer’s disease: role of amyloid
positron emission tomography

Hiroo Kasahara, MD, PhD1); Masaki Ikeda, MD, PhD2); Yoshio Ikeda, MD, PhD1)

1) Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
2) Division of General Education (Neurology), Faculty of Health and Medical Care, Saitama Medical University, Hidaka, Japan.
Abstract:

The relationship between Alzheimerʼs disease (AD) and cerebrovascular disease (CVD) is attracting attention. To investigate thiscomplex relationship, it is necessary to focus on biomarkers that can assess AD pathophysiology. Positron emission tomography(PET) to detect amyloid-β (Aβ) can visualize the distribution of Aβ accumulation in the brains of AD patients. Amyloid PET

imaging has been evaluated qualitatively, but a quantitative evaluation has also been developed to allow better comparison of data
across institutions. Quantitative amyloid PET analysis has been used in the development of many disease-modifying drugs against

AD. Cerebrospinal fluid and serum biomarkers have also been developed to investigate Aβ pathology, but the advantage ofamyloid PET imaging is its ability to assess Aβ accumulation in a site-specific manner.

Spatial assessment of Aβ accumulation by amyloid PET is useful when investigating its association with CVD. We have revealed

that more severe CVD findings are associated with milder Aβ accumulation in patients with AD. Simultaneous presence of Aβ and

CVD pathologies, compared to the presence of either pathology alone, has been shown to significantly accelerate the onset ofclinical dementia and cognitive decline. To prevent cognitive decline in AD patients, it is important to manage vascular risk factors
and prevent CVD.

Key Words: Alzheimer’s disease; dementia; white matter lesion; amyloid-β; cerebrovascular disease; positron emission tomography

Correspondence to:

Yoshio Ikeda, MD, PhD

Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Tel: +81 27 220 8060

Fax: +81 27 220 8067

E-mail: ikeday006@gunma-u.ac.jp
Introduction

neuropsychological testing but instead assesses patients based

disease with increasing prevalence and is characterized byhave been validated as biomarkers of Aβ pathology (A), whileI n t e r e s t i n g l y, p a t h o l o g i c a l i n d i c a t o r s o f A D a n destablished as biomarkers of tau pathology (T). In addition,

the brains of older adults, and the relationship between AD and18

on biomarkers. Aβ42 levels in CSF and amyloid PET findings

Alzheimerʼs disease (AD) is a progressive neurodegenerative

phosphorylated tau in CSF and tau PET findings have beencognit ive impairment and behavioral disturbances.

total tau in CSF, decreased glucose metabolism on

cerebrovascular disease (CVD) are often seen simultaneously in

F-fluorodeoxyglucose PET, and brain atrophy on magnetic

resonance imaging (MRI) are established biomarkers of

CVD is attracting attention. However, the role of CVD in AD

pathogenesis has not been clarified. To investigate theneurodegeneration (N). The National Institute on Aging andbiomarkers that can reflect the disease status of AD.

for AD based on biomarkers of Aβ, tau, and neurodegeneration,

Alzheimerʼs Association (NIA-AA) proposed diagnostic criteria

relationship between AD and CVD, it is necessary to focus on

called the A/T/N biomarkers3). Of these biomarkers for AD

Neuropatholog ical hallmarks of AD brains include

neurofibrillary tangles (NFTs) which contain phosphorylated

diagnosis, Aβ is the first biomarker to become abnormal in. Previous studies onthat abnormalities in biomarkers of Aβ dysregulation may

carriers with a pathogenic AD mutation4). This finding suggests

tau protein and senile plaques which contain extracellularly
deposited amyloid-β (Aβ) protein fibrils

1,2)biomarkers for AD have been conducted focusing on thesesolely serve as a defining AD signature. Amyloid PET, such as

pathological features. With the establishment of biomarkers for

11

C-labeled Pittsburgh Compound B PET (11C-PiB PET), candetect cerebral Aβ deposition in vivo and visualize theAD using cerebrospinal fluid (CSF) sampling and positron

distribution of Aβ accumulation in AD brains5). Postmortem

emission tomography (PET) scans, the recent diagnostic

studies have revealed that increased 11C-PiB uptake on PET

procedure of AD no longer relies solely on classical5

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Relationship between A β and CVD in AD
images corresponds to areas of abundant senile plaques6).

Ongoing Phase 2 and 3 clinical trials for AD are dominated by

Herein we describe the characteristics of amyloid PET anddisease-modifying drugs that target Aβ, and a significant

discuss the relationship between Aβ accumulation and CVD.

number of these studies are evaluating changes in Aβ

Advancements in radiotracers for amyloid PET and methods

treatment.

accumulation using amyloid PET evaluation before and after

for image analyses

The advantages and disadvantages of amyloid PET

The first radiotracer to visualize brain Aβ deposition in AD

patients was

18

F-2-(1-{6-[(2-fluoroethyl)(methyl)amino]-2-Although amyloid PET is used frequently in both clinicalpractice and research, Poul et al . indicated the following

naphthyl}ethylidene) malononitrile (18F-FDDNP)7). However,18

F-FDDNP is not capable of efficiently binding Aβ, while also

problems with amyloid PET13). Firstly, amyloid PET imaging

biomarkers for assessing Aβ deposition have insufficient inbinding to NFTs, making it less frequently used at present . PiB
8)vivo specificity. It has been shown that uncharged derivatives

is an uncharged derivative of thioflavin-T that has a highof thioflavin-T ( 11 C-PiB andaffinity for Aβ fibrils and shows very low binding to NFTs andis therefore widely used in clinical studies . On the other hand,
C-PIB use is limited because of the short half-life of 11C, andseveral radiotracers labeled with18

including estrogen sulfotransferase, an enzyme that is elevatedF have been developed as

during brain inflammation14,15). Additionally, quantification of

F-flutemetamol is a derivative of

the signal in gray matter is particularly problematic when there

C-PIB. 18F-flutemetamol has a high affinity for Aβ but exhibits

In addition to amyloid PET, immunological measurements,

alternatives. Among them,18

thioflavin-T, which has a chemical structure almost identical to11

F-flutemetamol) can benonspecifically retained by tissue targets other than Aβ,

9)

11

18

higher white matter uptake . Moreover,is cortical atrophy, as observed in AD brains.

F-florbetapir andsuch as Aβ42 levels in CSF, have also recently been used as

developed, and the synthesis devices have been approved

significantly correlated with Aβ deposition in amyloid PET16).

10)

18

18

F-florbetaben with trans-stilbene derivatives have beenmarkers of Aβ pathology. Reduction of Aβ42 levels in CSF is
Recently, serum Aβ biomarkers have been developed and areunder the Japanese Pharmaceuticals and Medical Devices Act

shown to correlate with CSF biomarkers17).

(PMDA). Furthermore, two of the above radiotracers( F-florbetapir and18

18

F-flutemetamol) are marketed as

Since immunoserological biomarkers are being developed at

diagnostic agents in Japan.

a lower cost than amyloid PET, amyloid PET imaging would

negative by inspection; they are rated as “positive” if the uptake

Indeed, the biggest advantage of amyloid PET seems to be its

In general, the amyloid PET images are rated as positive orneed to confer advantages over immunoserological biomarkers.

level in the cerebral cortex is higher than that in the whiteability to assess Aβ accumulation in a site-specific manner. For

matter. The standardized uptake value ratio (SUVR) represents

example, Hwang et al . reported that AD with Aβ accumulation

the average uptake in a reference region. As it is known thatwithout occipital Aβ accumulation18), an example of thein the occipital region showed a younger onset than ADa quantitative measure of tracer uptake, which is normalized toadvantage of using amyloid PET to identify Aβ distribution toradiotracer uptake in the cerebellar cortex does not differ
between AD patients and healthy controls , it is commonly

inform clinical characteristics. Another example is the use of6)

used as the reference region in amyloid PET analysis.

amyloid PET for investigating differences in cerebral AβGenerally, qualitative evaluation of amyloid PET imaging bydeposition at normally appearing white matter and white

SUVR values are useful for quantitative assessment, there is18

inspection shows consistent results across institutions. While

matter with high intensity lesions in T2-weighted MRI. Use of

F-florbetapir PET revealed that retention of the tracer in whitematter is associated with demyelination in AD19). Taken

considerable variation in the reported SUVR measurement

methods used among institutions. A common quantitative

together, these data suggest that amyloid PET will play an

better comparison of amyloid PET data across institutions. For

accumulation at specific brain regions.

important role in studies requiring to evaluate Aβ

output value, regardless of the tracer or method, would allow
this reason, the main objective of the Centiloid Project is to

The relationship between Aβ accumulation and CVD in AD

standardize amyloid PET results and reconstruct objective

quantitative data11). The tracer results were standardized by a

The pathologies of AD and CVD often overlap in the brains ofquantitative index of amyloid imaging, by scaling the outcome

older individuals, and epidemiological studies indicate thatof each particular analysis method or tracer to a 0 to 100

comorbid AD and CVD is common20). Several studies have

AD patients; the unit of measurement used in this scale was

hypertension, hypercholesterolemia, and diabetes mellitus, arereported that vascular risk factors ( VRFs), such as

scale, anchored by young controls ( ≤ 45 years old) and typical
named “Centiloid” . Quantitative amyloid PET analysis, asassociated with an increased risk of developing AD21,22,23).

12)

described above, has been introduced in the development ofFurthermore, it has been reported that VRFs are correlatedwith CVD24). The most common comorbidity in AD is stroke, andmany disease-modifying drugs targeting AD pathology.

6 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Hiroo Kasahara et al.
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disease biomarkers. Neurology. 2016;87:539-47.

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The results of various clinical studies on amyloid PET indicate

brains of living patients with Alzheimer disease. Am J

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Geriatr Psychiatry. 2002;10:24-35.

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In conclusion, amyloid PET can be used to evaluate Aβ

1407.

accumulation in different brain regions and is useful when11)	Homepage/Web site. The Global Alzheimerʼs Association

CVD. Various studies describe the association between Aβ

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standardizing quantitative amyloid plaque estimation by

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progression of CVD.

PET: A Questionable Single Primary Surrogate Efficacy
Measure on Alzheimer Immunotherapy Trials. J Alzheimers

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Ministry of Education, Culture, Sports, Science and Technology,

imaging probe candidates. Proc Natl Acad Sci USA.

Scientific Research (C) (21K15675 to H.K)” award from thesulfotransferase (SULT1E1) substrates and molecular

Japan.

2010;107:6222-7.

15)	Surmak AJ, Wong KP, Cole GB, et al. Probing Estrogen

Disclosures: The authors have no potential conflicts of interest

Sulfotransferase-Mediated Inflammation with [11C]-PiB in

to declare.

the Living Human Brain. J Alzheimers Dis. 2020;73:102333.

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8 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Raj N Kalaria et al.

Review article

Cellular and Molecular Neuropathology of Cerebral Small Vessel
Disease and Dementia

Raj N Kalaria FRCPath, FMedSci1); Yoshiki Hase MD PhD1); Roxana O. Carare MD PhD2)

1) Neurovascular Research Group, Translational and Clinical Research Institute,Newcastle University, Newcastle upon Tyne, United Kingdom2) Faculty of Medicine, University of Southampton, UK

Abstract:

Cerebrovascular disorders are inherently heterogenous.  They entail a variety of clinical, pathological and cognitive features.  In
recent years, cerebral small vessel disease (SVD) has been at the forefront mainly because it is attributed to a common cause of

strokes and responsible for long-term sequalae including disability.  Advances in neuroimaging, particularly magnetic resonanceimaging (MRI) have expounded on the radiological definition of SVD involving white matter hyperintensities and parenchymal

changes whereas it is difficult to appreciate covert pathology in intracranial arteries and arterioles.  SVD pathology incorporates

small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing and white matter attenuation.   Cerebral

vessels undergo loss of smooth muscle cells and disruption of the extracellular matrix within basement membranes withconsequences on interstitial fluid drainage.  The distribution and quantity of SVD pathology involving both parenchymal lesions

and arteriopathy vary with age, gender, vascular risk factors and genetically determined disorders.  However, both types of lesions
invariably correlate with progression of impairment or worsen cognitive function.  SVD is part and parcel of almost all types ofdementias.    The incorporation of SVD as a biomarker is much warranted in the biological definition of dementia.   Therapeuticinterventions to reduce SVD pathology via risk control will have a major impact on the burden of dementia.

Key Words: age, arteriolosclerosis, CADASIL, cerebral amyloid angiopathy, Collagen IV, familial dementia, small vessel disease,vascular brain injury, white matter hyperintensity

Correspondence to:Professor Rajesh N. Kalaria, Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality,
Newcastle upon Tyne, NE4 5PL, United Kingdom.

Tel: +44-(0)191-208-1352; Fax: +44-(0)191-208-1301
E-mail : raj.kalaria@newcastle.ac.uk
INTRODUCTION

vessels bearing smooth muscle cells or myocytes haveon magnetic resonance imaging (MRI) to denote parenchymal

leptomeningeal arteries, enter the brain parenchyma from the

Cerebral small vessel disease (SVD) is increasingly described

diameters from 40 up to 900 μm and they emerge from thechanges, particularly white matter hyperintensities (WMH).1-3)

surface of the brain to extend a variable depth into the

The most common consequences of SVD are (i) lacunar (small

parenchyma comprising both basal and pial penetrators.   The

haemorrhage (ICH) and (iii) subcortical ischaemic vasculararteries in SVD are arteriolosclerosis, fibrinoid necrosis andby diffuse white matter ischaemic damage.  In addition to age,with age and are actually affected in many disorders includingdeep) infarcts; (ii) primary non-traumatic intracerebral brain

major structural pathologies described in penetrating small

dementia, which may be caused by multiple lacunar infarcts or

micro-aneurysms.  Small cerebral arteries and arterioles change

hypertension and diabetes mellitus appear the main risk

hereditary angiopathies, inflammatory and infective

factors for SVD.   These risk factors are almost equally

vasculitides and toxic disorders.  

important for non-lacunar infarcts4) and are a cause of

In recent times, C Miller Fisher should probably receive thecognitive impairment and dementia ( Table 1).   The

credit for meticulous analysis of cerebral SVD or arteriolar

pathogenesis of lacunar infarcts has been the topic of intensive
research5)

pathology.  Fisher suggested segmental arterial disorganizationand imaging studies have suggested that theand small vessel atherosclerosis are the two most common

majority (>90%) of lacunes are found at the edge or havecauses of lacunar infarcts leading lacunar syndromes, whereas

definition of SVD implies much more and emphasizes distinct

Intracranial atherosclerosis occurs in very old age, particularly

proximal predilection to WMH.6)   However, the pathologicalfibrinoid necrosis was associated with large lacunes and ICH.7)  
in the branches of the main cerebral arteries.8)  There are few

covert changes within walls of cerebral vessels.  Small cerebral

9JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Cerebral Small Vessel Disease and Dementia
qualitative differences in atherosclerotic plaques and the

produces globular haemorrhages; if ‘healed’ by thrombosis andin carotid versus intracranial arteries.  In this review article, we

Alkaline phosphatase histochemistry and high-resolution

repertoire of the reactive cells associated with atherosclerosis

fibrosis, these are transformed into fibrocollagenous balls.  

focus on recent updates in the understanding of arteriolar

micro-radiography showed the great majority of ‘micro-

pathology in the context of sporadic and familial SVD type of

aneurysms’ to be complex tortuosities.   These are most

Features of Vascular Pathology in SVD

and their numbers increase with age, but hypertension has no

disorders (Table 1).

common at the interface between the grey and white matter

Arteriolosclerosis, Fibrinoid Necrosis and Micro-Aneurysms

effect on their prevalence. Micro-aneurysms are also not foundarteriolar vessels of 40–300 μm-diameter.

identification of microaneurysms in routine diagnostic analysis

in relation to lacunar infarcts.   However, definitive

Arteriolosclerosis describes non-fibrinoid hyaline thickening in  Normal intracerebral

9,10)arteries are relatively thin-walled and have a wide lumen in relation

to the wall thickness with their sclerotic index normally being <0.3.  

is very rare.

Arteriolosclerosis tends to be more associated with ischaemic white

Causes of Arteriopathies

impairment rather than lacunar infarcts.11)   The thickened walls

hypertension, cerebral amyloid angiopathy (CAA) and among

The main causes of arteriolosclerosis are ageing,

matter disease and vascular dementia or vascular cognitive

narrow the lumen and increase the sclerotic index (SI = 1 – [internal

common familial disorders such as cerebral autosomal

severity of degenerative fibrous thickening of the tunica

leukoencephalopathy (CADASIL) (Table 1).   These can be

dominant arteriopathy with subcortical infarcts anddiameter/ external diameter]), a measure devised to indicate

distinguished by location and type of staining to demonstrate

media.12,13)   Previous studies indicate thickened fibrotic arteries

protein accumulation or loss of arterial vascular smooth muscle

seldom rupture.

Fibrinoid necrosis appears not to be necessarily very

cells.   Hypertension or ageing-related arteriolosclerosis is

In the early stages, the walls are thickened by eosinophilicLongstanding hypertension likely increases risk of rupture ofdifferent14) from Miller Fisher’s description of lipohyalinosis.15)  

usually pronounced in subcortical arteries and arterioles.  
small arteries with consequent ICH.  Arteriolosclerosis in CAA

fibrinoid material, composed mainly of plasma proteins, withis largely leptomeningeal and cortical, and in CADASIL

abundant fibrin, formed by leakage of the blood-brain barrier

predominantly affects leptomeningeal and subcortical vessels,(BBB) together with remnants of smooth muscle cells.  At thisoften sparing those in the cortex.   Vessels affected by

fibrinoid-necrosis stage of SVD, the BBB is disrupted and thearteriolosclerosis show tinctorial staining for collagen and are

affected vessels are prone to rupture.   In time, the fibrinoid

intensely immunopositive for collagen I or collagen IV, formaterial is replaced by collagen produced by fibroblasts andexample.  Arterioles with CAA are Congo Red and Thioflavin S

the arteriolar walls become ‘glassy’ in appearance.   Lipids are

p o s i t i v e , a n d r e m a r k a b l y o f t e n a m y l o i d β ( Aβ) -usually only a minor component in these lesions, and hyalinosis

immunopositive.   In CADASIL and other monogenic SVD

refers to acellular fibrosis.   It has been recommended that the9)term ‘lipohyalinosis’ should therefore be abandoned anddisorders, arteriolar walls show granular basophilia in sections

change if histological or immunocytochemical stains verify thecan be shown by immunopositivity of fragments of mutatedconstituent of thickened arterial walls.   The homogeneous

others (Table 2).

may result from either fibrinoid change or collagenous fibrosis.  

Chronic Hypertensive Disease

distinguished by use of special stains but appear deceptively

deleterious effects are mediated by structural changes in bloodthese vessels would be fibro-hyalinosis, a term implying a

hypertension shifts the autoregulatory limits to the right,

stained with H&E or Periodic Acid Schiff (PAS) but specificity

replaced by descriptions based on appropriate stains: fibrinoid

proteins such as the ectodomain of NOTCH3 in CADASIL16) andpresence of fibrin, and fibrosis if collagen is the main

eosinophilia in haematoxylin- and eosin (H&E)-stained sections

These two are probably consecutive changes and can be readily

Hypertension is not itself a disease of blood vessels, but its

vessels, particularly in small arteries and arterioles.   Chronic

similar to H&E.14)   A description probably better describing

towards higher pressure values.  This is a protective response

rather uniform SVD change extending also to non-hypertensive

allowing maintenance of a constant cerebral blood flow (CBF)  

regressive conditions.

According to the traditional view, Charcot–Bouchard oreven at increased arterial pressure and prevents the ill effects

at weakened sites in vessel walls.   They resemble small sacs,

involving specific molecular mechanisms.17,18)  To maintain theof the excessive systemic pressure on delicate capillaries

miliary micro-aneurysms arise in the context of hypertension,
14)

upper and lower limits of autoregulation resistance vessels or

0.3 to 2 mm across, arising from parent arteries/arterioles
100–300 μm in diameter. The walls of the aneurysms consist

arteries must undergo gradual change within the vessel wall.9)  

elastica interna.   Rupture of microaneurysms typicallyarterial blood pressure falls to about 40 per cent of baseline

Symptoms of cerebral hypoperfusion develop when the meanof hyaline connective tissue, damaged smooth muscle cells and10 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Raj N Kalaria et al.
levels.  In hypertensive patients, such a reduction is reached atwithin subjects could reflect variations in the efficiency of

normotensive people.   Thus, one-third of asymptomatic

CAA.  Alternatively, it may relate to the relative amounts of Aβ,

cerebral hypoperfusion.19)   This may be exacerbated byof CAA.33)

Intramural Periarterial Drainage (IPAD), as its failure leads toa correspondingly higher level of arterial pressure than inwith higher levels of Aβ40 promoting a more ‘aggressiveʼ form

hypertensive patients were found to have focal or diffuseexcessive antihypertensive medication, to ischaemic levels

Electron microscopy reveals extracellular deposits ofsevere enough to cause tissue damage in both grey and whiterandomly orientated, straight, unbranched filaments ofin a hypertensive patient with stroke, decreases in blood

CAA tends to be associated with accentuated perivascularischaemia as a result of arterial changes.

Systematic morphometric analysis of sections of frontal,

Sporadic cerebral amyloid angiopathy

phospho-tau labelling of neurites around Aβ-laden arteries andmatter, especially along the arterial border zones.20)  Similarly,

indefinite length with a diameter of approximately 6–9 nm.  

pressure to levels tolerated by normotensives may worsen theneurofibrillary pathology, particularly if the CAA is severe.

temporal and parietal cortex from 51 AD brains revealed that

Sporadic CAA is predominantly a silent disease without overt

arterioles significantly exceeded that around non-Aβ-ladenclinical symptoms.   The most common type of CAA is
associated with deposition of Aβ (Aβ-CAA),

21,22)

blood vessels, which was, in turn, greater than corticalthe cleavage

immunolabelling away from blood vessels.36)  

product of Aβ precursor protein (APP).  Deposition of Aβ in theWith respect to the pathogenesis of CAA three main sources

walls of cerebral blood vessels occurs in sporadic CAA,

of Aβ accumulation in vessel walls may be considered. (i)Alzheimer disease, and Down syndrome but may also occur in

Systemic : Aβ is derived from cells throughout the body and isand spinal vascular malformations.24)  Aβ-CAA is also common

the brain parenchyma by specific receptors in the vesselother disorders such as dementia pugilistica,23) and cerebral

carried in plasma and transported bidirectionally to and fromwalls.37) (ii) Vascular: Aβ is produced locally by vascularin iatrogenic Creutzfeldt-Jakob disease (iCJD), observed in~90% shared in both growth hormone and dura mater iCJD

smooth muscle cells, endothelium and pericytes,38) all of which

age.  In those >60, the prevalence is a little over 30 per cent26)

failure of IPAD from the CNS. Aβ formed by neurons within the

Unlike detection of parenchymal Aβ deposition with tracers

including enzymatic degradation within the brain parenchyma

express APP.424 (iii) Drainage : Aβ accumulates because ofcases.25)   Sporadic Aβ-CAA rarely affects people <60 years ofand increases with age.

CNS is cleared from the interstitial fluid by several processes,

27)

such as Pittsburgh compound B (PiB) there are no establishedand the walls of blood vessels,39,40) transcytosis across the BBB,

methods to detect Aβ-CAA in the living brain.   Aβ-CAA is anwith endothelial cell uptake mediated by specific receptors

28)

independent risk for progressive dementia, associated withincluding lipoprotein receptor-related protein 1,41) and IPAD,

ischaemic damage to the white matter, and petechial cortical

together with other constituents of the interstitial fluid, along

haemorrhages or infarcts.   CAA comprises a group of protein

the perivascular extracellular matrix to meningeal arteries andmisfolding disorders characterized by the extracellular

probably cervical lymph nodes.  This drainage may be impaired

walls of blood vessels of the brain and meninges.29)   It is a(thought to supply the motive force for perivascular drainage),

Over 25 unrelated proteins are known to be involved infurther impedes vascular pulsatility.42) Precipitation within thedeposition of fibrillar proteins with amyloid properties in thein older people, as vascular disease reduces arterial pulsations

relatively common cause of brain haemorrhage in the elderly.30)  
amyloidosis31) and of these seven are associated with CAA

with resulting accumulation of Aβ in the arterial wall, which

perivascular extracellular matrix of amyloidogenic solutes such

(Table 1).  Brains with CAA are often characteristic because ofas Aβ in the course of their removal from the brain is probably

the distribution of the vascular disease, particularly SVD.  Thethe cause of most types of CAA.43) Reduced Aβ-degradingarteries is Aβ40, whereas that in capillaries is mainly Aβ42.   

factor: Miners et al .44) showed that neprilysin activity was

predominant form of Aβ that accumulates in arterioles and32)

On the basis of different distributions, several ways of grading  

Aβ-CAA patterns have been devised over the years.

22,33)

  Each ofenzyme activity within the vessel wall may be a contributory

lowest in meningeal blood vessels from patients with most
severe CAA, even after adjusting for smooth muscle content,

the up to four patterns33) is claimed to be distinct and are

and that raising or lowering neprilysin activity respectively

purposes the system proposed by Thal et al34) seems to havesmooth muscle cells on exposure to Aβ.  Exclusively neuronal

useful for quantification of research material but for routine

decreased or increased the death of human cerebrovascularbeen most often applied.   Type 1 CAA corresponds to Aβ in

production of Aβ is sufficient to cause CAA.45)

35)

cortical capillaries and other vessels whereas Type 2 involves

Affected blood vessels in Aβ-CAA may show segmental

leptomeningeal and cortical vessels, with the exception ofdilation or fibrinoid necrosis.  Serial sectioning and computer-cortical capillaries.  The type 1 of Thal34) corresponds to Type 3

assisted three-dimensional image analysis suggest that thedescribed by Mann et al.33)   The differing patterns in CAA

following sequential steps lead to blood vessel rupture and

11

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Cerebral Small Vessel Disease and Dementia
haemorrhage:46) (i) accumulation of amyloid in the arterial wall,  

(ii) destruction of smooth muscle cells, (iii) consequent dilation

decade.   The disease was subsequently called familial British

dementia (FBD) caused by the defective gene BRI2 .54) Amutation at another site on the same BRI2 gene causes(formation of micro-aneurysms) of the artery and (iv)heredopathia ophthalmo-oto-encephalica. 29) This disorder,

breakdown of the BBB, (v) deposition of plasma proteins in therenamed familial Danish dementia (FDD), is characterized byvessel wall (fibrinoid necrosis), and finally (vi) rupture andcataracts and ocular haemorrhages in the third decade,haemorrhage.   Fibrinoid change was more marked thandeposition of amyloid at sites of dilation and rupture.   This isfollowed by hearing problems and, in the fourth to fifthof cortical vessels may not directly cause microhemorrhages.47)  

Although CAA in both FBD (with deposition of ABri) and FDD

consistent with the proposal that the deposition of Aβ in walls

Fibrinoid change was also significantly associated withpossession of APOE ε2,48) which carries an increased risk of

decades, cerebellar ataxia and dementia.

(with deposition of ADan) is severe, with concentric splitting
and occlusion of affected vessels, ICH is rare.  CAA also affects

haemorrhage in Aβ-CAA.  Loss of vascular smooth muscle cells

small arteries and arterioles in white matter as well as inin CAA seems to depend at least partly on their uptake of Aβ

systemic organs.   In FDD, Aβ is sometimes co-deposited withof extracellular matrix proteins (e.g. MMP-9) weaken vessel

amyloid plaques, hyperphosphorylated tau-posit ive

and this, in turn, is influenced by APOE genotype.  Degradation

ADan in both vessels and parenchyma. In both disorders,

walls and is pivotal in the rupture of Aβ-laden arteries.   
49)

neurofibrillary tangles and neurites are also present in the

Other changes in the vessel wall may aggravate the angiopathy.  

brain parenchyma.

has been reported in hereditary cerebral haemorrhage withthe amyloid AGel is deposited systemically, particularly in thecorrelate with the striped cortex observed on in vivo 7T MR

gene on chromosome 9 cause AGel amyloidosis.   Remarkably,

For example, iron accumulation and calcification of vessel walls

In gelsolin-related familial amyloidosis of the Finnish type,55)

skin, peripheral nerves and cornea.  Two mutations in the GEL

amyloid angiopathy of the Dutch type (HCHWA-D) thatscans.50)

CNS deposition of AGel is widespread in spinal, cerebral, andmeningeal blood vessels, and extensive extravascular deposits

GENETICALLY DETERMINED SVDS

are present in the dura, spinal nerve roots and sensory

Hereditary amyloid β-peptide cerebral amyloid angiopathy

ganglia.56)(CAA)

Transthyretin-related and other CAAs

Primarily Aβ-CAA occurs in Dutch (HCHWA-D) and Flemish

TTR CAA is caused by mutations in the transthyretin (TTR)(HCHWA-F) types and in the different familial forms of

Alzheimer disease (FAD).3)   Mutations in APP that cause

gene, located on chromosome 18.   Patients may suffer frominvolve substitutions of amino acids 21–23 of Aβ, whereas

vision and hearing.   Currently >100 different mutations havehaemorrhages are mostly located within the Aβ domain anddementia, cerebellar ataxia, motor dysfunction, and decreased

those responsible for FAD are most often located in APP next tobeen identified in TTR.  Mutated TTR is prone to form amyloid

but outside of Aβ.   Enhanced Aβ accumulation within vessel

fibrils.   In addition to systemic ATTR deposition, common

walls causes cell loss and increasing propensity to rupture andconsequences of which include peripheral neuropathy andobstruction with resultant haemorrhages and infarcts.   In the

cardiomyopathy, nine mutations are associated with

Italian and Iowa families, CAAH is a common feature, alongoculoleptomeningeal amyloidosis with prominent CAA ofmeningeal vessels.57)  Patients with the p.Val30Met mutation inwith dementia.   In those FADs associated with presenilin-1

TTR 4.4% exhibit retinal amyloidotic angiopathy58), and there ismutations, CAA has been reported to be more common if thepresenilin-1 mutation is located beyond codon 200.   

early CNS involvement showing a topographic spread from51)

leptomeninges to cortical vessels and finally involving deep

Other hereditary CAAs

vessels, although with early brainstem and spinal cord

involvement.59)  

Hereditary cerebral haemorrhage with amyloid angiopathy of

CAA in patients with prion disease usually results fromthe Icelandic type (HCHWA-I, hereditary cystatin C amyloid
angiopathy) is a rare autosomal dominant CAA associated with

vascular deposition of Aβ. CAA due to prion protein (PrP)

normotensive adults.    In addition to the cerebral and

PrP amyloid (APrP) may be extensively deposited intissues, including the skin.  

surrounding neuropil.60)

deposition is rare and associated with stop mutations in PRNP .  

fatal brain haemorrhages in young and middle-aged
52)

meningeal arteries, ACys-amyloid is deposited in extracerebral
Worster-Drought et al53)

parenchymal and leptomeningeal vessels and in theoriginally described an autosomal

dominant CAA with non-neuritic plaques and neurofibrillary

Hereditary Non-Amyloid Angiopathies

tetraparesis and cerebellar ataxia with onset around the sixth

conditions characterised by SVD and predispose to ischaemic

Molecular genetic studies have identified several monogenic

tangle formation, clinically characterized by dementia, spastic

12 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Raj N Kalaria et al.
and haemorrhagic strokes and diffuse white matter disease61)

mutations with most frequently occurring in exon 4 of the

Other hereditary SVDs include cerebral autosomal recessive

substitution of a wild-type cysteine by another amino acid or(Table 2).   CADASIL is the most common hereditary SVD.  

gene.71)   Almost all of the mutations result in either avice versa in one of the 34 epidermal growth factor-like (EGF)

arteriopathy with subcortical infarcts and leukoencephalopathy

repeats in N3ECD.   Cysteine-sparing mutations, such as(CARASIL), the collagen type IV (COL4A1/A2)-related

p.Asp80Gly, appear to cause CADASIL with a phenotype

disorders, retinal vasculopathy with cerebral leukodystrophies(RVCLs),  and cathepsin A related arteriopathy with strokes andindistinguishable from cysteine mutations including

vary in phenotype, they demonstrate convergent effects oflarge exome databases involving global populations, theleukoencephalopathy (CARASAL).61)  Although hereditary SVDs

aggregation properties of N3ECD.72) Upon recent analysis offrequency of the archetypal cysteine altering NOTCH3

microangiopathy on cerebral grey and white matter, leading to(NOTCH3 cys) mutations in the EGFr domains were found to becognitive impairment.   Collectively, all these hereditary SVDs

involve mutations in single genes, whose products are

100-fold higher than expected based on estimates of CADASIL

development and maturation.62)(Table 2).

mutation located in EGFr domains 1-6 are predisposed to moreprevalence71).   Recent advances suggest individuals with a

responsible for cell signalling or extracellular matrix

severe classical phenotype including characteristic clinical and

CADASIL as a Model SVD

pathological features compared with those with a mutation in
7-34 domains 71,73).  

Heterogeneity within the CADASIL phenotype is now

The pathogenesis of CADASIL remains elusive. The unevenincreasingly recognised.  Multiple small infarcts, detectable on

T1-weighted MRI cause cognitive decline between 40 and 70

number of cysteine residues affects the formation of disulphidefollowed by impairment of memory and other cognitiveof the NOTCH3 receptor and consequently its functions.74)  The

bridges and therefore changes the three-dimensional structure

years of age, primarily in executive frontal lobe functions,formation of abnormal disulphide bridges could affect receptor

functions, leading to the development of a subcortical dementia

trafficking, processing, specificity for ligand binding and/orin ~80% after 65 years of age.   The characteristic

neuropathological feature is non-atherosclerotic and non-signal transduction.   Most mutations in NOTCH3 do not

medium-sized arteries of the white matter but also

processing, or signalling to CBF1/RBP-Jκ activation. It is more

amyloid arteriopathy, 63) affecting penetrating small andappreciably impair signal transduction activity, NOTCH3

leptomeningeal blood vessels.   Large intracerebral

likely that the misfolded, non-degradable N3ECDs that
accumulate within GOM75) over the years affect the function of

haemorrhages are rare but cerebral microbleeds are often
   Thevascular smooth muscle cells and block the drainage routes.76)

disrupted16) and may accumulate other proteins (see below)

cultivated vascular smooth muscle cells from CADASIL patients

described to occur in subcortical structures.

64,65)

Proteomic studies of CSF, isolated cerebral vessels andextracellular matrix (ECM) within the basal lamina iswith impact on IPAD.  In accord with other SVDs, alterations inhave provided various clues to the pathogenesis.   Proteinsnarrowing is the most consistent change and can be revealed

component, periostin),77,78) protein degradation and folding,retinal microvessel are also apparent in CADASIL.   Arteriolar

involved in inflammatory responses (Factor B, serum amyloid P

Autopsy shows

endoplasmic reticulum stress with activation of Rho kinase andeosinophilic material, pericyte degeneration and loss of smoothand endostatin),81) extracellular matrix proteins (tissue inhibitor

by fundoscopy and fluorescence angiography.

64)

unfolded protein response,79,80) vascular functions (clusterin

thickened arterial walls with fibrosis, accumulation ofmuscle cells in the central retinal artery and branches.66)  Otherof metalloproteinases 3 and vitronectin), 82) and serine

associated with white matter disease.

HTRA1)83) are evident that may or may not complex withpathological features of note include severe astrocytopathy

proteases (high-temperature requirement protein A1,

67)

One of the key pathological characteristics of CADASIL is the

N3ECD.   Majority of the studies favour that mutant NOTCH3

deposition of electron dense extracellular granular osmiophilic

induces gain of toxic involving misfolding or aggregation ofmaterial (GOM), which contains extracellular domains ofproteins. Prolonged retention of mutant NOTCH3 aggregates inbiopsies offers a means of intra vitam diagnosis and wassensitivity to other stresses.84)

Immunohistochemical demonstration of N3ECD in skin arteries

CARASIL

NOTCH3 (N3ECD).16,63,68)   Presence of GOM within dermal

the endoplasmic reticulum decreases cell growth and increases

reported to be completely congruent with genetic screening.69)
is also very useful in establishing diagnosis   provided clinical

CARASIL was first described as Maeda syndrome. 85,86)  

70)

symptoms are consistent with the disease.  Up to 280 distinct

CARASIL is characterised by severe non-amyloid arteriopathy,(EGFr) domains of NOTCH3 have been associated withanomalies and alopecia.  As in CADASIL, the recurrent strokes

mutations within the 34 epidermal growth factor receptor

leukoencephalopathy and lacunar infarcts together with spinal

CADASIL.  The vast majority of these (~70%) are missense point

lead to insidious deterioration with most subjects becoming

13

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Cerebral Small Vessel Disease and Dementia
cognitively impaired in older age.   Typical CARASIL is caused

Most glycine (gly) substitutions occur in the conserved Gly-X-Y

protease.   Both nonsense and missense as well as frameshift

cause COL4-related ICH with an estimated ~20%

by mutations in the HTRA1 gene, which encodes the serine

motifs within the triple-helical collagenous domain.  They also

plus splicing site mutations have been reported in the HTRA1

gene that causes typical CARASIL or HTRA-1 related SVD.   
86)

Heterozygous HTRA1-related SVD has a milder clinicalpresentation of CARASIL.   Differing locations of mutations

penetrance.96,97)   In addition, 10 different mutations in the 3’
UTR of COL4A1 have been described98,99) that all cause

PADMAL-like syndrome and some develop ICH although thefrequency is not known.  

found in symptomatic carriers with mild disease and classicalArteriolar pathology is characterised by moderate to severe

CARASIL suggests that distinct molecular mechanisms

segmental loss of arteriolar myocytes, fibro-hyalinosis, intimal

influence the development of SVD.   Mutations result inproliferation and microvascular degeneration often also50%) or loss of the protein.

associated with variable degrees of retinal arteriolar tortuosity,

involving the endothelium.   COL4A1 mutations are also

haploinsufficiency or reduced HTRA1 protease activity (21%85)

The arteriopathy is described by extensive loss of medial

and abnormalities of endothelial basement membranes in theskin.  Mutations in COL4A1 and A2 actually reduce expression

smooth muscle cells, intimal proliferation, and splitting of theperhaps weakening the vessel walls and giving way to bleeds.  

internal elastic lamina with severe disruption of the ECM in the

The mutation in 3’ UTR of COL4A1 disrupts miR-29 binding

pial arteries, perforating arteries, and arterioles.   CARASIL

and increases COL4A1 protein expression.13)  Mutant COL4A1/

extends the spectrum of diseases associated with the

COL4A2 chains accumulate in vascular smooth muscle cells

dysregulation of transforming growth factor (TGF) to readtransforming growth factor (TGF)-β signalling.   It may also

and cause endoplasmic reticulum (ER) stress responses, as in

HTRA1 cleavage sites.   However, defective TGF-β signalling

COL4A1 accumulates may also disrupt TGF-β signalling102) andCADASIL,84) possibly leading to cytotoxicity.100,101)   Mutant

influence the metabolism of APP, which includes several

due to mutations in the TGF-β receptors leads to hereditarycause abnormal angiogenesis underlying ICH development.  

signalling contributes to Marfanʼs syndrome and related

Retinal vasculopathies with cerebral leukodystrophy (RVCL)

TGF-β growth factors has also been linked to alopecia andand stroke (HERNS), cerebroretinal vasculopathy (CRV) and

Collagen type IV (COL4) Disorders

allelic disorders or different phenotypes of same diseasehaemorrhagic telangiectasia, whereas activation of TGF-β
disorders.87)   Dysregulation of the inhibition of signalling by

Hereditary endotheliopathy with retinopathy, nephropathy

spondylosis.

hereditary vascular retinopathy (HVR) were reported
independently but linkage analysis demonstrated that they are

spectrum.103) (Table 2).   They cause progressive central visual

Recently several conditions akin to SVD features have beenfound to be associated with mutations in collagen IV (COL4 ) A1
and A2 genes.

impairment.   Lesions occur in the pons, cerebellum and basal

   Two previous conditions described in large

ganglia in addition to the frontal and parietal lobes, and consist

88-90)

German and Swedish families as subcortical angiopathic
encephalopathy (SAE)91)

of foci of coagulative necrosis with negligible inflammation.  
Whilst heterozygous mutations in TREX1 cause RVCL,

and hereditary multi-infarct dementia of

the Swedish type92) were originally thought to be CADASIL- likehomozygous mutations in the same gene are linked to thedisorders are consistent with the clinical features of what is now

syndrome,104) which manifests as a progressive encephalopathy

but are now classified as COL4 type disorders.   Both thesetypical autosomal recessive form of Aicardi-Goutièresof early onset, brain atrophy, demyelination, basal ganglia

coined as PADMAL for pontine autosomal dominantmicroangiopathy and leukoencephalopathy.93)   Neurologicalcalcifications and chronic lymphocytic proliferation.   It is

manifestations of COL4A1 and COL4A2 mutations may vary

unclear how the carboxyl truncating mutations in TREX1 leadeven within families.94,95)   Depending on the age of onset,

to the phenotype or pathogenesis of RVCL involving

affected individuals present with infantile hemiparesis, seizures,arteriolosclerosis but it seems obviously due to disruption of

cognitive impairment and dementia.   Single or recurrent ICH

dissemination of TREX1 throughout the cell.105)

the deep brain regions: spontaneously, subsequent to trauma or

Cathepsin A related arteriopathy with strokes andvisual loss, dystonia, strokes, migraine, mental retardation,

the predicted transmembrane domain with subsequent

may occur in non–hypertensive young adults (foetus > adult) inleukoencephalopathy (CARASAL)

as a result of anticoagulant use (Table 2).  

Autosomal dominant COL4A1 -related disease with 100%CARASAL is a rare hereditary SVD affecting small cerebral

penetrance has been described in European Caucasian families,

arteries in adults due to mutations in the cathepsin- A (CTSA )described in the coding region of COL4A1/COLA2 that mostly

serine carboxypeptidase cathepsin-A, a member of thegene found on chromosome 20q13.12.  CTSA encodes for thewith 100% penetrance.   More than 50 mutations have been

involve glycine substitutions, some of which also cause ICH.  

14

peptidase S10 family, with various functions.   Patients with JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Raj N Kalaria et al.
CARASAL exhibit adult-onset leukoencephalopathy with earlysupported by a grant from Alzheimer’s Research UK NCG-

onset clinical manifestations involving the brainstem.  

2019B-001.  

from other SVDs with secondary leukoencephalopathies, suchediting the manuscript.  

CARASAL is delineated from CADASIL and CARASIL but also

Disclosures:  The authors declare that they have no competingas granulomatous encephalitis, lymphoma, vasculitis,

mitochondrial disorders and WMHs due to diabetes,interests.

hypertension, or smoking and also from primary

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19

Common conditions

Sporadic small vessel disease

Primary or
Secondary Vascular
Disorder(s)*Arteriolosclerosis

20
Branching arteries

Fabry disease, familial hemiplegic migraine,
hereditary haemorrhagic telangiectasia, Vascular
Ehlers-Danlos syndrome, Marfan syndrome,
Psuedoxanthoma elasticum, Arterial tortuosity
syndrome, Loeys-Dietz syndrome, polycystic kidneydisease; Neurofibromatosis type 1 (vonRicklinghausen disease), Carney syndrome (Faciallentiginosis and myxoma)

Monogenic
disorders involving
strokeMild and Major VCI

Mild VCI

Cortical and subcortical infarcts,
haemorrhagic infarcts

Cortical and subcortical stroke-likelesions, microcystic cavitation,
cortical petechial haemorrhages,
gliosis, WML

Mild and Major VCI

Mild and Major VCI(Independently affect cognition)

Mild VCI

Mild VCIHypertensive encephalopathy with
impairment; strategic infarctdementia

Small vessel dementia; subcorticalischaemic vascular dementia;
strategic infarct dementia

Form(s) of VCI- mild or major VCI(VaD) †

Data in Table modified from Kalaria et al,109) and several original references.8)   Several disorders may also occur with other co-morbidities such as coronary artery disease, congestive heart failure,
hypertension, diabetes, hyperlipidaemia, hypercoagulability, renal disease, atrial fibrillation and valvular heart disease.  *Other miscellaneous causes of stroke including mechanical, invention induced orrare genetic syndromes such as trauma, iatrogenic, decompression sickness, air or fat embolism, transplantation and Werner’s syndrome can lead to cognitive impairment. † VCI determined when two or
more cognitive domains are affected per minimal harmonisation guidelines or minor VCI.110)  Abbreviations: CAA, cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy; CARASIL; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; ICH, intracerebral haemorrhage; MCA, middle
cerebral artery; MELAS, Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like Episodes; MERRF, PCA, posterior cerebral artery; PVS, perivascular spaces; SLE, systemic lupus
erythematosus; SVD, small vessel disease; VaD, vascular dementia; VCD, vascular cognitive disorder; WML, white matter lesion.

Mitochondrial disorders (MELAS, MERRF,  Leigh’s
Metabolic disorders disease, Myoclonic epilepsy with ragged red fibres),
Menkes disease, Homocystinuria, Tangier’s disease

Intracerebral small arteries,
territorial arteries

Leptomeningeal arteries,
intracerebral subcorticalarteries

CADASIL, CARASIL, retinal vasculopathy withcerebral leukodystrophies (RVCLs), Moyamoya
disease, Hereditary angiopathy, nephropathy,
aneurysm and muscle cramps (HANAC)

Monogenic stroke
disorders

Lacunar infarcts/lacunes,
microinfarcts, WML

Leptomeninges, intracerebral Cortical microinfarcts,
arteries
lacunar infarcts,  WML

Sporadic and Familial CAAs (Amyloid β, prion
protein, cystatin C, transthyretin, gelsolin)

Vasculitides

Amyloidangiopathies

White matter changes, SVD likelesions

Various cerebral andsystemic vessels

Vasculitis (infectious and non-infectious);
rheumatoid arthritis

Non-atherosclerotic
non-inflammatory
vasculopathies

Cortical infarcts,
lacunar infarcts/lacunes,
microinfarcts, WML

Predominant Tissue changes

No pattern of brain infarctions:
haemodynamic, thromboembolic, or
due to occlusion of a perforatingartery.  
Subarachnoid haemorrhage; lacunar
infarcts, PVS

Perforating and penetratingarteries, lenticulostriate
arteries

Vascular Distribution

Arterial dissections (carotid, vertebral andVertebral, basilar, Branches
intracranial), fibromuscular dysplasia, dolichoectaticof MCA, mural haematoma
basilar artery, large artery kinking and coiling,
perforating artery; SVD
radiation induced angiopathy, moyamoya disease

Hypertensive vasculopathy

Table 1
Spectrum of disorders with SVD pathology associated with cognitive impairment or dementia

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Cerebral Small Vessel Disease and Dementia

TREX1Cathepsin-A

COL4A1;
COL4A2(dominant in coding
regions; 3’ UTR in
COL4A1)
TREX1 (dominant)
CTSA(dominant)

20-30

14-50

30-50

20-40

36-52

COL4A1 and COL42- related disorders /PADMAL*RVCL disorders: HERNS (Chinese
descent);
CRV (cerebroretinal vasculopathy);
HVR (hereditary vascular retinopathy)

CARASAL

Hereditary small vessel disease of thebrain (SVDB) †21-

Unknown functions

ER stress response; disruption of multienzyme complexes in lysosomes

Lysosomal peptidase complexes with β-galactosidase, neuraminidase; predicted
ECM dysregulation-

Disruption of cell death mechanisms,
impaired DNA degradation and repair

Weakening of vascular BM; ER stressresponses.  

Promotes serine-protease-mediated cell
death, suppresses TGFβ expression

Aberrant cell-cell signalling, activates
unfolded protein response and impaired
gene transcription (NICD)

Proposed dysfunction(s)3’ → 5’-prime exonuclease DNase III

Collagen IV, α1 and α2 chains; ECM
disruption

Serine protease;  ECM dysregulation

Transmembrane cell signalling receptor;
SMC loss; ECM changes

Protein type/cellular abnormalities* COL4A1 and A2 gene disorders consist of 5 major phenotypes:111) (1) perinatal haemorrhage with porencephaly, (2) hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy(HIHRATL)112), (3) SVD with Axenfeld-Rieger anomaly (anterior segment dysgenesis of the eye), (4) hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) and (5) PADMAL,93)
which also incorporates subcortical angiopathic leukoencephalopathy and hereditary multi-infarct dementia of the Swedish type.91,92)   † Several other disorders prominently characterised byleukoencephalopathy and cognitive impairment are described in isolated families. ‡ Age of onset signifies when first cerebrovascular event or gait disturbance due to spasticity was recorded.
Abbreviations: BM, basement membrane; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL, cathepsin A related arteriopathy with strokes
and leukoencephalopathy;  CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; ECM, extracellular matrix;  NICD, Notch intracellular domain; PADMAL,
pontine autosomal dominant microangiopathy and leukoencephalopathy; RVCL, autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Not known

COL4A1 and
A2

HTRA1
(>50 in symptomatic
HTRA1
carriers or typical
CARASIL)CARASIL
Autosomal récessive

NOTCH3

Protein

20-60

NOTCH3(dominant >280)

Onset Age Gene(yrs.) ‡(mutations)CADASIL(most common); Autosomal dominant)DisorderTable 2
Molecular genetics and pathology of cerebral arteriopathies

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Raj N Kalaria et al.

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Cerebral Small Vessel Disease and Dementia

Figure 1
Schematic of a coronal brain section showing different types of cerebral SVD pathology.   Modified from Kalaria andSepulveda-Falla.3)   Numbers in boxes [1-7] correspond 1) perivascular and deep WM attenuation, 2) lacunar infarcts(<1.5cm), 3) WM infarcts (1-2 cm), 4) microinfarcts (<0.5 cm), 5) lobar or deep microbleeds or haemosiderin, 6) CAA or
CAA related ICH, 7) superficial siderosis and 8) perivascular spaces.  Increased perivascular spacing occurs because of
reduction in arterial vascular tone and failure of IPAD113).  The WM changes ensues due to a chronic hypoxic state anddecline in oligodendrocytes114,115).   White arrows in panels show location of key lesion(s).   B, Microscopic images of
cerebral arterioles showing gradual changes a, some loss of SMC; b and c, degrees of fibrinoid necrosis and d, hyalinosis
or glassy like appearance of vessel wall.  Abbreviations: ICH, intracerebral haemorrhage; SVD, small vessel disease; WM,
white matter.  Magnification bar: 100 μm.  

22 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Hikari Takeshita

Young Investigator Award (review article)

The deleterious effects of Alzheimer's disease pathology onskeletal muscle

Hikari Takeshita, PhD1,2)

1) Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
2) Department of Medical Science Technology, Faculty of Medical Science Technology,Morinomiya University of Medical Sciences, Osaka, Osaka, Japan
Abstract:

Cognitive dysfunction and skeletal muscle dysfunction tend to coexist, and the combined condition of MCI and physical frailty isdefined as cognitive frailty. In this review, to understand the pathomechanism of skeletal muscle dysfunction in Alzheimer's

disease (AD), the most common cause of cognitive impairment, we first describe the physiological functions of Aβ peptide, thecausative factor of AD, and its precursor, APP, in skeletal muscle. Next, the mechanism of skeletal muscle dysfunction associatedwith AD is discussed based on the findings of inclusion body myositis, which shows pathological conditions similar to AD, such as

the accumulation of Aβ42. Then, recent findings on the effects of skeletal muscle secretory peptides on AD pathology will bepresented and the physiological significance of the brain-skeletal muscle connection will be discussed. Finally, we will present ourexperimental results on the skeletal muscle phenotype of AD mouse models and discuss the effects of Alzheimer's diseasecausative factors on skeletal muscle.

Key Words: Cognitive frailty, Alzheimer’s disease, Muscle atrophy

Correspondence to:

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine
2-2 Yamadaoka, Suita, 565-0871, Japan.

E-mail: takeshita@geriat.med.osaka-u.ac.jp
Introduction

muscle weakness or reduced ability to walk7, 8).

been explored in many clinical studies, and the coexistence of

weight loss of more than 5% of normal weight9) and that weight

The relationship between physical and cognitive function has

In addition, it has been reported that AD is associated withphysical and cognitive decline has been identified as anloss begins gradually more than 10 years before the diagnosis

and Aging (IANA) and the International Association of

the disease10, 11). Furthermore, muscle mass loss is observedof AD and accelerates especially 2-3 years before the onset of

emerging risk. In 2013, the International Academy on Nutrition

from the early stages of AD and continues to decline as theGerontology and Geriatrics (IAGG) defined cognitive frailty (CF),as the coexistence of physical frailty and mild cognitive

disease progresses12, 13). And, it has also been reported that

addition, CF was defined as the absence of dementia, such asleg stand time decline early in AD patients, and that walking

attention not only to the existence of common

cognitive impairment14).

balance functions such as the Functional Reach Test and one-

impairment, MCI (defined as Clinical Dementia Rating = 0.5). In
Alzheimer's disease (AD)1). The definition of CF has drawn

ability and muscle strength decline with the progression ofThus, it has been suggested that loss of muscle mass andpathophysiological mechanisms in dementia and physicalphysical disability in AD may occur before the manifestation of

weakness, but also to the possibility that skeletal muscle

dementia, and it has been hypothesized that skeletal muscle

dysfunction may occur before cognitive impairment manifests.

symptoms in AD patients are a manifestation of latent

Cross-sectional studies have reported an association between

neurological deficits in patients who do not meet diagnostic

physical and cognitive function, and cohort studies havecriteria for dementia15, 16, 17).

showed both that cognitive decline was associated with the riskof physical decline and that the rate of concomitant cognitive

Although there are many clinical studies on AD and skeletal2)

impairment increased with the severity of physical frailty

3, 4)

.

muscle disorders, the pathophysiological mechanisms of why

On the other hand, CF is reported to have a higher rate ofskeletal muscle disorders occur in AD and whether skeletal, but prospective

muscle disorders exacerbate the pathophysiology of AD are still

higher when there is a decline in physical function, such asrole of AD pathogenic factors in skeletal muscle, inclusion bodyprogression to vascular dementia than AD5, 6)cohort studies have reported that the risk of developing AD isunclear. In this review, we will first discuss the physiological

23

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

The deleterious effects of Alzheimer's disease pathology on skeletal muscle
myositis (IBM), a skeletal muscle disease very similar to AD pa-

muscle disease in the elderly and is characterized by weakness

pathology, followed by the results of our brief validation

logically, the presence of atrophic myofibers, fringe vacuoles,of proximal and distal skeletal muscles33, 34). Histopatho-

thology, and the effects of skeletal muscle atrophy on AD

and a variety of proteins including ubiquitin, Aβ protein,experiments using AD model mice and the resulting discussion.

emerin, lamin A/C, valocin-containing protein (VCP), histones,

Physiological Function of APP in Skeletal Muscle

43 kDa TAR DNA binding protein (TDP-43), and p62 have beenreported in skeletal muscle with IBM33, 35, 36). The similarity ofIn the brains of AD patients, senile plaques andthese pathologic findings to neurodegenerative diseases suchneurofibrillary tangles occur in large numbers, and brain

as AD and amyotrophic lateral sclerosis (ALS) is controversial,

atrophy results from the associated neuronal cell death. Senile

but the relationship between these diseases and IBM is not wellplaques are caused by the extracellular deposition of amyloid

understood37).

beta protein (Aβ), which is produced by the cleavage of

To investigate the influence of Aβ peptide accumulation on

amyloid precursor protein (APP), and neurofibrillary tangles

are caused by the accumulation of phosphorylated tau protein

skeletal muscle, Sugarman et al. and Kitazawa et al. generated

expressed in vivo outside the brain18), and in skeletal muscle,

Swedish APP mutation is overexpressed in skeletal muscle

in neurons.

MCK-APP mice, an IBM mouse model in which a human

APP is a ubiquitous protein that is widely

APP has been identified at the neuromuscular junction19). APP

under the regulation of the muscle creatine kinase (MCK)highest during the formation of synaptic connections20, 21, 22, 23).

which a mutation in the presenilin-1 (PS1) gene associated withpromoter38), and MCK-APP/PS1 mice, double transgenic mice in

expression increases during neuronal differentiation and isfamilial AD was added to MCK-APP mice39). MCK-APP and MCK-

And, overexpression of human wild-type APP in mice increases

presynaptic terminals24), and increased APP mRNA expression

APP/PS1 mice are models with increased production of Aβ40

has been reported in regenerating human muscle fibers fromand Aβ42, respectively, in skeletal muscle. MCK-APP/PS1 mice

important for synapse formation and maintenance in vivo25) .

compared to MCK-APP mice and exhibited histopathologic

patients with neuromuscular diseases, suggesting that APP isshowed increased accumulation of phosphorylated tau

Conversely, it has been reported that mice lacking APP havefeatures similar to IBM, including a central core, intracellulardecreased body weight and reduced locomotor activity andaccumulation of Aβ peptide, and increased inflammation

Thus, APP expression is also essential in skeletal muscle toseverely affected in MCK-APP/PS1 mice and developed at an

to form synapses at the neuromuscular junction.

skeletal muscle, as in the brain, induces tau phosphorylation

forelimb grip strength compared to wild-type controls26, 27).

around affected muscle fibers. Physical function was also more

earlier age39). These results suggest that Aβ42 accumulation inmaintain and improve skeletal muscle function due to its ability

and induces cellular damage.

Similar to APP, β-site APP cleaving enzyme 1 (BACE1) and

BACE228), the enzymes of β-secretase, and presenilins 1 and 2

On the other hand, p62, which is abundant in IBM muscle(PS1 and PS2), the catalytic subunits of γ-secretase, have beenfibers, is known to be deposited with neurofibrillary tangles infound to be expressed in skeletal muscle29). In addition, Aβ

AD and Parkinson's disease. Recently, p62 has been reported toperipheral tissues of AD patients, including skin and skeletal

pathways involving p62 are known to selectively degrade tau

accumulation and phosphorylated tau have been reported inmuscle30, 31, 32)

function as an autophagy receptor protein, and autophagy. Regarding the presence of Aβ peptide in skeletaloligomers40). Deletion of p62 in a mouse model of AD (taumuscle, quantification of Aβ40 and Aβ42 peptide levels intransgenic mouse: PS19 model) has been reported to increase

temporalis muscle of AD patients and controls showed that Aβ

the accumulation of tau oligomers in the hippocampus, leading

40 tended to be higher in AD patients than in controls, but not

to brain atrophy and increased inflammation41). Thus, inpatients than in controls30).

thought to be one of the mechanisms of pathogenesis.

skeletal muscle on skeletal muscle morphology and function, as

Impact of Skeletal Muscle NEP Expression in the Pathogenesis

inclusion body myositis, as in AD, autophagy defects are

significantly, while Aβ42 was significantly higher in AD
Next, we discuss the effects of Aβ peptide accumulation inof IBM and AD

suggested by studies of the pathogenesis of inclusion body
myositis.

Neprilysin (NEP), a peptidase, efficiently degrades bioactive

peptides such as cardioprotective BNP, antihypertensive

Skeletal muscle diseases with similar pathophysiology andbradykinin, and Aβ peptides. Regarding the physiologicalsymptoms to AD

function of NEP in skeletal muscle, it has been reported that its

In the skeletal muscle diseases inclusion body myositis

expression is enhanced during skeletal muscle differentiation

hyperphosphorylated tau are known to be present in skeletal

correlates with the degree of myofiber regeneration using IBM(IBM), polymyositis, and dermatomyositis, APP deposition andusing primary human myoblasts and that NEP expression

muscle. Inclusion myositis is the most common age-related

muscle biopsy samples, suggesting an important role in24 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Hikari Takeshitaskeletal muscle regeneration42). In addition, studies using

AD model mice for 2 weeks resulted in memory impairment,

muscle biopsy samples from IBM patients showed that NEPsuggesting that skeletal muscle atrophy may increase theprotein expression was significantly increased compared tosynthesis and secretion of hemopexin from muscle andskeletal muscle from normal controls, and in particular, NEP

promote cognitive dysfunction in AD model mice.

peptides42). This is thought to be a compensatory response to A

Skeletal Muscle Phenotype of APP23 Miceskeletal muscle is also attracting attention as a new treatment

we evaluated skeletal muscle morphology and strength inprotein was highly enriched in abnormal fibers with Aβ

β peptides accumulation. Interestingly, NEP gene transfer into

To investigate the effects of AD pathology on skeletal muscle,

for AD. It has been reported that introduction of an adeno-

APP23 mice, a mouse model of AD, and compared them toassociated virus (AAV) expressing the mouse NEP gene into thewild-type mice. APP23 mice are transgenic for APP with ahindlimb muscles of 3X-Tg-AD mice, a mouse model of AD, andSwedish mutation in the Thy-1 promoter, and the formation of

peptide levels and amyloid deposition43). Similar results haveusually appear around 6 to 12 months of age.

overexpression of NEP in the muscles reduced brain soluble Aβ

intracerebral amyloid plaques and cognitive dysfunction

been observed using other techniques and AD mouse model.

In male APP23 mice and wild-type littermates, we evaluatedIntroducing human NEP plasmid into the skeletal muscle ofskeletal muscle function and cognitive function at 3 months of

APP/PS1 mice, a mouse model of AD, using ultrasoundage. The grip strength test we developed was used to assess
skeletal muscle function49), and the passive avoidance test andcombined with microbubbles, significantly reduced brain Aβ

peptide levels after one month44). These results indicate that

open field test were used to assess cognitive function. Then, as

peripheral expression of NEP has a direct effect on the brain

factors related to both muscle strength and cognitive function,and demonstrate the efficacy of inducing NEP expression in

glucose tolerance was assessed by the ipGTT test and voluntarymuscle for the prevention and treatment of AD.

locomotion was assessed by placing a running wheel in thecage over a 3-day period. After these experiments, skeletal

Effects of Skeletal Muscle Secreted Substances on the Brainmuscle was harvested for histologic evaluation. As a result, grip

Physical inactivity has been cited as a factor strongly

strength, body weight, and some skeletal muscle weights ofassociated with the development of AD45), and there are several

APP23 mice were lower than those of wild-type mice (Fig.1 A,

hypotheses about the mechanism by which exercise is ef-

B). The cross-sectional area of gastrocnemius muscle fibers was

fective in preventing AD. In this regard, it has recently been

also significantly smaller in APP23 mice than in wild-type micereported that brain-derived neurotrophic factor (BDNF), whose(Fig.1 C). There were also no significant differences between

volume . Irisin released into the blood from skeletal muscle

glucose tolerance using the ipGTT test. Results of cognitive

containing protein 5 (FNDC5), a transmembrane precursor

field test showed no significant differences between APP23

secretion is stimulated by exercise, is associated with brain

APP23 and wild-type mice in food intake or assessment of46)

during exercise, is cleaved from fibronectin type III domain-function tests using the passive avoidance test and the open

protein expressed in muscle under the control of PGC-1α.

mice and wild-type mice. However, APP23 mice showed

FNDC5/irisin is known to stimulate the expression of brain-significantly more voluntary movements than wild-type mice

derived neurotrophic factor (BDNF) in the hippocampus, andduring the three days of free activity as measured by the

reduced levels of FNDC5/irisin have been reported in therunning wheel (Fig.2). These findings suggest that skeletalmouse models .

early stage of cognitive dysfunction. In addition, the results ofskeletal muscle atrophy on cognitive function in 5XFAD mice, a

independent of glucose intolerance.

hippocampus and cerebrospinal fluid in AD patients and in AD

muscle dysfunction is already apparent in APP23 mice at the47)

On the other hand, Nagase et al. examined the effects of

the ipGTT test suggest that this skeletal muscle dysfunction ismouse model of AD48). By inducing muscle atrophy in 12-week-

Furthermore, although APP23 mice showed increased

old 5XFAD mice by immobilizing their hind limbs in a castvoluntary exercise, skeletal muscle function and skeletal

prior to the onset of memory impairment, memory

muscle mass were rather decreased, suggesting that theperformance was normal in mice without induced muscle

process of exercise-induced muscle hypertrophy is impaired inatrophy, but memory deficits developed in mice with muscle

APP23 mice.

atrophied skeletal muscle showed that hemopexin, a gly-

overexpression of mutant APP specifically in the central

atrophy. A comprehensive study of molecules secreted by

In addition, APP23 mice are known as a model for

coprotein that binds free heme in the blood, is particularly

nervous system, but we confirmed gene expression of mutant

elevated, and the amount of hemopexin is increased in skeletal

APP in skeletal muscle. A recent study reported that brain Aβ

muscle, blood, and the hippocampus of the brain in mice with

42 affects skeletal muscle, as a model in which Aβ42 wasmuscle atrophy48). In addition, continuous administration of

injected into the dorsal hippocampus of rats also showed

reduced muscle strength and skeletal muscle mass 50) .

hemopexin directly into the ventricles of younger, 6-7 week old

25

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

The deleterious effects of Alzheimer's disease pathology on skeletal muscle

Figure 1
Comparison of muscle strength (A), wet weight of gastrocnemius and soleus muscles (B), and myofiber crosssectional area of gastrocnemius muscle (C) in APP23 and wild-type mice.
WT, Wild-type

Figure 2
Comparison of voluntary locomotor activity between APP23 and wild-type mice over three days.
Assessed by the number of revolutions of the running wheel.

26 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Hikari Takeshita
Therefore, it is possible that the skeletal muscle impairment in

Predictor of Alzheimer Disease, Vascular Dementia, and All

APP23 mice is also dependent on the presence of Aβ42, but

Dementia Among Community-Dwelling Older People: A

more detailed studies are needed.

Systematic Review and Meta-Analysis. Journal of theAmericanDiscussion and Conclusion

Medical

Directors

2016;17(10):881-8.

This review first discussed the possibility that skeletal

Association.

6)		Sargent L, Brown R. Assessing the Current State ofmuscle dysfunction precedes cognitive dysfunction, based on

Cognitive Frailty: Measurement Properties. J Nutr Healthfindings from several clinical trials and the definition ofAging. 2017;21(2):152-60.

cognitive frailty. Next, the negative effects of AD pathogenic7)		PA B, AS B, RS W, SE L, DA B. Association of muscle strength

based on findings from IBM's pathophysiology studies. Thisdecline in community-dwelling older persons. Archives offactors, such as Aβ peptide, on skeletal muscle were discussedwith the risk of Alzheimer disease and the rate of cognitive

series of discussions assumes that AD pathogenic factors suchneurology. 2009;66(11).

as Aβ42 affect skeletal muscle even before AD pathology8)		AS B, RS W, PA B, JL B, DA B. Grip strength and the risk of

becomes apparent. However, the only reports of Aβ peptide

incident Alzheimer's disease. Neuroepidemiology.

quantification in skeletal muscle are studies using temporalis

2007;29(1-2).

muscle, and little is known about the detailed phenotype of9)		H W, C P, K S, G F. Weight change in Alzheimer's disease.

nature of muscle biopsy, which makes it difficult to obtain a10)	Johnson DK, Wilkins CH, Morris JC. Accelerated weight loss

skeletal muscle in AD patients. This is due to the invasive

Journal of the American Geriatrics Society. 1996;44(3).

muscle biopsy sample unless there is an obvious skeletal

may precede diagnosis in Alzheimer disease. Archives ofmuscle disease. For this reason, it is and will remain nearly

Neurology. 2006;63(9):1312-7.

impossible to test for skeletal muscle Aβ peptide in human11)	Stewart R, Masaki K, Xue QL, Peila R, Petrovitch H, White

necessary to further verify the fluctuation of Aβ peptide inweight and incident dementia - The Honolulu-Asia aging

muscle biopsy samples prior to the MCI stage. Therefore, it isLR, et al. A 32-year prospective study of change in bodyskeletal muscle before cognitive dysfunction becomes apparent

study. Archives of Neurology. 2005;62(1):55-60.

using experimental animal methods, and this will be our future12)	Burns JM, Johnson DK, Watts A, Swerdlow RH, Brooks WM.

study topic.

Reduced Lean Mass in Early Alzheimer Disease and Its

Association With Brain Atrophy. Archives of Neurology.

Disclosures: The author declare no conflicts of interest

2010;67(4):428-33.

associated with this manuscript.

13)	Murata S, Ono R, Sugimoto T, Toba K, Sakurai T. Functional

Decline and Body Composition Change in Older Adults

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n e u r o d e g e n e r a t i o n . J o u r n a l o f n e u r o c h e m i s t r y.

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SQSTM1 in the elimination of toxic tau species in a mouseneurology. 2003;179(2).

model of tauopathy. Aging cell. 2022;21(7).

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29

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

A case of Moyamoya disease with Graves’ disease

Case report

A case of Moyamoya disease with Graves’ disease
presenting clinical and radiological improvement
only after treatment for hyperthyroidism

Ryo Sasaki MD, PhD1); Masafumi Hiramatsu MD, PhD2); Toru Yamashita MD, PhD1)

1) Department of Neurology, Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
2) Department of Neurosurgery, Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University, Japan.

Abstract:

Graves’ disease, an autoimmune thyroid disease that results in hyperthyroidism, is rarely complicated by progressive stenosis or

the occlusion of proximal intracranial arteries. The combination of these two pathologies was classically categorized as “quasi-

Moyamoya disease”, but the revised diagnostic criteria for Moyamoya disease established a new disease concept of “Moyamoya

disease with Graves’ disease”, for which an appropriate treatment is still unclear. In the present case, a 35-year-old woman showedtransient hemiparesis and poor concentration. After serum analysis and brain imaging, she was diagnosed as having Moyamoya
disease with Graves’ disease. Her symptoms and radiological findings improved dramatically after medical treatment for Graves’disease without any other interventions. The present case represents a valuable reference for selecting treatment steps for thisrare disease with a unique pathophysiology.

Key Words: Moyamoya disease, Graves’ disease, hyperthyroidism, TIA, cognitive impairment

Abbreviations used: A/E, all extremities; CSF, cerebral spinal fluid; DSA, digital subtraction angiography; FLAIR, fluid-attenuatedinversion recovery; HDS-R, Hasegawa dementia scale-revised; ICA, internal carotid artery; 123I-IMP-SPECT, 123I-N-isopropyl-p-

iodoamphetamine single photon emission computed tomography, MCA, median cerebral artery; MMSE, mini-mental state

examination; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; TIA, transient ischemic attack; TPO,
thyroid peroxidase; TSH, thyroid stimulating hormone.
Address correspondence and reprint requests to:
Dr. Toru Yamashita

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1
Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Tel: 81-86-235-7365, Fax: 81-86-235-7368
Email: pwag680v@okayama-u.ac.jp
Introduction

peroxidase antibody and hyperthyroidism were more frequent

that is characterized by severe stenosis/occlusion of thecriteria of Moyamoya disease were modified, thereby

internal carotid artery (ICA), with the formation of collateral

Graves’ disease” rather than quasi-Moyamoya disease (Kuroda

Moyamoya disease is a progressive cerebrovascular diseasein adults than had previously been expected, so the diagnostic

proximal median cerebral artery (MCA) or distal end of theestablishing the disease concept of “Moyamoya disease withvessels that look like puffs of cigarette smoke (Suzuki et al.

et al., 2021). The standard medical treatment options for1969). Patients with Moyamoya disease present variable

Moyamoya disease include antiplatelet agents and surgicalsymptoms such as ischemic stroke/transient ischemic attack

revascularization. Although both treatments were reported to(TIA), intracranial hemorrhages, seizures, headaches, andbe effective for symptomatic Moyamoya disease patients

disease, an autoimmune thyroid disease caused byMoyamoya disease with Graves’ disease was unclear.

rarely complicated by Moyamoya disease. Graves’ disease withhaving Moyamoya disease with Graves’ disease showing

cognitive or psychiatric changes (Scott et al, 2009). Graves’

without complications, the appropriate treatment for

autoantibodies of the thyroid stimulating hormone receptor, is

In this report, we present a 35-year-old woman diagnosed as

intracranial artery stenosis was classically categorized astransient hemiparesis and poor concentration. Her symptoms“quasi-Moyamoya disease”, with this disease group having

and radiological findings improved dramatically after medical

certain causative complications typical of Moyamoya disease.

treatment for Graves’ disease.

However, it was recently discovered that elevated anti-thyroid30

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Ryo Sasaki et al.
Case reporttriiodothyronine (fT3, 15.20 pg/ml, normal 2.30-4.00 pg/ml),in her right hand, and transient weakness in her right limb, so

anti-TPO antibody (998.5 IU/mL, normal upper limit 3.3 IU/

A 35-year-old woman showed poor concentration, numbness

thyroglobulin (Tb) (127.82 ng/mL, normal 3.71-35.12 ng/mL),she visited a local hospital. A general examination revealedmL), and anti-TSH receptor antibody (7.53 IU/l, normal upper

hyperreflexia in all extremities (A/E) without muscle weakness.

limit 2.00 IU/L). Serum level of TSH remained undetectable. A

Blood tests showed elevated levels of free thyroxine (fT4, 3.43

cerebral spinal fluid (CSF) study showed normal pressure,ng/dl, normal 0.75-1.45 ng/dl) and anti-thyroid peroxidase

normal cell count (1/µl, monocyte 100%), and a normal level oflevels of thyroid stimulating hormone (TSH, undetectable).

A whole body CT showed no evident features of malignancy.

(TPO) antibody (540 IU/ml, normal < 16 IU/ml) and decreased

protein (38 mg/dl, normal 10-40 mg/dl).

Magnetic resonance imaging (MRI) of her brain showed no

A brain MRI showed leptomeningeal high signal intensity (“Ivyshowed bilateral MCA stenosis (data not shown). She wasinversion recovery (FLAIR) images (Fig. 2A, B). An MRA

examination (Fig. 1).

with the poor depiction of distal MCA. A 123I-N-isopropyl-p-

brain infarction and magnetic resonance angiography (MRA)sign”) in the frontal and parietal lobe on fluid-attenuatedreferred to our hospital and was admitted for a closer

revealed bilateral proximal MCA stenosis (Fig. 2C, arrowheads)

iodoamphetamine single photon emission computed

She was 155.5 cm tall and weighed 48.9 kg. Her bloodpressure was 152/84 mmHg and her heart rate was 95 beats/

tomography (123I-IMP-SPECT) image showed low accumulation

medication. After admission, she claimed poor concentrationand occipital lobe.

in the bilateral frontal lobe (Fig. 2D, arrowheads), parietal lobe,

minute. She had no medical or family history or past use of

She was diagnosed with Moyamoya disease with Graves’and general fatigue all day. A neurological examinationdisease. Cerebral angiography, which may provide detailed

revealed a slightly drowsy state but showed a normal score in

vessel information, was abandoned because the iodine contrast

the mini-mental state examination (MMSE, 30/30) and

Hasegawa dementia scale-revised (HDS-R, 29/30), normal

media could potentially worsen her thyroid function. We

pathological reflex, and a standard sensory system without any

condition, and then perform angiography or transcatheter

planned to treat Gravesʼ  disease first to normalize her

muscle power, generally hyperreflexia in A/E without

intervention. We started by administering 20 mg of potassiumother abnormal findings. Serum analysis showed continuously

iodide followed by 15 mg of thiamazole. After the start ofelevated fT4 (4.79 ng/dl, normal 0.75-1.45 ng/dl), freeFig. 1)
Clinical course of the present case: The ischemic attack and cognitive symptoms withhyperthyroidism improved dramatically after the administration of potassium iodide and thiamazoleand completely disappeared after induction of cilostazol.

31

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

A case of Moyamoya disease with Graves’ disease

Fig. 2)
A brain magnetic resonance imaging (MRI) showing leptomeningeal high signal intensity (“Ivy sign”) on fluid-attenuatedinversion recovery (FLAIR) (A) especially in the frontal lobe (B, arrowheads). A magnetic resonance angiography (MRA) image
showing bilateral proximal MCA stenosis (C, arrowheads). A 123I-N-isopropyl-p-iodoamphetamine single photon emission
computed tomography (123I-IMP-SPECT) image revealed hypoperfusion in the bilateral frontal lobe and left occipital lobe (D,arrowheads). A brain MRI at 352 days after the first symptom showing improved leptomeningeal high signal intensity (E, F)
without a significant improvement of MRA finding of bilateral proximal MCA stenosis (G, arrowheads). A digital subtraction
angiography (DSA) image showing bilateral MCA (left > right) stenosis with an abnormal vascular network (“moyamoya vessels”)(H, I, arrowheads).

32 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Ryo Sasaki et al.
treatment, fT3 and fT4 gradually decreased to a normal range,

vascular stenosis due to Moyamoya disease is caused byand her cognitive symptom (poor concentration) disappeared 2

neointimal hyperplasia, disruption of the internal elastic

months after the start of this treatment. In addition, thelamina, and medial attenuation (Fox et al., 2021). In addition,

frequency of transient muscle weakness in the right upper andincreased thyroid hormones may cause progressive vascular

lower extremities decreased to about once a month (Fig. 1).

narrowing through a rise in vascular sensitivity to the

At 352 days after the first symptom appeared, she was

sympathetic nervous system (Liu et al., 1994).

admitted to our hospital’s neurosurgery department for

The present case clearly demonstrates that treatment ofreassessment. A brain MRI showed an improvement ofhyperthyroidism should be considered before antithrombotic

The MRA finding of bilateral proximal MCA stenosis did notdisease. To achieve a successful and minimally invasive

leptomeningeal high signal intensity (Fig. 2E, F, arrowhead).

drugs or surgical therapy for Moyamoya disease with Graves’

improve significantly (Fig. 2G, arrowheads). A digitaltreatment, staged management is recommended. This includes

subtraction angiography (DSA) showed bilateral MCA stenosis

diagnosis of Ivy sign by MRA, initial treatment for(left > right, Fig 2I, black arrowhead) with an abnormal

hyperthyroidism, a detailed examination by angiography with

vascular network (“Moyamoya vessels”) (Fig 2H, 2I,

iodine contrast media after normalization of the thyroid

arrowheads). After adding 200 mg of cilostazol medical

function, and consideration of antiplatelet agents if stenosis

treatment, her motor and cognitive symptoms completely

still persists. The present case represents a valuable reference

disappeared (Fig. 1).

for appropriate treatment steps for this rare disease with aunique pathophysiology.

Discussion

Disclosures: The authors disclose no potential conflicts ofA typical symptom of Moyamoya disease, transient

hemiparalysis, was observed in the present case, butinterest.

neuropsychiatric symptoms such as poor concentration or
general fatigue are relatively rare (Hiruma et al., 2022).

Acknowledgments

regardless of the coexistence of cerebral infarctions (Karzmark

Scientific Research (C) 20K09370, 20K12044, Challenging

can cause related neurocognitive dysfunction leading toand by Grants-in-Aid from the Research Committees (Toba K,(Nakamizo et al., 2018). In the present case, our therapeutic

Development.

severe cortical hypoperfusion potentially leading to theReferences

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Research 21K19572, Young Research 20K19666, 21K15190,

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KPJ, Calviere L, van der Zwan A, Klijn CJM. Cognitive

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disease with Gravesʼ  disease. Report of three cases and areview of the literature. Intern Med. 2006; 45: 649-653.

11)	Liu JS, Juo SH, Chen WH, Chang YY, Chen SS. A case ofGraves’ diseases associated with intracranial moyamoya
vessels and tubular stenosis of extracranial internal carotid
arteries. J Formos Med Assoc. 1994; 93: 806-809.

34 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Greetings from the President of the Japanese Society
for Vascular Cognitive Impairment
Yoshio Ikeda, MD, PhD

Department of Neurology
Gunma University Graduate School of Medicine
General oral presentations including those received young

It is my great honor to administrate the Japanese Society forinvestigator’s award were on the cutting edge, and contributed

Vascular Cognitive Impairment as the 4th president. Thisto provide useful scientific information for participants.

society has been developing with great support of the former

The purposes of academic activities of this society include topresidents, members of each committee, academic members,
and secretariats. This society was initially established as thestudy the vascular factors related to the occurrence andrenamed to the Japanese Society for Vascular Cognitive

researchers in the basic and clinical fields to promote research

progression of various types of dementia, and integration ofJapan Vas-Cog Study Group in April 2010, and has been

activities. In addition, doctors and researchers in the fields such

Impairment also known as the Vas-Cog Japan in October 2014.

As of December 2022, the number of academic members is

as neurology, cardiology, geriatrics, psychiatry, andadvisors and 2 auditors. I sincerely thank all colleagues forperspectives beyond their specialties. We are developing

neurosurgery carry out activities from a wide range of209, and it is composed of 68 councilors, 22 directors, 3

unique activities that are not recognized in other academic

their effort to raise awareness of the Vas-Cog Japan.

societies.

Since COVID-19 pandemic began, all of social, educational,

According to the efforts of editorial board members, the Vas-

cultural and academic activities were restricted. The mRNA

Cog Journal has been resized larger since an issue of year

vaccines and the novel medicines for the SARS-CoV-2 could

2022 than the previous one. Contents of the journal werereduce the number of patients with severe symptoms, however,refined and its visibility was improved. Further investigations

COVID-19 is still big threat, and repeating to increase andare being promoted by the journal editorial board to publish

decrease the number of patients. After struggling against the

SARS-CoV-2 for three years, introduction of so-called “new-our papers in PubMed Central (PMC) in the near future.

reverse our academic activities. Due to COVID-19 pandemic,

therapies on Alzheimer’s disease patients at the early stage

Recent results of clinical trials of anti-amyloid beta antibody

lifestyle” and treatment/prevention options could gradually

revealed promising effect to reduce amyloid beta-deposition in

the Vas-Cog Japan 2020 meeting was suspended, and the Vas-

Cog Japan 2021 meeting was totally held online. Finally, we

the brain and improve cognitive function. However, it is still

Tokyo as hybrid style. The number of participants was 101 on

The Vas-Cog Japan society is focusing on elucidation of the

difficult to treat patients with dementia at the advanced stage.

could hold the Vas-Cog Japan 2022 meeting and gather inpathophysiology of dementia, especially from the aspect ofsite and 98 on the web. I was very pleased to be able to discussvascular risk factors. We will also try to establish effective

face to face at the meeting. I greatly appreciate co-presidents

preventive and therapeutic interventions, which in turn willDrs. Kazuo Kitagawa and Koichi Kozaki for their tremendous

lead to great social contributions. I think that the activities ofcontribution to conduct the meeting. Theme of the 2022

this society fit well with the academic needs of specialists andmeeting was “cerebral small vessel disease and cognitive

professionals in many fields. We sincerely look forward to yourimpairment, frailty, sarcopenia”. All of sessions such as special

participation.

and educational lectures, symposiums and others were

fascinating, and we discussed an important relationshipbetween cerebral small vessel disease and frailty/sarcopenia.

35

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Reports of the Vas-Cog Japan 2022

Department of Neurology, Tokyo Women’s
Medical University

Department of Geriatric Medicine, Kyorin
University School of Medicine

Kazuo Kitagawa MD, PhD

Koichi Kozaki MD, PhD
conference chairs. We had two education programs by

The Vas-Cog Japan 2022 was held on August 6th, 2022

professors Ikeda and Hanyu, two YIA sessions, and four

(Saturday) at Osaki Bright Core Hall and also on the WEB. The

symposiums. As a sponsored seminar, we had two lunch andhall is about 10 minutes-walk from Osaki station across

two afternoon seminars. Furthermore, we held education

Meguro River, very popular and famous in the cherry blossom

seminars for occupational health physicians. We hope all theseason. The society meeting was either postponed or held on

the WEB due to COVID-19 pandemic these three years. Thisparticipants really enjoyed our program.

after 2019. A total of 224 researchers participated in theparticipation and all the support to the meeting.

We would like to express our deep appreciation for theyear’s meeting was held on site and face-to-face, first since
meeting, and hot discussions were exchanged.

The theme of this year’s meeting was “Cerebral small vessel

disease and cognitive impairment, frailty and sarcopenia”. We

are happy to meet many researchers in the field of neurology,

geriatric medicine, cardiology, metabolic diseases andpharmacology, who are involved in these topics. Plenary

lectures were “Cerebral small vessel disease: bridge from

cerebral vessel disease and dementia” by Kazuo Kitagawa, and“Frailty and dementia in the elderly” by Koichi Kozaki, two36 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Welcome to Vas-Cog Japan 2023
Theme: Innovation in vascular cognitive impairment research

Congress Chairperson of the 13th Annual
Meeting of the Japanese Society for Vascular
Cognitive Impairment (Vas-Cog Japan)
Professor, Department of Neurology, The Jikei
University School of Medicine

Congress Vice-chairperson of the 13th Annual
Meeting of the Japanese Society for Vascular
Cognitive Impairment (Vas-Cog Japan)
Professor, Department of Neurology, Tokyo
Medical University

Masahiko Suzuki MD, PhD

Hiroo Terashi MD, PhD
I will be the Vice-chairperson of the 13th Annual Meeting of

It gives me great pleasure to welcome you to the 13th

Vas-Cog Japan (on Saturday, August 5, 2023, at Roppongi Hills

annual meeting of Vas-Cog Japan in a hybrid format.

Mori Tower), which will be presided over by Professor

This annual meeting will be held on August 5th, 2023, at

Masahiko Suzuki of the Jikei University School of Medicine.

Roppongi Academy Hills, Tokyo, which is located on the 49th

floor of Roppongi Hills Mori Tower with a panoramic view of

The theme of the Meeting is “Innovation in Vascular Cognitive

The theme of this meeting is “Innovation in Vascularfrom various fields will actively interact with one another, andImpairment Research.” We hope that clinicians and researchers

Tokyo.

Cognitive Impairment Research”, which includes both basic andthat the Meeting will serve as a venue for sharing creative

In addition, pre-symposium to Vas-Cog 2023 in Gothenburg

format. However, if the situation permits, we would like a large

research information. The Meeting will be held in a hybrid

clinical research to facilitate further development in the field.

number of people to attend the Meeting at the venue. We lookwill be jointly held with the tremendous support from both Dr.

forward to seeing you in Tokyo.

Ihara (Director, National Cerebral and Cardiovascular Center)

and Prof. Mizuno (Kyoto Prefectural University)

Although the COVID-19 pandemic situation still holds

uncertainty, I hope that you will enjoy the wonderful view ofTokyo from this facility and this opportunity to interact withfellow scholars to exchange wisdom and inspire innovation in
the field.

37

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Meeting report of Vas-Cog Asia 11 from Kaohsiung
Toru Yamashita MD, PhD
General Secretary of Vas-Cog Asia

reception was held to allow researchers to communicate with

I would like to report the great success of Vas-Cog Asia 11,

each other while taking care to avoid infections. We arewhich was held at Kaohsiung   (Taiwan) on November 26th

reminded of the importance of researchers actually meeting(2022) always jointing with Asia-Pacific Stroke Conferenceeach other, reporting on their recent activities, and interacting(APSC) based on the great supports by Professors Byung-Woo

Yoon (APSO president, Seoul) and Ku-Chou Chang (APSC2022

with each other.

entry into Taiwan, allowing entry without a quarantine period(2023) under direction of our President Tsong-Hai Lee (Taipei).

realized. During the conference period, the local elections in

Cog meetings to present and discuss on vascular factors of all

Next Vas-Cog Asia 12 is going to be held in Hong Kong

Chair, Taiwan).  Regulations against COVID-19 were relaxed for

All of you are welcome to actively join these forthcoming Vas-

with only a self-check antigen test, and local participation was

type dementia.

Taiwan were held, and I could feel the excitement in the city.



At Vas-Cog Asia, around 50 researchers from various

countries including Japan, India, Taiwan, Korea, China,

Thailand, and Indonesia gathered locally or on the web to
discuss the latest topics in dementia related to cerebrovasculardisorders, as shown below photo. Among others, there was areport that PDGFRα in spinal fluid is useful as a marker ofblood-brain barrier damage in patients with Alzheimerʼsdisease, which led to much discussion. In the evening, a38

December 19, 2022

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Reports of Vas-Cog Japan Council Meeting
Kenjiro Ono, MD, PhD

Department of Neurology, Kanazawa University
Graduate School of Medical Sciences
The 13th board and council meeting of the Japanese Society*	The chief editor of the academic magazine, Dr. Toshiki Mizuno

members onsite, 33 members on the WEB, on the 6th oflecturers submitted their manuscripts, and we were able tofor Vascular Cognitive Impairment was held together with 21

	From the 8th issue onwards, the chairman and special

August 2022. The representative director and committeeenrich the content, but the increase in the number of pages

were approved by members.

reported that the cover only was in color and the middle

members reported the topics shown below and all proceedings

increased the publication costs. From issue 9 onwards, it was
pages were in black and white to reduce costs, and that all［Membership］

members of the committee were making efforts to collect

204 regular members (As of June 22, 2022)

advertisements in line with the publication costs.

［Report from each committee leader］* The leader of board for finance, Dr. Kenjiro Ono*	The leader of board for the ARIKATA, Dr. Ryuichi Morishita	A committee meeting was held, and it was discussed that an	A committee has been held, and it was reported that there wasincrease in the number of members is necessary for thean opinion that we are proceeding from PMC publication

financial soundness of the society. Among them, there aretoward becoming an academic organization, and that wemany neurologists, so it was proposed to invite other fields

should apply for additional applications to the Japanesesuch as neurosurgeons to join this society and to create aSociety of Anti-Aging Medicine as regarding the credits ofspecialist system.

other academic societies,. It was decided to proceed with thespecialist system as an issue for future consideration.

*	The leader of board for COI, Dr. Masahiko Suzuki

	Although the committee did not hold a meeting this year, it*	The leader of board for increasing membership and public

was reported that a committee meeting would be held torelations, Dr. Kazuo Kitagawa

	A committee reported that this society may invite doctors

prepare the English version of the COI report.

who are active in other academic societies to join as［Plans for future meetings］

from the facilities of executives such as directors andRoppongi Academyhills

symposium speakers, and encourage young doctors to join

1. The 14th Meeting (5th of August 2023)

councilors in order to increase the number of members. In

Chairmen: Dr. Masahiko Suzuki

addition, regarding the links between academic societies, if a

2. Refer to the last page for subsequent schedules.

director of our society is a director of another academic

society, we may explain that we would like you to work on

the links with other academic society.

39 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2023 NO.9）

Editor’s Note
Masayuki Satoh, MD, PhD

Professor
Department of Dementia and Neuropsychology,
Advanced Institute of Industrial Technology,Tokyo Metropolitan Public University Corporation
This volume includes very interesting articles. Usingof Moyamoya disease with Graves’ disease, who complicated byquantitative amyloid PET analysis, Dr, Kasahara reported that

progressive stenosis or occlusion of proximal intracranial

more severe cerebrovascular disease (CVD) findings arearteries. The symptoms and radiological findings improved

associated with milder amyloid-β (Aβ) accumulation indramatically after medical treatment for Graves’ diseaseof Aβ and CVD pathologies has been shown to significantly

the present investigation of dementia is carried out mainly

patients with Alzheimer’s disease (AD). Simultaneous presence

without any other interventions. As shown in this volume, too,accelerate the onset of clinical dementia and cognitive decline.

about Aβ.

Professor Kalaria explained, in his excellent review, theLast year, the effectiveness of a new anti-amyloid antibody

relationship between findings of magnetic resonance imaging

drug, namely the Lecanemab , was reported. The therapy of theloss of smooth muscle cells and disruption of the extracellular

cost of the drug, the anti-amyloid therapy to AD has the(MRI) and small vessel disease (SVD). Cerebral vessels undergo

AD is supposed to enter the new stage. But, besides the highmatrix within basement membranes with consequences on

essential problem which should have been resolved. The Nuninterstitial fluid drainage. The distribution and quantity of SVD

study by professor Snowdon had revealed that the dementia

pathology involving both parenchymal lesions and arteriopathy

did not always occur even if the pathological process of thedetermined disorders. SVD is part and parcel of almost all types

suffered from the dementia with almost normal brain

skeletal muscle dysfunction in AD. The author described thetheir brain pathology showed very severe Amyloid deposition.

vary with age, gender, vascular risk factors and genetically

Amyloid cascade reached the final stage. Some persons hadof dementias. Dr. Takeshita showed the pathomechanism ofpathology, and others had been cognitively normal thoughphysiological functions of Aβ peptide, the causative factor ofThis fact means that, in order to occur the AD, another factor isAD, and its precursor, APP, in skeletal muscle. Then, thenecessary except the Amyloid deposition. But we have notmechanism of skeletal muscle dysfunction associated with AD

known what this factor is. We can say that the essential andis discussed based on the findings of inclusion body myositis,

important problem remains unsolved for the realization of thewhich shows pathological conditions. Dr. Sasaki reported a casedisease-modifying therapy to the AD.

The past and future annual meeting of Vas-Cog Japan
The   1 st Meeting : August, 2010 (Tokyo) 	

Chairman : Ken Nagata and Toshiya Fukui

The   3rd Meeting : August, 2012 (Tokyo) 	

Chairman : Ryuichi Morishita, Yasuo Terayama, and Koji Abe

The   2nd Meeting : August, 2011 (Tokyo) 	
The   4th Meeting : August, 2013 (Tokyo) 	
The   5th Meeting : August, 2014 (Kyoto) 	

The   6th Meeting : August, 2015 (Tokyo) 	

Chairman : Koji Abe and Shokei Mitsuyama
Chairman : Mikio Shoji and Haruo Hanyu

Chairman : Toshiki Mizuno and Hidekazu Tomimoto

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 10th Meeting : August, 2019 (Tokyo) 	

Chairman : Masahiro Akishita and Yoshio Ikeda

The   9th Meeting : August, 2018 (Beppu) 	

Chairman : Katsuya Urakami and Etsuro Matsubara

The 11th Meeting : August, 2021 (Tokushima) 	Chairman : Shunya Takizawa and Masataka Sata
The 12th Meeting : August, 2022 (Tokyo) 	

Chairman : Kazuo Kitagawa and Koichi Kozaki

The 14th Meeting : August, 2024 (Gifu) 	

Chairman : Takayoshi Shimohata

The 13th Meeting : August, 2023 (Tokyo) 	
The 15th Meeting : August, 2025 (planned) 	

Chairman : Masahiko Suzuki
Chairman : Kazuma Sugie- to be continued -49