 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Vas-Cog Journal
No.8 April 01. 2022

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

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Table of Contents

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

4＜ Presidential Lecture ＞ 
Aldosterone plays a pivotal role in dementia  ��������������������

5＜ Special Lecture ＞ Experience in translational research for acute ischemic stroke ������������

9

 ut microbiota and atherosclerotic cardiovascular diseases.
G
Prevention of atherosclerosis via altering gut microbiota or modulating its products. � � 13

＜ Review article ＞ 
Potential biofluid biomarkers for vascular dementia ����������������� 19
Does blood pressure affect the risk of cognitive decline and dementia? �������� 25＜ Young Investigator Award ＞ T au phosphorylation as a molecular mechanism linking diabetes mellitus and Alzheimer’s
disease ������������������������������������� 29＜ Case report ＞ A juvenile case of Alzheimer’s disease with preceding ulcerative colitis �������� 34
Greetings from the President of the Japanese Society for Vascular Cognitive Impairment � 37
Reports of the Vas-Cog Japan 2021 ������������������������� 38
Welcome to Vas-Cog 2022
Theme: Cerebral small vessel disease and cognitive impairment, frailty, sarcopenia���� 39
Meeting report of Vas-Cog Asia 10 from India��������������������� 40
Reports of Vas-Cog Japan Council Meeting ���������������������� 41
Sponsors  ������������������������������������� 43
Editor’s Note/
The past and future annual meeting of Vas-Cog Japan ���������� Inside Back Cover

3

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Editorial
Toshiki Mizuno, MD & PhD

Professor of Neurology, Kyoto Prefectural University of Medicine
2021 is an important year for the development of treatment

important role in this process. Immunotherapy using anti-Aβ

for Alzheimer’s disease (AD). The US FDA approved

antibodies induces not only excretion of Aβ but also

big news in Japan, as well as in the USA, because patients hopepresence of human sporadic CAA inflammation. Initial clinical

Aducanumab from Biogen/Eisai for AD on June 7, 2021. It was

inflammation of the cerebral arteries. These results indicate thefor an effective treatment for AÐ.   The development of new

trials for AD using immunization against Aβ have produced

therapies for AD has been mainly based on the amyloid cascade

Amyloid-Related Imaging Abnormalities (ARIA), involving

decreasing A-beta (Aβ), inhibiting aggregation of Aβ, removing

detected in clinical trials of aducanumab for AD patients similar

hypothesis. Many ideas have been proposed to focus on

edema or hemorrhage and CAA inflammation. This was also

neuritic plaques by specific antibodies and so on. However, few

to these experimental trials. Even if sporadic AD is treated byclinical trials have reached their third phase. Failure of these

immunotherapy, CAA will be induced by enhanced excretion ofclinical trials focusing on Aβ suggest that we should doubt that

Aβ. These results indicate that clinical trials to remove Aβ by

the core pathogenesis of AD is Aβ. Familial AD teaches us that

immunotherapy can be useful only if the total volume of Aβ in

mutations of the amyloid precursor protein can be a genetic

the brain is small and also suggests that development of ways

altered by inhibition of Aβ. Inhibition of Aβgeneration andincreased by immunotherapy.

know if this strategy will be effective against sporadic AD.

collect more data about effectiveness and safety ofantibodies also teach us about the pathological process ofwhether immunotherapy against Aβ is really effective and safe

cause of AD, but it has not been shown that sporadic AD can be

to protect cerebral arteries from Aβ is necessary if Aβ is

aggregation may be necessary to treat familiar AD, but we don’t

It is critical that the Japanese PMDA order Biogen/Eisai toExperimental and clinical trials for AD using anti-Aβ

Aducanumab. Our clinicians and researchers should consider

cerebral amyloid angiopathy (CAA). CAA has been recognized

for AD. The Journal of VAS-COG Japan welcomes the focus onas an important additional pathological feature of AD, but wethese topics and invites discussion of dementia from the

don’t know the physiological mechanisms of this disease.

viewpoint of neural degeneration, vessel disease, protein

Genetic CAA and AD models and trials have shown that Aβ is

misfolding and inflammation.

excreted from the brain through arteries and microglia play an

4 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Shusuke Yagi et al.

Presidential Lecture (review article)

Aldosterone plays a pivotal role in dementia

Shusuke Yagi1,2); Masataka Sata1)

1) Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical sciences, Tokushima, Japan
2) Department of Community Medicine and Human resource Development, Tokushima University Graduate School of
Biomedical sciences, Tokushima, Japan
Abstract:

The number of the elderly with dementia is increasing as the number aging people is increasing. The increase of dementia has

been social problem, because the most majority cause of bedridden in the elderly is dementia replaced by cerebrovascular disease.
Hypertension is associated with increased risk for dementia both in Alzheimer’s disease and vascular dementia. However,interventional studies failed to establish the relationship between blood pressure lowering and dementia. Antihypertensive

treatment with renin-angiotensin-aldosterone system (RAAS) blocker may be an additional strategy for preventing dementia

because systemic or local RAAS activation exacerbate neurovascular damage through enhancement of oxidative stress. Especiallyaldosterone, the most downstream component of RAAS, plays a pivotal role on progression of dementia. Thus, mineralocorticoid

receptor blockade might be beneficial for preventing dementia.

Key Words: Renin-angiotensin-aldosterone system, Hypertension, Alzheimer’s disease, Vascular dementia, Mineralocorticoid

receptor blockers

Corresponding author:

Shusuke Yagi, MD, PhD, 3-18-15 Kuramoto-cho, Tokushima,770-8503, Japan
E-mail: syagi@tokushima-u.ac.jp

Introduction

Alzheimer’s disease (AD) and vascular dementia (VD)

number aging people is increasing. The increase of dementia(AD) and vascular dementia (VD), and it has been thought thatbedridden in the elderly is dement ia replaced bydeposition through a damage of cholinergic neurons and

The number of the elderly with dementia is increasing as the

Major phenotype of dementia includes Alzheimer’s diseasehas been social problem, because the most majority cause of

the major cause of these two types of dementia is amyloid β

cerebrovascular disease. Dementia is related to bedridden andvascular injury, respectively. The two phenotype of dementia

prevention of dementia is thus crucial in terms of promoting

hypertension. AD is a neurodegenerative disease evoked bydeterioration in the quality of life as well as survival rate, andshares the risk factors of life-style related disease, especiallypublic health and decreasing national medical expenses1,2).

damage of cholinergic neurons, leading to deposition of

Several studies showed that onset of dementia could be delayed

amyloid β peptide, especially in the cerebral limbic systemby pharmacological agents such as cholinesterase inhibitors

which includes the hippocampus. VD is evoked by neuraland antibody for amyloid β3); however, strategy of thedamage from a single stroke blocking brain circulation fortreatment of dementia has not been established yet. It ismemory and cognition or from multiple strokes. VD also results

stage after deposit, thus, early detection of cognitive

arteries through exposure to highly pulsatile pressure and flow,

thought to be difficult to remove amyloid β at an advanced

from damage of subcortical small vessels of the medullary

impairment, early stage of dementia, by screening andleading to white matter damage, lacunae and loss of corticalconnection1). These two types of dementia are sometimes

management of hypertension from middle-age are crucial
issues1).

overlapped; thus, it is sometime difficult to distinguish the

impairment and dementia, and the renin-angiotensin-

imaging studies. The prevalence of this mixed-type dementia

Hypertension is the most pivotal risk factors for cognitive

phenotype of dementia only from symptoms, biomarkers, andaldosterone system (RAAS) play pivotal roles for hypertension

has been increasing. Dysfunction of the drainage pathway ofin a blood pressure (BP)-dependent or independent manner.

amyloid β in the perivascular space due to hypertension and/Thus, the RAAS is a pivotal target for prevention of dementia

or other atherosclerotic risk factors leading to disruption of the(Figure). In this review, we focus on effects of the RAAS on

blood-brain barrier (BBB) is thought to be one of the causes ofcognitive impairment resulting in dementia.

amyloid β deposition. Enhanced interstitial fluid drainage inthe hippocampus leading to sieving of high molecular weight

5

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Aldosterone and dementia
solutes and increased concentration of waste products arespace, leading to activation of perivascular macrophages, whichthought to be other causes of amyloid β deposition .

results in enhanced oxidative stress through NOX2 activation.

4)

Thus, inflammation of the perivascular space damages theHypertension is a risk factor for dementia.

neurovascular unit, leading to dementia9).

Local RAAS blockade is, thus, crucial to prevent dementia inHypertension is related to increased risk for dementia.

addition to systemic RAAS blockade; however, controversy has

Longitudinal cohort studies have shown that there is a positive
association between hypertension and dementia5). These results

remained regarding which drugs are useful for blocking theEspecially elevated systolic BP in mid-life was associated with

Recent studies have indicated that the ability of prevention

suggest that lowering of BP reduce the incidence of dementia.

brain RAAS.

cognitive function. Thus, lowering BP from an old age does notof dementia depends on BBB penetration and is independent of

period is thought to be important strategy for preserving

penetration might have beneficial effects compared without

BP-lowering effects1). Thus, RAAS inhibitors with ability of BBB

prevent dementia and BP lowering beginning in the mid-life

those without ability of BBB penetration.

dementia.

There has been a concern that angiotensin-converting

However, interventional studies failed to establish therelationship between BP lowering and dementia. The Syst-Eur

enzyme (ACE) activation is associated with amyloid β

nitrendipine, a calcium channel blocker, in elderly patients

memory clinic cohort, ACE activity in the cerebrospinal fluid

deposition since ACE is involved in amyloid β metabolism. In a

study reported that antihypertensive treatment with
reduced the incidence of dementia, especially AD rather than(CSF) was reportedly associated with brain atrophy and cerebral

treatment with indapamide, a diuretic, in elderly patients did

lower CSF ACE levels, are not preferred for antihypertensive

VD6). The HYVET-COG trial reported that antihypertensive

small vessel disease, suggesting that ACE inhibitors, which may

not reduce the incidence of dementia7); however, meta-analysis

treatment10). However, whether ACE activity is associated withshowed that there were significant favorable effects ofthe prevalence of dementia is still controversial. Recently,

w i th d a ta f r o m o t h e r p l a c e bo - c o n t ro l l e d t r i a l s o ffailure and hypertension. Neprilysin is involved in theantihypertensive treatment when these data were combinedsacubitril-valsartan has been widely used in patients with heart

antihypertensive treatment, and the combined risk ratio

degradation of amyloid β; thus, there has been another concern

favored treatment . BP lowering, thus, seems to have athat sacubitril-valsartan may evoke dementia. Several studies

7)

potential role in prevention of dementia.

have been shown that administration of sacubitril-valsartan is

not associated with the onset of dementia during a short-term

RAAS on dementia

observational period. Therefore, long-term studies assessing

associated with dementia. In systemic RAAS, Angiotensin II alsosacubitril-valsartan on cognitive function11).

the circulation. Circulating aldosterone activation enhances

Mineralocorticoid receptor blockers

Several animal studies showed that RAAS activation is

cognitive outcomes are needed to establish the effects ofstimulates the release of aldosterone from the adrenal cortex to

Aldosterone is a key player in the reabsorption of sodiumoxidative stress, resulting in neurovascular damage.

and fluid, and in potassium excretion in epithelial cells of the

Not only systemic RAAS activation but also local RAAS

renal collecting ducts via cytosolic mineralocorticoid receptor

activation is thought to play a crucial role in neurovascular(MR) activation12). It has been believed that the main role ofdamage. In the local RAAS, The RAAS components have been

aldosterone was to maintain extracellular volume after sodium

identified in various organs such as the heart, kidney, andbrain. The brain expresses genes that encode all components ofabsorption in renal distal tubules, leading to elevating BP, as a

the systemic RAAS, indicating that neurovascular damage candeveloped RAAS through evolutionary process because of

inhibitors. In addition to the production of local RAAS

intake of salt in the age of gluttony leads to RASS activation,

the RAAS8). The local RAAS could be activated independently of

result ofoccur even though the systemic RAAS is suppressed by RAAS

activation of RAAS cascade13). Human-being has

transition of living place from water to land, however, over-components, local infiltration of RAAS components, especiallyresulting in cardio-cerebro vascular events and dementia.

dementia. Angiotensin II receptors are abundantly expressed in

and incidence of hypertension with aging14). Several studies

angiotensin II, plays an important role in the progression ofHigher aldosterone levels were associated with increased BP

have revealed that aldosterone also has additional

the brain, especially in the circumventricular organs, where

physiological and/or pathophysiological effects, including

BBB does not exist between the vasculature and neurons andvarious bioactive chemicals are transmitted from the

suppression of nitric oxide (NO) bioavailability and enhancing

Enhanced permeability of the BBB due to hypertension

addition, MR can be activated in a ligand independent manneroxidative stress, leading to vascular inflammation 15). In

vasculature to the neurons.

under the RAAS activation through Rac1, small G protein16).

promotes the infiltration of angiotensin II into the perivascular6 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Shusuke Yagi et al.
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no conflicts of interest.

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Hypertension in Nonhypertensive Persons. N Engl J Med.

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15)	Yagi S, Sata M. Pre-clinical data on the role of21)	Yagi S, Kadota M, Aihara K-I, Nishikawa K, Hara T, Ise T, etmineralocorticoid receptor antagonists in reversing

al. Association of lower limb muscle mass and energy

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16)	Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H,

Tanaka H, et al. Modification of mineralocorticoid receptor

function by Rac1 GTPase: implication in proteinuric kidneydisease. Nat Med. 2008;14:1370–6. doi:10.1038/
nm.1879.

FigureMR antagonist
Renin

Angiotensin II

Aldosterone

Hypertension
Neuron damage

Dementia

Vascular damage

Cardio-cerebrovascular disease

Figure legend
Renin-angiotensin-aldosterone system (RAAS), especially aldosterone of the most downstreamof the cascade, plays a pivotal role on progression of dementia. Mineralocorticoid receptor(MR) blockers might have beneficial effects on preventing dementia.

8 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Takayoshi Shimohata

Special Lecture (review article)

Experience in translational research for acute ischemic stroke

Takayoshi Shimohata，MD, PhD

Department of Neurology, Gifu University Graduate School of Medicine
Abstract:

Translational research (TR) refers to a series of research processes from basic research in academia to the application of new
drugs and medical technologies in clinical practice. Compared to conventional basic research, in which the goal is the publicationof papers, TR involves a long period of research and many hurdles, including many failures. Therefore, perseverance is required toovercome these hurdles. In addition, it is difficult for a researcher to complete a project alone; thus, it is necessary to appeal to

and work closely with many collaborators. It is also important to have a mission to help others through research. In this paper, I

outline the points for successful TR, including those from basic research to non-clinical studies, related to obtaining intellectual
property rights, and regarding industry-academia collaborations.

Key Words: stroke, translational research, patent, industry-academia collaboration

Correspondence to:

Department of Neurology, Gifu University Graduate School of Medicine
1-1, Yanagido, Gifu 501-1194, Japan
E-mail: shimohata@gmail.com
I. Introduction

repositioning of existing drugs should be considered.

Therefore, it is the responsibility of the researchers publishingexperimental systems are the optimal method to evaluate efficacy.

Next, we move on to basic research, in which in vitro/in vivo

Even a paper with academic value will not lead to a cure.

Ideally, experiments using animal models should be decided

their results to aim for practical applications, a process calledbased on the design of the final clinical trial. After confirming the“translational research” (TR). We have developed three seeds of

drug discovery for acute ischemic stroke for eventual clinicalefficacy of a candidate drug in basic research, more rigorous non-antibody in combination with tissue plasminogen activatorstudies) are conducted. In clinical pharmacology, absorption,clinical studies (pharmacodynamic, pharmacokinetic, and toxicity

applications (an anti-vascular endothelial growth factor (VEGF)[tPA] , progranurlin , and oxygen-glucose deprivation (OGD)1)

distribution, metabolism, excretion, half-life time, dosage,

2)treated microglia and peripheral blood mononuclear celltherapyfrequency of administration, and route of administration are). However, drug discovery requires overcoming many

examined. In my experience, the accuracy and rigor of data

3,4)

hurdles, and many seeds of drug discovery fail to cross theobtained in university laboratories are insufficient at this stage;“death valley.” In this paper, I introduce five points necessary for

thus, it is necessary to take advantage of the expertise ofovercoming the “death valley,” based on our experiences.

pharmaceutical companies with more experience. Finally, healtheconomic issues, namely, pharmacoeconomics, must be

II. ‌Understanding the path from drug discovery to clinical trials

considered. In other words, consider the relationship between

The realization of drug discovery is a long road; the processdevelopment costs, product prices, and cost-effectiveness.

of which requires some understanding. Before starting research

III. ‌Knowing the limitations and improving the quality of

to develop a therapeutic drug, it is necessary to thoroughly

animal experiments

consider if there is a need for the drug, what the indications

will be, and how the drug will differ from existing drugs. The

In addition, the quality of animal experiments should matchnext step is to investigate prior research on therapeutic

the level of human clinical trials by selecting models that arelatter, the patent information platform J-PlatPat (https://www.

“rodents are not small humans.” A recent paper examined why

candidates and the existence of intellectual property. For thesimilar to patients’ conditions, with the understanding thatj-platpat.inpit.go.jp/) is useful. If there are no problems, thedrugs that are effective in animal studies are ineffective inhuman clinical trials5); the authors statistically compared thetype of drug should also be examined. Specifically, consider
whether to focus on small molecules, peptides, or antibodies. At

study design, publication bias, power, and true reportused in basic research, side effects, and the possibility of drug

ischemic stroke in early phase clinical trials and animal studies

probability (TRP) of 50 phase III clinical trials for acute

this time, the presence or absence of inhibitors or activators

9

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Translational research for strokeof each drug. The results suggest that the causes of thisthoroughly discussed.

primary endpoints, and evaluation methods), publication bias,

First, patenting poses a dilemma for graduate students’

middle cerebral artery is occluded, therapeutic intervention isacademic conference before filing a patent application, the seedin the acute phase by infarct volume. There is not only a large

Therefore, until the patent application is completed, graduate

disparity were differences in study design (treatment timing,

There are some difficult hurdles in obtaining patent rights.

and low power (Table 1). In other words, in animal studies, theeducation. If a graduate student presents a paper at an

performed shortly after ischemia, and evaluation is performed

becomes public knowledge and the patent cannot be granted.

barrier between animal experiments and clinical trials, but also

students will not be able to present at conferences, which may

between animal experiments, early clinical trials, and phase III

lower their motivation.

trials. Therefore, an ideal animal study should include a large

Second, obtaining a patent is costly. Drugs that will become

sample size , randomization, blinding, use of animals withinternational products require international patents; thus,

to match that in clinical trials, and evaluation of functional

experience, only applying in Japan and the US is insufficient,comorbidities, a delay in the timing of therapeutic intervention

patent applications must be filed in multiple countries. In my

impairment rather than infarct size. To reduce publication bias,

which bio-venture capitalists and pharmaceutical companies

is not easy to find a drug that works under these conditions,international applications based on the Patent Cooperation

papers with negative results should also be submitted. While itconsider a problem. In general, national applications,only such a drug can be expected to have a high success rate inTreaty, and transition to patent countries are filed, in this order.

clinical trials.

Each of these procedures is costly; in particular, translation

The difficulty mentioned above is the large sampling offees and payments to foreign patent attorneys and patentindividuals. There is a limit as to what can be done in a single

offices are expensive, and securing financial resources is aa small number of cases should be standardized and animal

and Technology Agency (JST), venture capital, drug discovery

laboratory; thus, protocols for drugs that have been effective inserious problem. Specifically, support from the Japan Science

experiments should be conducted through multicenter studies.

ventures, and pharmaceutical companies should be considered;

It is also necessary for journals to more frequently publish

however, obtaining such support is not easy.

IV. Learning about and obtaining intellectual property rights

obtain a substance patent, if possible. A substance patent inmanuscripts reporting results from negative studies.

Third, application patents are a higher hurdle for drug

discovery compared to substance patents; thus, the goal is to

Securing intellectual property rights is essential for the

drug discovery refers to a patent obtained for a newly createdrealization of drug discovery. In academia, it is difficult todrug, while an application patent refers to that obtained whenthus, joint research with pharmaceutical companies isdiffers from its original indication. In the case of drug

conduct clinical trials and apply for regulatory approval alone;an existing drug is found to be useful for a new disease thatnecessary. Therefore, patent applications are needed to develop

discovery using an application patent, the intention of theindustry-university collaborations.

owner of the substance patent (generally, a pharmaceuticalFirst, it is necessary to understand the requirements for filingcompany) is a decisive factor in the subsequent development.

a patent application: the invention must be industrially

While joint development is pursued in some cases, in many

applicable, novel, inventive, not previously applied for, and notothers, the patent does not match the company’s policy and thecontrary to public morals. Particular attention must be paid topatent is rejected without the company showing interest.

“novelty.” If the research results are made “publicly known” bydisclosing information about the invention at conferences or in

V. Identifying an industry-university partner

except in cases where it is possible to apply for an “exception

industry-university collaboration, is usually a pharmaceutical

Therefore, it is important not to make the research resultscompanies for joint development. One way is to use “openpapers, the invention loses its novelty and cannot be patented,

The final outlet for drug discovery, that is, the partner of an

to loss of novelty” under Article 30 of the Japanese Patent Law.

company. However, it is difficult to find pharmaceutical

public knowledge before filing a patent application.

innovation.” This is an attempt by pharmaceutical companies toand I recommend first consulting with the intellectual property

discovery seeds and technologies of outside academics and bio-

accustomed to writing patent specifications, it is common toand its research theme match, an industry-university

a firm that is familiar with your invention and to communicate

the “List of research recruitment activities of pharmaceuticalunderstood manner so the claims and patent scope can bepharmaneeds/#recruitment). In addition, the opportunities for

Deciding if and when to file a patent application is difficult

create innovative new drugs by incorporating the drug

department of your university. Since medical doctors are notventures. If a pharmaceutical company’s drug discovery goals

ask a patent attorney’s office to do so. It is important to choose

collaboration is likely. Such information can be obtained fromthe contents of the invention to the patent attorney in an easily

companies” website (https://japantechnologygroup.jp/10 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Takayoshi Shimohata
References

matching, as shown in Table 2, allow active participation. Evenif a match is not made, it is beneficial for obtaining advice.

1)		Kanazawa M, Takahashi T, Nishizawa M, et al: Therapeutic
Strategies to Attenuate Hemorrhagic Transformation After

VI. Understanding what is expected of pharmaceuticalTissue Plasminogen Activator Treatment for Acute

After obtaining a patent, a university-launched venture is2) 	Kanazawa M, Kawamura K, Takahashi T, et al: Multiple

companies and investors

Ischemic Stroke. J Atheroscler Thromb 2017; 24:240-253

started or an industry-academia collaboration is formed with atherapeutic effects of progranulin on experimental acutepharmaceutical company, with the goal of reaching clinicalischaemic stroke. Brain 138:1932-48, Brain 2015;

trials. It is important to recognize the difference in thinking

138:1932-1948

between conventional research that aims to publish papers and3) 	Kanazawa M, Miura M, Toriyabe M, et al. Microglia

industry-university collaborations that aim for clinicalpreconditioned by oxygen-glucose deprivation promote

applications and practical uses. For example, pharmaceutical

functional recovery in ischemic rats. Sci Rep. 2017;

companies conduct rigorous research and development by

7:42582

setting goals and using Gantt charts to track progress towards4) 	Hatakeyama M, Kanazawa M, Ninomiya I, et al: A novel

accustomed to this type of research planning. In addition, thecells preconditioned by oxygen-glucose Deprivation. Sci

achieving them, while academic researchers are nottherapeutic approach using peripheral blood mononuclear

availability of research time is uncertain due to clinical andRep 2019; 9:16819

educational commitments, making it difficult to follow a Gantt5) 	Schmidt-Pogoda A, Bonberg N, Koecke MHM, et al. Why

cases, it is necessary to compromise and hold regular face-to-in Patients: A Systematic Comparison of Preclinical, Early

chart and keep the collaborative research on track. In such

Most Acute Stroke Studies Are Positive in Animals but Not

face research meetings to ensure the success of bridge

Phase, and Phase 3 Clinical Trials of Neuroprotective

research.

Agents. Ann Neurol 2020; 87:40-51

The priorities in industry-academia collaboration are not6) 	Carlson CR, Wilmot WW. It’s as simple as NABC: how Liz got

needs, approach, benefits, and competition (NABC) that arewhat customers want. Crown Business, New York, 2006.

necessarily academic values but can be summarized as theimportant in innovation.

6)

her job. In: Innovation: The five disciplines for creating

The NABC can be replaced by the

pp85-100

following four questions. Needs: Is the drug really necessary?

Approach: Is the methodology correctly used in this study?
Benefit: Does the drug provide a benefit? Competition: Can the

drug beat the competition? These questions should beconsidered during the design stage of basic research rather

than after the basic research is performed.
VII. Conclusion

In summary, achieving therapeutic innovation requires anunderstanding of the ecosystem and the process of therapeutic

drug development. In addition, I have learned that, in TR, it isimportant to have a passion to contribute to the world andcorresponding persistence. If you work hard, you will meet

supportive people. Although TR is a series of hurdles, the many
people you encounter in the process are also a great joy inretrospect.

Disclosures: Takayoshi Shimohata is an academic advisor to

ShimoJani LLC, a drug discovery venture.

11

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Translational research for stroke

Table 1
Differences between animal studies, early phase clinical trials, and phase III clinical trials5)

Number of studies
Success rate

Sample size (of animals, etc.)
Co-morbid disease
Intervention timing
Randomized and blinded

Animal experiments

Early-phase clinical trials

209

75

Phase III clinical trials
50

69%

32%

6%

Few

Many

Significantly more

None to rare

Existence(at the present moment)

Existence(at the present moment)

Fast

Slow

Slow

(>3 hours mainly)(>12 hours mainly)(>3–12 hours mainly)

Primary endpoints

Few

Many

Most common

Infarct size

Functional prognosis

Functional prognosis

Publication bias

Existence(at the present moment)

Existence(at the present moment)

None

Table 2
Opportunities for matching with pharmaceutical companies(1) DSANJ	The Japan Pharmaceutical Manufacturers Association and the Osaka Chamber of Commerce and Industry aresponsored by the Japan Agency for Medical Research and Development. Information will be provided in advance andinterviews will be conducted with interested companies.
(2) BioJapan	Organized by the BioJapan Organizing Committee. Posters and materials will be displayed at booths and visitors can
exchange business cards and meet pharmaceutical company representatives.
(3) BIO tech	Organized by Reed Exhibitions Japan, Ltd.
(4) New technology briefing.
	Sponsored by the Japan Science and Technology Agency (JST).
(5) Drug discovery seed consultation meetings	Organized by medU-net (Medical University Industry-Academia Network Council).

12 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Tomoya Yamashita et al.

Special Lecture (review article)

Gut microbiota and atherosclerotic cardiovascular diseases.
Prevention of atherosclerosis via altering gut microbiota or
modulating its products.

Tomoya Yamashita; Naofumi Yoshida; Takuo Emoto;
Yoshihiro Saito; Tomohiro Hayashi; Ken-ichi Hirata

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine
Abstract:

Cardiovascular diseases (CVDs) have become a major health problem, because of the associated high morbidity and mortality

among patients. Gut microbiota have been recently implicated as a novel endocrine organ that play critical roles in regulating thehost cardiometabolic function through producing bioactive metabolites. This review investigated the evidence from several clinicaland experimental studies indicating an association between gut microbiota and atherosclerotic CVDs. We mainly focused on theanti-atherogenic gram-negative bacteria, Bacteroides vulgatus and dorei , and their producing lipopolysaccharide. Further, we

would pay attention to gut microbiota-derived deleterious metabolites, trimethylamine N-oxide, and described the present statusof its related research. We believe some of the methods to change the gut microbiota or reduce the deleterious metabolites could
be clinically applied to prevent CVDs in the near future.

Key Words: cardiovascular disease, gut microbiota, lipopolysaccharide; coronary artery disease, trimethyl amine N-oxide, heart

failureCorrespondence to:

Tomoya Yamashita, M.D., Ph.D.

7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 670-0017 Japan
E-mail: tomoya@med.kobe-u.ac.jp
1. Introduction

with emphasis on the possible molecular mechanism.

death in developed countries. Although the gut is not the first

2-1. Coronary artery disease and gut microbiota

it is not only the organ handles digestion and absorption but

microbiota is involved in the incidence and progression ofgut regulates the differentiation of immune cells and protects

specific profile of gut microbiota in coronary artery disease

known as the gut microbiota. The host-gut microbiota

potential of gut microbiota3). We used terminal restriction

Cardiovascular diseases (CVDs) remain the leading cause oforgan that we would think about the pathophysiology of CVDs,

Several studies have been conducted to elucidate which gut

atherosclerotic CVD (Table 1)1~5). At first, we tried to clarify thealso the largest immunologically active organ in the body. The(CAD) patients to investigate a diagnostic and therapeutic

the host from invading microorganism, which are collectively

fragment length polymorphism (T-RFLP) analysis to detect theinteraction has been the focus of increasing interest in recent

profile of gut microbiota in CAD and control patients who haveyears. Although these microorganisms sometimes cause

infectious diseases, they also have beneficial functions for hostdiabetes, hypertension, and/or dyslipidemia.

studies demonstrated that gut microbiota produces andStreptococcus , and Enterococcus ) was significantly increased

absorbed into the host systemic circulation and serve as asignificantly decreased in the CAD group compared with themicrobiota works as virtual endocrine organs, communicates

Another paper based on a shotgun sequencing metagenome-

We found that the order Lactobacillales (Lactobacillus ,including nutrient absorption and vitamin production. Recent

and the phylum Bacteroidetes (Bacteroides + Prevotella ) was

releases many metabolites and toxins, some of which areControl group (Figure 1A).

mediator of microbial influence on the host. Thus, the gut

wide association study of fecal samples from 218 CAD patientswith host distal organs including heart and vasculature throughmetabolism- and immune-dependent pathways. Dysbiosis,

and 187 healthy subjects in China was reported 4). The

with host many diseases including CVDs. This review aims toand the abundance of the genus Bacteroides was found to beabundance of the genus Streptococcus was significantly higher

imbalanced condition of gut microbiota, is shown to be related

decreased in the patients with CAD than in the healthy

highlight the relationship between gut microbiota and CVDs

13

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Gut microbiota and CVD
subjects. These results were almost the same as ours. Given

structure of lipid A moieties of LPS are different among

maintaining a healthy gut ecosystem6), and that the abundance

activating TLR4. This structural difference might mainly

atherosclerotic ischemic stroke and transient ischemic attackacylated lipid A moieties, for example the LPS derived from B.

that Bacteroides species are known to have an important role inbacterial species and the number of acyl chains are critical forof Bacteroides species was found to decrease in patients withdetermine LPS activity8, 9). Generally, the tetra- and penta-(TIA) and obesity (Figure 1B), we hypothesized that some ofvulgatus and B. dorei , elicits reduced TLR4 responses

may help to prevent coronary atherosclerosis progression. We(Figure 2D).

2)

7)

the Bacteroides species may have the potential to regulate orcompared to the E. coli-derived hexa-acylated lipid A moiety9,10)
Our research findings suggest that Bacteroides treatment

further analyzed the gut microbiota using 16S ribosomal RNA

random sequencing and found that Bacteroides (B.) vulgatus

may serve as a novel and attractive therapeutic strategy forand dorei were significantly decreased in CAD patientssuppressing inflammatory response in CVD, and pave the way

compared with controls5) (Figure 1C).  

for further studies investigating fecal LPS levels and preventionof CVD.

2-2. Bacteroides treatment could inhibit atherosclerosis inmice.

2-3. Future perspective on clinical application of LPS researchfindings

To investigate the effect of oral administration of B. vulgatus

and B. dorei on atherosclerotic lesion formation in

Accumulating evidence suggest that systemic endotoxemia

atherosclerosis-prone apolipoprotein E-deficient mice, we

and gut microbiota-derived LPS are involved in the onset andlesion. Oral administration of Bacteroides 2 species

diseases, such as inflammatory bowel disease, obesity andgavage the cultured Bacteroides 2 species and assessed theprogression of not only CVD but also many inflammatory

significantly reduced atherosclerotic lesion5) (Figure 2A). Taken

related metabolic diseases10,11). High fat diet definitely increases

these, we could say that Bacteroides 2 species are anti-

plasma LPS levels at least in mice and plasma LPS is basicallyatherogenic bacteria at least in mice. To clarify the anti-

considered as “toxin” in inflammatory diseases, and is involvedof Bacteroides 2 species-treated mice and found decreasing

therapy which directly reduces blood or fecal LPS do not exist.

atherogenic mechanisms, we assessed the inflammatory status

in the pathophysiology of progression of CVD. Until now,

plasma TNF-α levels and lipopolysaccharide(LPS) activities

Development of clinical application of managing endotoxemia

determined by the limulus amoebocyte tests5) (Figure 2B).   

or gut microbial modulation using microbial drugs could be a

Bacteroides is dominant gram-negative rod bacteria in

novel therapeutic option.

human gut and has LPS in its body. Therefore, we measured

fecal LPS levels as an indicator of LPS produced by gut

3-1. Trimethylamine N-oxide (TMAO) as a risk for CVDs

significantly lower in mice gavaged with Bacteroides 2 species

metabolite, trimethylamine N-oxide (TMAO), is an independent

bacterial functional genes based on 16S rRNA gene sequencepatients with CVDs by using a metabolomics approach12,13).

microbiota and found that the fecal LPS activities were

Dr. Hazen and his colleagues reported that the gut derived

than in control mice (Figure 2B). We next predicted gut

predictor for cardiovascular events in a large clinical cohort of

Phosphatidylcholine, a dietary component found in foodusing PICRUSt and found that the expression of genes involvedin LPS biosynthesis, especially lipid A biosynthesis gene, wassources such as cheese, egg, and meat, is converted to choline

species (Figure 2C).

(TMA) by gut microbial enzyme, TMA lyase. TMA is absorbedhydrophilic sugar moieties bound to a hydrophobic region

flavin-containing monooxygenases, a host liver enzyme12).

significantly decreased in mice gavaged with Bacteroides 2

in the gut, and subsequently metabolized to trimethylamine

The basic chemical structure of LPS is described asfrom the gut into portal vein and then converted to TMAO via

known as lipid A (Figure 2D). The hydrophilic region of LPS is

L-carnitine, an abundant nutrient in red meat containing a TMA

8)composed of the O-antigens (species-specific repeating

structure similar to that of choline, is also the source of TMA

oligosaccharide subunits) and the core polysaccharide, and thisand contributes the elevation of plasma TMAO and accelerates
atherosclerosis 14) . TMAO is shown to be elevated inregion has only a minimal effect on the pro-inflammatory

cardiovascular patients with CAD, thrombosis15), chronic kidney

activity of LPS. On the other hand, the hydrophobic lipid A

disease16) and heart failure (HF)17) and linked to adverse

region is structurally conserved among various gram-negative

bacteria, and consists of a phosphorylated diglucosamine

cardiovascular events and all-cause mortality13) (Figure 3).

the ligand of toll-like receptor 4 (TLR4) and the most criticalregulation of multiple macrophage scavenger receptors andi nclu d i n g m o n o c y t e - ma c ro p h a g e a n d p ro vo k e s t h e

and additional treatment with antibiotics could cancel the

backbone with four to seven attached acyl chains8). The lipid A,

Oral administration of phosphatidylcholine promoted up-

toxic portion of LPS, activates the innate immune systemenhanced atherosclerosis in apolipoprotein E-deficient mice,inflammatory action in the host 9,10). More interestingly,

deleterious effects. TMAO was shown to increase the form cell

14 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Tomoya Yamashita et al.
formation, decrease the cholesterol reverse transport, andactivate the platelet aggregation

12, 15)

plasma TMAO levels in HF patients. We should clarify what

. Taken these, TMAO iskinds of bacteria are involved in increasing TMAO in HF andthought to aggravate atherosclerosis and also increase the

how to intervene the bacteria for decreasing the plasma TMAO.  

cardiovascular events, and it is reasonable to conclude that

TMAO acts as a gut microbiota-derived uremic or

3-3. Therapeutic candidates to reduce plasma TMAO

However, the cause and result relationship of increasing the

From clinical perspective, a new intervention to suppress

production

cardiovascular toxin contributing to systemic inflammation.

plasma TMAO levels and worsening CVDs have not been

plasma TMAO in patients with CVDs is desired. A natural

clarified yet. Further, the intervention to TMAO could improvestructural analog of choline, 3,3-dimethyl-1-butanol (DMB), has

the prognosis of CVDs also still remains unknown.  

been shown to non-lethally inhibit TMA production from

cultured bacteria24). However, despite the high dose of DMB

3-2. The composition of gut microbiota in HF and plasma

provided, choline induced TMAO elevations, increased platelet

TMAO

aggregation, and shortened thrombus formation time were notfully rescued in mice. They, therefore, tried to develop second-

Alterations in gut microbial composition have been describedin patients with HF18-22), especially with reduced diversity andgeneration TMA lyase inhibitors with improved therapeuticpotential25). Especially, a new choline TMA lyase inhibitor,

depletion of core gut microbiota. However, the causal

involvement of gut microbiota composition and HF

iodomethylcholine, improved remodeling and cardiac function

heterogeneity of HF makes us difficult to focus on specific gut

constriction26).

patients with HF and that intestinal edema caused by HF affects

component are also another option to reduce plasma TMAO by

in heart failure murine model with transverse aortic

pathophysiology remains unclear. We can suspect that

Probiotics treatment or alteration of gut microbiota

microbiota from the data of comparison between controls andthe composition of gut microbiota21). At the genus level,suppressing TMA production in the gut via modulation of gut

Bifidobacterium , Gordonibacter , and Bilophila was abundant inmicrobiota or gut microbiota-derived metabolites.

HF patients compared with controls . We also assessed the22)plasma-related metabolites both in patients with

4. Summary and Conclusion

same patients after treating HF, compensated phase. Plasma

and their products can influence host health and diseases. The

decompensated HF when admitted to the hospital and in the

Many human and animal studies support that gut microbiota

TMAO concentrations were elevated in HF patients compared

identification of bacterial function that can modulate hostwith controls, but there were no significant difference between

physiological and pathophysiological processes has opened thecompletely different pattern of plasma brain natriuretic peptide

targets for preventing CVDs. Especially, to remove or reducethat TMAO elevation was neither temporal nor was ahopeful and effective therapeutic strategies to improve theof HF. Although it was difficult to assess how this change of gut

how the toxin levels are regulated, decided, and can be

microbial functional genes involved in the production of TMA

causal relationship between the gut microbiota and CVDs, tobacterial genes of choline TMA lyase, were shown to bewhat kind of intervention can be therapeutic method. We hopedecompensated and compensated phase of HF, which waspossibility for numerous microbial pathways as therapeutic(BNP), sophisticated biomarker of HF21). These data suggested

the detrimental bacterial products, LPS and TMAO, could betherapeutic target after hospitalization to prevent a next event

prognosis of CVD patients. However, we have not yet clarified

microbiota affected plasma TMAO, we assessed three key

changed. Taken these, further studies are needed to clear theusing shotgun sequencing metagenome analysis. CutC/D ,know whether the intervention can be effective or not, andincrease in HF patients compared with controls , but cntA/B ,future active studies in association with gut microbiota and23)

genes of carnitine TMA lyase, and genes of betaine reductase

their metabolites could improve the prognosis of CVD patients.

were not changed (Figure 3). Bliophila , increased in HF patientsin our study 22), is shown to have cutC/D and probably produces

Sources of Funding: This work is supported by the PRIME frommight be related with the high plasma TMAO levels in HF(18069370; T.Y.), the Japan Society for the Promotion of

TMA by choline TMA lyase. Therefore, the increasing Bilophila

the Japan Agency for Medical Research and Development

patients. Although our data was confused, additional analysis of

Science KAKENHI (grant No. 17K09497, 20H03676; K.H.,

shotgun sequencing metagenome analysis revealed that the

19H03653, 20K21603; T.Y.), and Senshin Medical Research

amount of cntA/B genes (but not cutC/D genes) was correlatedFoundation (T.Y.).

with plasma TMAO in HF patients and it probably provoked theDisclosures: Authors have no potential conflicts of interest to

most critical contribution to the increase in TMAO levels inHF23). Genus Escherichia and Klebsiella have cntA/B anddeclare.

depletion of these bacteria might be effective to reduce the15

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Gut microbiota and CVD
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mortality risk in chronic kidney disease. Circ Res. 2015;

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Reduced Trimethylamine-N-Oxide Level in Patients Withlevels of intestinal microbe-generated metabolite

Large-Artery Atherosclerotic Stroke or Transient Ischemic

trimethylamine-N-oxide in patients with heart failure:

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refining the gut hypothesis. J Am Coll Cardiol. 2014; 64:3)		Emoto T, Yamashita T, Sasaki N, et al. Analysis of Gut

1908-14.

Microbiota in Coronary Artery Disease Patients: a Possible

Link between Gut Microbiota and Coronary Artery Disease.

18)	Kamo T, Akazawa H, Suda W, et al. Dysbiosis and4)		Jie Z, Xia H, Zhong SL, et al. The gut microbiome inof patients with heart failure. PLoS One. 2017; 12:

J Atheroscler Thromb. 2016; 23 : 908-21.

compositional alterations with aging in the gut microbiota

e0174099.

atherosclerotic cardiovascular disease. Nat Commun.

19)	Katsimichas T, Ohtani T, Motooka D, et al. Non-Ischemic

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With Altered Intestinal Microbiota. Circ J. 2018; 82: 1640-

and Bacteroides dorei Reduce Gut Microbial

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Lipopolysaccharide Production and Inhibit Atherosclerosis.

20)	Cui X, Ye L, Li J, et al. Metagenomic and metabolomic

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With Decompensated and Compensated Heart Failure. Circassociated gut microbiome with increased capacity forJ. 2018; 83: 182-92.

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22)	Hayashi T, Yamashita T, Takahashi T, et al. Uncovering the8)		Vatanen T, Kostic AD, d’Hennezel E, et al. Variation inrole of gut microbiota in amino acid metabolic

Microbiome LPS Immunogenicity Contributes todisturbances in heart failure through metagenomic

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metabolism in heart failure. Int J Cardiol. 2021; 338: 138-10)	Yamashita T, Yoshida N, Emoto T, et al. Two Gut Microbiota-24)	Wang Z, Roberts AB, Buffa JA, et al. Non-lethal Inhibition of

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causality. Nature reviews Microbiology. 2013; 11 : 639-25)	Roberts AB, Gu X, Buffa JA, et al. Development of a gut

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microbe-targeted nonlethal therapeutic to inhibit12)	Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism ofthrombosis potential. Nat Med. 2018; 24: 1407-17.

phosphatidylcholine promotes cardiovascular disease.

26)	Organ CL, Li Z, Sharp TE, et al. Nonlethal Inhibition of Gut

Nature. 2011; 472: 57-63.

Microbial Trimethylamine N-oxide Production Improves13)	Tang WH, Wang Z, Levison BS, et al. Intestinal microbial

Cardiac Function and Remodeling in a Murine Model ofmetabolism of phosphatidylcholine and cardiovascularHeart Failure. J Am Heart Assoc. 2020; 9: e016223.

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Risk. Cell. 2016; 165: 111-24.

16

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Tomoya Yamashita et al.

Figure 1
Characteristics of gut microbiota in coronary artery diseases (CAD).
A. Phylum Bacteroidetes is decreased in CAD patients.
B. ‌Several papers indicated Bacteroides species are decreased in atherosclerotic CVD and obesity.
C. We found Bacteroides vulgatus and dorei were decreased in CAD patients. *p<0.05

Atherosclerotic lesionarea (×104 μm2)40Bacteroidestreated mice

*

**

2.0
2 .0

1.5
1 .5

1.0
1 .0

0.5
0 .5

0

0 .0

*

30

2 .5

Fecal LPS activity
×105 (EU/g)

Control mice

Plasma LPS
activity (EU/mL)

B

A

D

5

4
4

3
3

2
2

1
1

0
0

Control Bacteroides**

5

Control Bacteroides
acyl chains

n

20
10
0

core
polysaccharide

O-antigen
Control Bacteroides

C LPS biosynthesis,*

Lipid ALPS biosynthesis,Core PS, O antigen* ; p<0.05

Control
Bacteroides

lipid A

Penta- or Tetraacylated lipid A(Bacteroides)

Hexa-acylated lipid A(E. coli)

654** ; p<0.01
Figure 2

Effects of treating Bacteroides (B) species on mouse atherosclerotic lesion formation and structure of LPS and lipid A.
A and B. ‌Oral administration of B vulgatus and B dorei prevented atherosclerosis in apolipoprotein E-deficient mice, and reduced
the plasma and fecal LPS activities. *p<0.05, **p<0.01
C. ‌Oral administration of B vulgatus and B dorei decreased the bacterial LPS biosynthesis gene, especially lipid A, in mice.
*p<0.05
D. ‌LPS consists of O-antigens, inner and outer core polysaccharides, and lipid A moiety. Escherichia coli has hexa-acylated lipid
A that induces strong immune responses via activating TLR4. Bacteroides species have tetra- or penta-acylated lipid A
which elicits less inflammation.

17

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Gut microbiota and CVD

Figure 3
Metabolism of gut microbiota-derived TMAO and its biological functions.
This panel indicates the metabolic pathways of producing TMA by gut microbial enzymes and TMAO from TMA by
our host liver enzyme. TMAO was shown to induce deleterious effects on CVD including heart failure.  

Table
Characteristics of gut microbiota in atherosclerotic cardiovascular diseases.

Year (Reference No.)

Study population

12 patients withcerebrovascular2012 Nat commun.
symptomatic
Karlsson FH et al. (1)atherosclerosis and 13
healthy conrols
2015 J Am Heart
Assoc.
Yin J et al. (2)141 patinets withstroke/transientischemic attack (TIA)
and 94 controls

2016  J Atheroscler
Thromb. Emoto T etal.  (3)(2018  Circulation
Yoshida N et al.) (5)“39 coronary arterydisease (CAD) patients,
30 no-CAD controlswith coronary risk
factors, and 50
healthy volunteers.”

2017 Nat commun.
Jie Z et al.  (4)218 patinets withatherosclerotic
cardiovascular disease(ACVD) and 187
healthy controls.

Country

Analytic method

SwedenMetagenome
Collinsella ↑ , Eubacterium ↓ , Roseburia ↓ inshotgun sequencing
patients with symptomatic atherosclerosis

China

16SrRNA random
sequencing

Enterobacter ↑ , Magasphaera ↑ ,Oscillibacter ↑ , Desulfovbrio ↑ ,Bacteroides ↓ , Prevotella ↓ ,Faecalibacterium ↓  in stroke/TIA patients.

Japan

Terminal restriction
fragment length
polymorphism(16SrRNA random
sequencing)

Lactobacillales ↑ , Bacteroidetes ↓(Bacteroides vulgatus and Bacteroides dorei↓ )  in CAD patients   

Metagenome
shotgun sequencing

Enterobacteriaceae ↑ , Streptococcus ↑ ,Lactobacillus salivarius ↑ , Solobacterium
moorei ↑ , Atopobium parvulum ↑ ,Ruminococcus gnavus ↑ , Roseburia
intestinalis ↓ , Faecalibacterium prausnitzii↓ , Bacteroides ↓ , Prevotella copri ↓ in
ACVD patients.

China

18

Results

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Tsuneo Nakajima et al.

Review article

Potential biofluid biomarkers for vascular dementia

Tsuneo Nakajima, MD1); Shuko Takeda, MD, PhD2,3); Ryuichi Morishita, MD, PhD2)

1) Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University
2) Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University
3) Osaka Psychiatric Medical Center, Osaka Psychiatric Research Center

Abstract:

Vascular dementia (VaD) is the second most common causative disease of dementia, after Alzheimer’s disease (AD). Regarding thediagnosis of VaD, the presence of cerebrovascular impairments such as cerebral infarction and intracranial hemorrhage isconfirmed by brain imaging and then followed by the temporal causality that cognitive dysfunction develops. As VaD has a wide
range of pathologies and clinical symptoms, its diagnosis and the development of therapeutics specific to VaD could be difficult.

The challenge is in searching for biomarkers that reflect the pathological conditions, prognosis, and severity of VaD and thedetailed stratification of patients. Breakdown of the blood-brain barrier and extracellular matrix, along with axonal disorders,

demyelinating disorders, and gliosis, plays a significant role in the pathogenesis of cerebrovascular impairment. Increased
cerebrospinal fluid (CSF)/serum albumin quotient, decreased matrix metalloproteinase-2 index, and increased neurofilament lighthave been reported as biomarkers of these disorders. Measuring CSF amyloid-β 42 (Aβ42), tau, and phosphorylated tau (p-tau) as
biomarkers of AD has proved useful, but the significance of these markers in VaD has not been investigated in detail. The
complications of VaD and AD are common, so determining which is closer to the core of the pathological conditions is often
difficult. Biomarkers specific to VaD are expected to be useful for the differential diagnosis and prognosis prediction of dementia.
Key Words: vascular dementia, CSF biomarker, blood-brain barrier, white matter lesions, mixed dementia

Correspondence to:
Shuko Takeda

Department of Clinical Gene Therapy, School of Medicine, Osaka University 2-2 Yamada-oka, Suita 565-0871, Japan
E-mail: takeda@cgt.med.osaka-u.ac.jp

Significance of evaluating VaD using biomarkers

brain imaging have increased, revealing the presence ofhas the second highest prevalence after Alzheimer’s diseaseassociated with the onset of clinical stroke. Thus, the concept

cerebrovascular impairments, which are not necessarily

Vascular dementia (VaD) is a leading cause of dementia that

(AD)1). The risk factors of VaD are lifestyle-related diseasesof VaD disease has changed tremendously, and the fact that

thus, the number of patients with VaD has been increasing

pathological factors and the heterogeneity of clinical symptoms

such as hypertension, diabetes, and dyslipidemia, and aging;

VaD shows a complexity of pathogenesis formed by multiple

owing to population aging. VaD can be diagnosed on the basis

has been revealed. On the basis of the diagnostic criteria of theof its gradual progression, focal neurological signs/symptoms,

National Institute of Neurological Disorders and Stroke andcognitive impairment, patient history of multiple ischemic

Association Internationale pour la Recherché et l’Enseignement

temporal relationship between cerebrovascular impairment anddementia (MID), strategic single-infarct dementia, small vessel

stroke, neuroimaging for cerebrovascular impairment, and theen Neurosciences, VaD can be further divided into multi-infarct

cognitive dysfunction . However, because clinical symptoms

disease dementia (SVD), hypoperfusion VaD, hemorrhagic VaD,

2)

are often not specific, diagnostic accuracy based on theseand others. Hereditary VaD includes cerebral autosomal

criteria is insufficient, often delaying the diagnosis . In recent

recessive arteriopathy with subcortical infarcts and3)years, new concepts of vascular cognitive impairment (VCI)4)

leukoencephalopathy (CARASIL), cerebral autosomal dominant

and vascular cognitive disorders , including mild cognitive

arteriopathy with subcortical infarct and leukoencephalopathy

5)

impairment (MCI), have been proposed for early diagnosis and(CADASIL),

and

other

adult-onset

hereditaryleukoencephalopathies . SVD is the most prominent type7), andprevention by early intervention.

2)

Traditionally, VaD has been considered to be related to thethe importance of slowly progressing changes in the brain

multiple infarction dementia . With the widespread use ofpattern of SVD is quite in contrast to VaD, which occurs after

associated with SVD has been recognized8). This progression

amount of neuronal loss due to multiple infarctions called
6)

brain magnetic resonance imaging (MRI), opportunities foran acute stroke (cerebral infarction/hemorrhage). In fact, SDV

19

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Potential biofluid biomarkers for vascular dementia
is the most common neuropathological feature in elderly

VaD28-30). The CSF/serum albumin quotient is a standard

dementia9).

this ratio indicates enhanced permeability of the barrier20).

patients and is highly associated with an increased risk of

indicator of BBB and choroid plexus function. An increase in

Brain MRI is an important imaging modality for diagnosing

Elevated CSF/serum albumin quotient in patients with VCI has

been reported in many clinical studies31-34). Table 1 shows the

VaD and is useful for the morphological assessment of

cerebrovascular damage and cerebral atrophy. Nevertheless,

VaD biomarkers reported thus far.

because of the limitations of the temporal resolution of MRI

c e n t r a l r o l e i n t h e p a t h o p h y s i o l o g y o f c o g n i t i ve

Both the innate immune system and inflammation play a

microscopic pathological changes are difficult to detect
scanners5). Evidence has shown that microinfarction is a major

impairment35,36). CSF levels of tumor necrosis factor-α (TNF-α),risk factor of VaD10); however, microinfarctions are difficult totransforming growth factor-β (TGF-β), and vascular endothelial

detect with conventional 1.5- and 3-Tesla MRI scanners11).

growth factor (VEGF)37,38); the acute inflammatory protein αLately, microinfarctions with a diameter of 0.7 mm can be

1-antichymotrypsin39); and the glial cell activation marker YKL-

average microinfarction size is approximately 0.3 mm insecretory glycoprotein involved in innate immunity that goes

resolution of MRI scanners .

inflammatory stimulation41). The CSF level of LCN2 was

40 were elevated in patients with VCI40). Lipocalin 2 (LCN2) is a

detected using 7-Tesla high-resolution MRI scanners, but theup to the central nervous system in response to injuries anddiameter, which is far smaller than the standard temporal
12)

reported to increase in patients with VaD42).

Cerebrospinal fluid (CSF) measurements reflect pathologicalchanges in the central nervous system 13). Hence, CSF

MMPs are members of a family of endopeptidases that arebiomarkers are used to diagnose various neurological diseases,

active in the extracellular matrix, cell surface, and intracellulartherapeutic agents. The CSF biomarkers of VaD could

MMP-12 mainly show activities in the brain20). Whereas MMP-

monitor disease progression, and determine the effects ofenvironment. MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, andaccurately stratify patients with VaD who have clinically

2 is detected in CSF in patients with physiological conditions,

CSF biomarkers are useful for revealing the mechanism of the

CSF concentrations, except when accompanied bydiverse symptoms and improve the accuracy of diagnosis14,15).

other MMPs (mainly MMP-3 and MMP-9) have extremely low

development of VaD16). VaD is heterogeneous in its etiology andinflammation43). Changes in the CSF concentration of many

MMPs have been reported in SVD33,44,45). In addition, the CSF

pathological characteristics, so patient stratification usinglevel of the tissue inhibitor of metalloproteinases-1 (TIMP-1),

biofluid biomarkers may help in the efficient development ofspecific therapeutic agents

17,18). As VaD varies greatly between

an inhibitor of MMP, has been reported to increase in patientswith VCI33,39).

patients in terms of severity and cognitive prognosis, it is
crucial to develop biomarkers that reflect these19,20).

The neurofilament (NF) is a major structural protein inneurons that consists of three subunits, namely low (NF-L),CSF biomarkers of VaD

medium (NF-M), and heavy (NF-H), with different degrees ofpathological processes of VaD20,21); however, their clinicalnerve cell death and axonal damage47). Significant increases inphosphorylation46). NF is expected to be a sensitive marker ofSome studies have reported CSF biomarkers that reflect theusefulness remains controversial. White matter lesion (WML) is

NF-L levels in CSF have been reported in patients with severe

and hypoxia in vascular beds supplied by long arterioles . It iscorrelation between the severity of WMLs and NF-L levels in

WML 32-34,48). Other reports have also shown a positivea characteristic of SVD that is caused by chronic hypoperfusion
22)

CSF49). The myelin basic protein (MBP) is a major structural

also thought to result from the destruction of the blood-brain

component of the myelin sheath50), and patients who have hadbarrier (BBB) accompanied by the activation of proteases suchas matrix metalloproteinases (MMPs)14,23). WML is associateda subcortical infarction stroke have been reported to havewith multiple processes such as axonal degeneration, gliosis,

significantly higher MBP levels in CSF51). Sulfatide is an acidic

The blood-CSF barrier (BCB) and BBB are vital for isolating

It is regarded as a marker of white matter damage. Increased

maintaining an optimal microenvironment for the centralcompared with healthy subjects and patients with AD52). The

and demyelination24-26).

glycolipid in the myelin sheath produced by oligodendrocytes.

the central nervous system from systemic circulation andsulfatide levels in CSF have been reported in patients with SVD

CSF level of sulfatide has also been shown to be a potential

nervous system. The barrier function is maintained by theinteraction of endothelial cells, pericytes, and astrocytes27). The

predictor of WML progression53).

cytokines from the peripheral circulation into the brain

quotient, decreased MMP-2 index, and elevated CSF level of

disruption of the BBB allows the entry of toxic inflammatory

Among all these biomarkers, increased CSF/serum albumin

parenchyma, which consequently damages neurons7). An

NF-L without alteration of AD-related core biomarkers are

dysfunction may play an important role in the pathogenesis of

However, a single marker is inadequate for diagnosing or

considered the most clinically useful biomarkers of VaD14,54).

increasing number of studies have shown that BCB/BBB

20

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Tsuneo Nakajima et al.
differentiating VaD from AD. Thus, a combination of biofluidreflect the pathophysiology of VaD is essential for thebiomarkers and diagnostic imaging markers is considereddevelopment of new therapeutic agents for VaD.

biomarkers of VaD remain an unexplored field. Nonetheless, asAcknowledgements

essential for improving diagnostic accuracy 20) . Blood

samples can be collected less invasively than CSF samples, weThis work was supported by JSPS KAKENHI Grant Number

could expect better results from future studies .

21H02828 (grant-in-Aid for Scientific Research (B)) (S.T.) and20)

the research grant from Cell Science Research Foundation

Application of AD core biomarkers to VaD and mixed(S.T.).

dementia

Disclosures: Authors have no potential conflicts of interest to

Approximately 50% of cases of dementia are complicated bymultiple causative diseases55). The most common cause of

declare.

mixed dementia is the combination of AD and VaD . Mixed
56)

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JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Potential biofluid biomarkers for vascular dementia

Table 1Category

Blood-CSF or BCB/BBB dysfunction

Reference

CSF/serum albumin quotient (QA) ↑→31-34

TNF-α ↑

37

TGF-β ↑

38

VEGF ↑

38

α1-Antichymotrypsin ↑39

YKL-40 ↑40

LCN2 ↑

42

MMP-2 index ↓45

MMP-3 activity ↑45

MMP-9 ↑

33,44

MMP-10 ↑33

TIMP-1 ↑

33,39

NFL ↑

32-34,48

MBP ↑

33

Sulfatide ↑52

Inflammatory and glial activation

Extracellular matrix breakdown

Axonal and myelin damage

24 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Fumitoshi Niwa et al.

Review article

Does blood pressure affect the risk of cognitive decline anddementia?

Fumitoshi Niwa MD PhD1,2); Toshiki Mizuno MD PhD.1)

1) Department of Neurology and Gerontology, Graduate School of Medical Science,
Kyoto Prefectural University of Medicine, Kyoto, Japan
2) Department of General Medicine and Medical Education, Graduate School of Medical Science,
Kyoto Prefectural University of Medicine, Kyoto, Japan
Abstract:

Hypertension (HTN) is known to be associated with cognitive decline and dementia. It causes cerebral vascular damage, whichleads to pathological changes not only in vascular dementia but also in Alzheimer’s disease. Epidemiological evidence alsosuggests that HTN in midlife is probably a risk factor for dementia. Conversely, blood pressure variability or hypotension may also

be associated with cerebral damage and cognitive decline. Blood pressure must be controlled for dementia prevention. We discuss
the relationship between blood pressure dysregulation and cognitive decline and dementia with respect to current evidence andclinical research.

Key Words: Blood pressure, Blood pressure variability, Cognitive decline, Dementia, Hypertension, Hypotension

Correspondence to:Fumitoshi Niwa

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Address: 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
E-mail: bunniwa@koto.kpu-m.ac.jp
Introduction

pressure dysregulation on cognitive function. Next, we discussleading risk factor for various diseases in elderly people. The

mechanisms of cognitive decline.

30–79, the world prevalence of HTN in 2019 was 34% among

Vascular dementia (VaD) and Alzheimer’s disease (AD)Hypertension (HTN), one of the most common disorders, is athe current evidence and clinical research on the pathological

NCD Risk Factor Collaboration noted that among people aged
men and 32% among women1). The high prevalence of HTN has

VaD and AD are the most prevalent types of dementia. Some

resulted in a huge public health burden. HTN is known to beelderly people appear to have both types. Kalaria et al. noted

pathological evidence of overlap between VaD and AD4). In theirassociated with cognitive decline and dementia. While poor

quality of life is associated with cognitive impairment, thestudy, clinical criteria for the diagnosis of these conditions

effect of blood pressure control on cognitive decline must be

suggested by autopsy findings of mixed pathological features,

overlapped by 20% to 30%, whereas greater overlap was

association between HTN and cognitive impairment and theincluding cerebrovascular lesions and neurodegenerationconsidered.

resulting from amyloid and tau accumulation up to Braak stage V

Smoking and conditions such as HTN, diabetes mellitus, andhyperlipidemia are established risk factors for vascular

AD. Magnetic resonance images (two horizontal slices) in a patient

revealed that these vascular risk factors are associated with theMixed-type dementia, as in this patient, is common, particularly inwith dementia (Fig. 1) show both ischemic lesions and atrophy.

dementia (VaD). On the other hand, recent studies havethe oldest age group (i.e., more than 85 years of age).

progression of not only VaD but also Alzheimer’s disease (AD).

Although dementia in elderly patients is often associated

In a previous review of several studies of dementia, the findings

with AD, most cases of early-onset dementia are VaD, whichsuggested that the outcomes of non- pharmacologicaloccurs after stroke (infarction or hemorrhage). HTN in earlyintervention of vascular risk factors are comparable with thoseof treatment with acetylcholinesterase inhibitors2). A review

and middle adulthood probably accelerates atherosclerosis andSkoog in 1997 . The association between pathological features25). White matter lesions have been extensively found inarticle about blood pressure and dementia was published by

cerebral vascular damage, leading to dementia, as shown in Fig.

3)of AD and HTN has also been extensively explored.

neuroimaging of patients with dementia. These lesions have

In this review, we focus on the effect of HTN and blood

mixed pathological features; this finding is hypothesized to be

25

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Blood pressure and risk of cognitive decline and dementia
attributable to HTN-related mechanisms, including oxidative

cognitive decline 15) . BPV has a potential role in themechanism remains unclear.

but also dementia, including AD16). Ambulatory blood pressure

stress or systemic inflammation 6). However, the actual

pathogenesis or progression of not only cardiovascular disease
monitoring and home blood pressure measurement may be

On the other hand, AD is caused by different pathophysiologicalmechanisms involving amyloid and tau accumulation. Amyloid

important for assessing both HTN and future risk of dementia.

amyloid angiopathy, which causes micro circulat ion

blood pressure monitoring is preferable to intermittent

Furthermore, for BPV measurement, continuous beat-to-beatbeta deposition is manifested by senile plaque and cerebral

monitoring. Wearable devices for continuous blood pressure

insufficiency or cerebral hemorrhage (Fig. 2) . Hypoperfusion
5)

can cause the accumulation of not only amyloid beta but also

monitoring would enable more accurate detection of BPV17).

suggested that the glymphatic system or intramural periarterial

Hypotension and dementia

also affected in AD7,8). Damage of these pathways may bedamage through the same mechanism as that of BPV. Evidence

Therefore, as shown in Fig. 2, factors that damage thedementia has been reported in cross-sectional studies, in whichwith the progression of AD5). Thus, AD and VaD may be closely

decrease during the course of the dementia process or whether

hyperphosphorylated tau5). Furthermore, some reports have

Hypotension or shock can also accelerate cerebral ischemic

drainage, which are systems of clearance of amyloid, may bethat hypotension is a risk factor for cognitive decline andassociated with small vessel disease caused by arteriosclerosis.

authors have speculated about whether blood pressure levels

cardiovascular system, including HTN, are probably associatedlow blood pressure induces or accelerates cognitive decline

linked and indistinguishable pathologically (Fig. 1).

through reduced cerebral blood flow. Some studies have

Hypertension and dementia

demonstrated that low blood pressure or orthostatic

hypotension is associated with cognitive impairment in elderly

Dementia and mild cognitive impairment are common inpeople18). Of interest is that in some epidemiological studies ofpatients with HTN. Epidemiological evidence that HTN is a risk

factor for cognitive impairment has been reported. The results

patients with dementia, results indicated that blood pressure

Asia Aging Study, for example, indicated that cognitiveof dementia and continues to decline in patients with AD19).

manifested several decades earlier9,10). Since then, results ofcardiovascular disease, low blood pressure levels in elderly

begins to decrease approximately 3 years before the diagnosis

of initial studies from the Framingham Study and the Honolulu-

Although hypotension may protect healthy elderly people from

impairment was associated with higher blood pressure that had

patients who are frail and have associated diseases may cause

several epidemiological studies of HTN have suggested that

HTN in middle age is more likely to be a risk factor for

cerebral hypoperfusion and accelerate cognitive decline18).

Aging Study, the risk ratio of VaD in patients with untreated

Blood pressure control for dementia prevention

39.5), whereas that of AD is 1.2 (95% CI: 0.37–4.04), in

dementia, the effects of intervention and treatment for

Joensuu demonstrated that the odds ratio of AD in Finnish

a treatable risk factor. In previous studies of whether

cognitive decline than that in old age. In the Honolulu- Asia

If HTN or BPV is a key factor in the development of

HTN in midlife was 11.8 (95% confidence interval [CI]: 3.52–

comparison with patients without midlife HTN10). Kuopio andcontrolling blood pressure must be considered because HTN ispatients with midlife HTN was 2.8 (95% CI: 1.1–7.2) , whichantihypertensive drugs would prevent cognitive decline, the1.10–3.54) . A systematic review and meta-analysis of 209

antihypertensive drugs delay the onset of or ameliorate

association,

Cochrane Database of Systematic Reviews20). The Systolic Blood11)

findings have been inconsistent. Clinical evidence thatwas similar to that in Linxian county in China (1.97; 95% CI:
12)

cognitive decline has not been established, as shown in theprospective studies revealed extensive evidence of this13)

although some investigations yieldedinconsistent findings, which suggest that HTN-related risk for

Pressure Intervention Trial showed that more intensive blood

blood pressure alone8).

significant cognitive benefits21). However, the Cochrane Reviews

cognitive decline cannot be attributable to chronic elevation inpressure control with antihypertensive drugs did not result in

The association between blood pressure variability (BPV) anddoes not contain studies indicating whether treating HTN in

Blood pressure fluctuation is characterized by changes in blood

longitudinal cohort studies of patients with HTN who takethe risk of cognitive impairment has also been investigated.

midlife delays or prevents dementia in later life20). Furtherpressure from office visit to visit or from day to day and,antihypertensive drugs are required.

increasingly recognized as playing a clinically important role inConclusion

events14). In one meta-analysis, the findings suggested that highaffect cognitive function, which is impaired not only byindependently of absolute blood pressure values, is

In conclusion, studies have shown that HTN may adversely

the progression of target-organ damage and cardiovascular

cerebral vascular disease but also by neurodegenerative

BPV was associated with an increased risk of dementia and26 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Fumitoshi Niwa et al.
Epidemiol. 1990;43(5):475-80. doi: 10.1016/0895-

disease in some pathological pathways. Although no consistent4356(90)90136-d. PMID: 2324788.

epidemiological evidence has been obtained so far, HTN isprobably to some extent a risk factor for dementia, especially10)	Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood

associated with cerebral damage and cognitive decline. Thus,

Neurobiol Aging. 2000 Jan-Feb;21(1):49-55. doi: 10.1016/

pressure and dementia: the Honolulu-Asia aging study.

in later life. Conversely, hypotension and BPV may also be

s0197-4580(00)00096-8. PMID: 10794848.

blood pressure control may play an important role in the11) Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascularclinical approach for dementia prevention.

risk factors and Alzheimer’s disease in later life:

Disclosures: Authors have no potential conflicts of interest to

longitudinal, population based study. BMJ. 2001 Jun

16;322(7300):1447-51. doi: 10.1136/bmj.322.7300.

declare.

1447.

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Blood pressure and risk of cognitive decline and dementia
S y s t R e v. 2 0 2 1 M a y 2 4 ; 5 ( 5 ) : C D 0 0 4 0 3 4 . d o i :Intensive vs Standard Blood Pressure Control on Probable

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21) SPRINT MIND Investigators for the SPRINT ResearchGroup, Williamson JD, Pajewski NM, et al. Effect of

Figure 1
Brain damage from hypertension and/or blood pressure fluctuation. Magnetic resonance images (fluid-attenuated inversion recovery
images) of a patient (an 80-year-old woman) with dementia, whose Mini-Mental State Examination score was 19/30.

Figure 2
Possible pathophysiological mechanisms of brain damage occurring after hypertension, which led to cognitive
decline or dementia. This flowchart was modified from the review article5) by Zlokovic et al.

28 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Yuki Ito et al.

Young Investigator Award (review article)

Tau phosphorylation as a molecular mechanism linking diabetes
mellitus and Alzheimer’s disease
Yuki Ito, MS1,2); Shuko Takeda, MD, PhD1,2);
Tsuneo Nakajima, MD3); Ryuichi Morishita, MD, PhD1)

1) Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University
2) Osaka Psychiatric Medical Center, Osaka Psychiatric Research Center3) Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University
Abstract:

Alzheimer’s disease (AD) is a progressive neurological disease that leads to dementia and ultimately death due to cognitive decline
caused by the loss of neurons in the brain. It has been reported that type 2 diabetes increases the risk of developing AD dementia,
although the molecular mechanism linking type 2 diabetes and AD is unknown. The high incidence of AD in patients with type 2

diabetes may be explained by the effect of diabetes on tau pathology, one of the cardinal neuropathological features of the AD

brain. Clinical studies using biofluid biomarkers report that tau in cerebrospinal fluid is increased by diabetic conditions; however,studies using post-mortem brain and positron emission tomography imaging provided controversial results regarding the effect oftype 2 diabetes on tau pathology. In animal models, the effects of type 2 diabetes on tau have been extensively examined at themolecular level. The effect of type 2 diabetes increases phosphorylated tau in the brain via multiple intracellular signaling

pathways. Therefore, tau phosphorylation may underlie the pathological interplay between diabetes and AD. A better

understanding of the molecular mechanisms linking these two diseases may provide novel insights into diagnostic and therapeutic
developments for AD.

Key Words: Alzheimer’s disease, tau, diabetes mellitus, phosphorylation, cerebrospinal fluid biomarker

Correspondence to:
Shuko Takeda

Department of Clinical Gene Therapy, School of Medicine, Osaka University
2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
E-mail: takeda@cgt.med.osaka-u.ac.jp
Introduction

35% of dementia cases could potentially be prevented byeliminating these modifiable risk factors5).

It is estimated that the number of people with dementia

Diabetes mellitus, one of the modifiable risk factors forworldwide will nearly triple to more than 152 million by

2050 . To extend the healthy life spans of elderly people, thedementia, has a high prevalence among the elderly. It is1)

development of preventions and treatments for people withestimated that in 2021, 537 million people over 20 years of

About 70% of patients with dementia suffer from Alzheimer’s

patients with diabetes mellitus are classified as type 2 diabetes,

age worldwide had diabetes mellitus6). More than 90% of

dementia is urgently needed.

disease (AD) and about 20% from vascular dementia (VaD) .

which is mainly caused by insulin resistance or a relative

2)

AD, a progressive neurodegenerative disease, is characterized

deficiency. Many epidemiological studies have reported thatare extracellular accumulations of β-amyloid (Aβ), andto AD by about two-fold7,8). In the Rotterdam study, the relative

accumulations of phosphorylated tau protein. AD ultimately

was 1.9-fold, which is comparable to developing VaD withby two neuropathological features: senile plaques (SPs), which

type 2 diabetes increases the risk of developing dementia due

risk of developing AD in elderly patients with type 2 diabetes

neurofibrillary tangles (NFTs), which are intraneural

diabetes8). In addition, the relative risk of AD increases about

leads to death due to cognitive decline caused by the loss ofneurons in the brain . More than 95% of AD cases are afour-fold in patients with diabetes treated with insulin8). The

is the apolipoprotein E (ApoE) epsilon 4 allele, which ishigher in those with diabetes compared to those without

3)

sporadic form of AD, and a genetic risk factor for sporadic AD

Hisayama study reported that the risk of AD was 2.1 times

believed to promote the development of SPs. A variety of risk

diabetes, and the incidence of AD was significantly associatedfactors for dementia have been reported, including aging andwith increased blood glucose levels in oral glucose tolerance

lifestyle-related diseases4). Livingston et al . reported that about

tests7). Many studies support the idea that type 2 diabetes,

29

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

DM exacerbates AD via phosphorylation of tau
especially with insulin resistance and impaired glucose

biomarkers can potentially reflect dynamic pathologicaltolerance, increases the risk of developing AD.

changes in the AD brain, which might allow for the sensitive
detection of the effect of type 2 diabetes on tau.

The impact of type 2 diabetes on the tau pathology ofpatients with Alzheimer’s disease

The effect of diabetes mellitus on tau pathology in animal models

researchwhich are pathologically phosphorylated in AD brains20). The

Tau contains up to 85 potential phosphorylation sites, 44 of

Evidence from post-mortem brain and functional imaging

hyperphosphorylation of tau causes neuronal dysfunction and

The high incidence of AD due to type 2 diabetes may be

explained by the impact of diabetes on tau pathology, as thethe aggregation of tau21), leading to the formation of NFTs andwith the severity of cognitive dysfunction andtype 2 diabetes involves insulin resistance and deficiency,

neurodegeneration in AD brains22). Since the pathogenesis of

cerebral accumulation of pathological tau is known to correlate

neurodegeneration . Some studies have reported that type 2

many analyses have focused on the phosphorylation of tau via

9)diabetes increased NFTs compared to controls under thepresence of ApoE epsilon 4 risk

10,11)

insulin signaling.

, suggesting the impact of

The administration of streptozotocin (STZ) is used as themouse model of insulin deficiency. Clodfelder-Miller et al .

diabetes on tau-related pathology. However, other post-mortem

brain studies have reported the absence of a relationshipreported that STZ treatment increased the amount of tau(Table 1). Therefore, studies based on post-mortem brain

mice23). This result was also reproduced in studies using non-phosphorylation at multiple sites in the brains of C57BL/6

between type 2 diabetes and the development of NFTs12,13)

tg24-26) and tau-transgenic (Tau-tg) mice27). These results imply

analyses have reported controversial findings regarding thethat peripheral insulin deficiency increases theeffect of type 2 diabetes on tau pathology.

phosphorylation of tau in the brain.

Positron emission tomography (PET) has been used as a

In studies using mice fed with a high-fat diet, many studies

novel imaging biomarker for tau pathology. Tau PET imaging

have reported higher levels of phosphorylated tau in theenables the visualization of tau deposits in the brains of living

patients. It has been well validated that in vivo PET signals

brain28-30), while a few studies have reported no difference inthe levels31). However, these discrepancies may be due to thetightly correlate with postmortem histopathology in patientswith tauopathy14), a class of neurodegenerative diseases

experimental conditions (e.g. the duration of the loading,characterized by the cerebral accumulation of tau. However, acomposition of the diet, and amount of food intake). The

impact of diabetes on the tau load in the brain15).

genetically diabetic (db/db ) mice compared to wild-type

Studies using biofluid biomarkers

mice crossbred with genetically diabetic mice are increased

study using tau PET imaging did not observe any significant

amount of phosphorylated tau is increased in the brains of

mice32). The levels of phosphorylated tau in the brains of AD
compared to non-diabetic AD mice33). These two results indicate

Cerebrospinal fluid (CSF) levels of tau predict the amount ofthat the phosphorylation of tau is increased in both type 1

NFTs in the brain that was confirmed by correlation analysis
using postmortem brain . Studies using CSF biomarkers

diabetes (i.e. the STZ-administration model) and type 2 diabetes

on AD-related neuropathology (Table 1). CSF levels of tau weremodels).

compared to those without type 2 diabetes . Type 2 diabetes

in the brain using diabetic Tau-tg mouse models. In studies using

the CSF of patients with mild cognitive impairment (MCI) .

tau was reportedly increased28) and maintained29). In summary,

16)

reported that type 2 diabetes could have a significant impact

mice brains (i.e. diet-induced obesity and genetically diabetic

significantly higher in AD patients with type 2 diabetes

In addition, some studies have analyzed the aggregation of tau

17)

was associated with elevated levels of phosphorylated tau in

Tau-tg mice fed with a high-fat diet, the amount of aggregated

18)

The severity of insulin resistance (i.e. HOMA-IR) was correlated

type 2 diabetes increases the phosphorylation of tau in thewith increased phosphorylated and non-phosphorylated tau

brains of animal models, the same as in the human brain.

levels in CSF in ApoE4 carriers, while the effect was not

The molecular mechanism underlying tau phosphorylation

observed in ApoE4-negative patients19). This means that theinduced by diabetes mellitus

impact of type 2 diabetes on CSF tau levels could be affected byboth AD- and diabetes-related factors.

Both observational studies in humans and experimental

The discrepancy between the results from post-mortem brain

studies using animal models suggest that type 2 diabetes

and CSF biomarker studies regarding the effect of type 2

increases the phosphorylation of tau. It has been reported that

diabetes may be explained by the difference in the nature of themany kinases and phosphatases regulate the phosphorylation

tau examined in each study. Post-mortem brain studiesof tau20) and type 2 diabetes could affect the activity of these

CSF biomarker studies measure soluble extracellular tau. CSF

conditions may be associated with the phosphorylation of tau.

kinases 34). Alteration of kinase activity due to diabetic

primarily measure highly aggregated intracellular tau, whereas30 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Yuki Ito et al.
Insulin signaling is associated with kinase activity and may link

diabetes increases tau levels in CSF, although the results of

Insulin is thought to increase the phosphorylation of tau by

animal models, type 2 diabetes increases phosphorylated tau in

type 2 diabetes with the phosphorylation of tau.

altering the activity of its downstream kinase35)

post-mortem brain research appear to be controversial. In

via Akt, a

the brain via multiple intracellular signaling pathways.

kinase widely expressed in the brain and involved in various

Therefore, it is crucial to comprehensively analyze thecellular activities, such as cell development, differentiation, andalterations in tau phosphorylation at multiple sites andsurvival36). The activated form of Akt (phosphorylated at

intracellular signaling pathways related to type 2 diabetes

inhibits the enzymatic activity of GSK3β. The activation ofunderlying the relationship between type 2 diabetes and tau

Ser473) increases the phosphorylation of GSK3β at Ser9 and(Figure 2). A better understanding of the mechanisms

GSK3β increases the phosphorylation of tau when insulin

phosphorylation could lead to the development of new

signaling in the brain is impaired. Many reports have focused

therapeutic targets for AD.

on insulin signaling-related factors, such as insulin receptor,

Acknowledgement

Akt, and GSK3β, as the mechanism for the increased
phosphorylation of tau in the brain

23,25,28,29,31). These studies

This work was supported by JSPS KAKENHI Grant Number

reported that highly phosphorylated levels of Akt at Ser473 28,29)

21H02828 (grant-in-Aid for Scientific Research (B)) (S.T.) andand GSK3β at Ser923,28,29) occurred in association with highthe research grant from Cell Science Research Foundation

phosphorylated tau levels.

(S.T.).

The phosphorylation of tau may be induced by mechanisms

Disclosures: The authors have no potential conflicts of interest

other than insulin signaling25). Other reports have suggested

that the neuroprotective intracellular signaling pathway,

to declare.

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associated with cerebrovascular but not Alzheimer’s

12;27(50):13635-48.

disease neuropathology. Alzheimers Dement. 201627)	Imamura T, Yanagihara YT, Ohyagi Y, et al. Insulin

08;12(8):882-9.

deficiency promotes formation of toxic amyloid-β4213)	Sonnen JA, Larson EB, Brickell K, et al. Different patterns ofconformer co-aggregating with hyper-phosphorylated tau

cerebral injury in dementia with or without diabetes. Archoligomer in an Alzheimer’s disease model. Neurobiol Dis.

Neurol. 2009 Mar;66(3):315-22.

2020 04;137:104739.

14)	Saint-Aubert L, Lemoine L, Chiotis K, et al. Tau PET imaging:28)	Elahi M, Motoi Y, Shimonaka S, et al. High-fat diet-induced

present and future directions. Mol Neurodegener. 2017 02
20;12(1):19.

activation of SGK1 promotes Alzheimer’s disease-health, and Alzheimer disease biomarkers in an elderly

28;30(18):1693-710.

associated tau pathology. Hum Mol Genet. 2021 Aug15)	Vemuri P, Lesnick TG, Przybelski SA, et al. Age, vascular29)	Leboucher A, Laurent C, Fernandez-Gomez FJ, et al.

sample. Ann Neurol. 2017 Nov;82(5):706-18.

Detrimental effects of diet-induced obesity on τ pathology16)	Buerger K, Ewers M, Pirttilä T, et al. CSF phosphorylated tau

are independent of insulin resistance in τ transgenic mice.

protein correlates with neocortical neurofibrillary

Diabetes. 2013 May;62(5):1681-8.

pathology in Alzheimer’s disease. Brain. 2006 Nov;129(Pt30)	Wu Z, Chen C, Kang SS, et al. Neurotrophic signaling

11):3035-41.

deficiency exacerbates environmental risks for Alzheimer’s17)	Motta C, Assogna M, Bonomi CG, et al. Diabetes mellitus

disease pathogenesis. Proc Natl Acad Sci U S A. 2021 Juncontributes to higher cerebrospinal fluid tau levels

22;118(25).

selectively in Alzheimer’s disease patients with the APOE431)	Kacířová M, Železná B, Blažková M, et al. Aging and high-fat

genotype. Eur J Neurol. 2021 Dec;28(12):3965-71.

diet feeding lead to peripheral insulin resistance and sex-18)	Moran C, Beare R, Phan TG, et al. Type 2 diabetes mellitus

dependent changes in brain of mouse model of tau

and biomarkers of neurodegeneration. Neurology. 2015

pathology THY-Tau22. J Neuroinflammation. 2021 Jun

Sep 29;85(13):1123-30.

22;18(1):141.

19)	Starks EJ, Patrick O’Grady J, Hoscheidt SM, et al. Insulin32)	Chen JL, Luo C, Pu D, et al. Metformin attenuates diabetes-

Resistance is Associated with Higher Cerebrospinal Fluid

induced tau hyperphosphorylation in vitro and in vivo by

Tau Levels in Asymptomatic APOEɛ4 Carriers. J Alzheimers

enhancing autophagic clearance. Exp Neurol. 2019

Dis. 2015;46(2):525-33.

01;311:44-56.

20)	Martin L, Latypova X, Wilson CM, et al. Tau protein kinases:

involvement in Alzheimer’s disease. Ageing Res Rev. 201333)	Niedowicz DM, Reeves VL, Platt TL, et al. Obesity and21)	Alonso A, Zaidi T, Novak M, et al. Hyperphosphorylation

accelerated β-amyloid deposition in a novel murine model

diabetes cause cognitive dysfunction in the absence of

Jan;12(1):289-309.

of mixed or vascular dementia. Acta Neuropathol Commun.

induces self-assembly of tau into tangles of paired helical2014 Jun 10;2:64.

filaments/straight filaments. Proc Natl Acad Sci U S A.

34)	Saini V. Molecular mechanisms of insulin resistance in type2001 Jun 05;98(12):6923-8.

2 diabetes mellitus. World J Diabetes. 2010 Jul22)	Trojanowski JQ, Lee VM. Paired helical filament tau in

15;1(3):68-75.

Alzheimer’s disease. The kinase connection. Am J Pathol.

35)	Zhou M, Chen S, Peng P, et al. Dulaglutide ameliorates STZ

1994 Mar;144(3):449-53.

23)	Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, et al. Tau

induced AD-like impairment of learning and memory

vivo after streptozotocin-induced insulin deficiency.

through GSK3β. Biochem Biophys Res Commun. 2019 0324)	Ke YD, Delerue F, Gladbach A, et al. Experimental diabetes36)	C ormier KW, Woodgett JR. Recent advances inis hyperphosphorylated at multiple sites in mouse brain in

ability by modulating hyperphosphorylation of tau and NFs

Diabetes. 2006 Dec;55(12):3320-5.

26;511(1):154-60.

understanding the cellular roles of GSK-3. F1000Res.

mellitus exacerbates tau pathology in a transgenic mouse

2017;6.

model of Alzheimer’s disease. PLoS One. 2009 Nov

19;4(11):e7917.

25)	Jolivalt CG, Lee CA, Beiswenger KK, et al. Defective insulin

signaling pathway and increased glycogen synthasekinase-3 activity in the brain of diabetic mice: parallels

32 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Yuki Ito et al.
Table 1. Effect of diabetes mellitus on Alzheimer’s disease pathology reported
by post-mortem brain and cerebrospinal fluid biomarker studies.

AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; SPs: senile plaques; NFTs: neurofibrillary tangles; 
DM: diabetes mellitus; IR: insulin resistance; Aβ: β-amyloid

Figure 1. Tau phosphorylation sites implicated in the interplay
between diabetes and Alzheimer’s disease (ref. 23-33).

Figure 2. Conceptual scheme of the mechanism linking between type 2 diabetes andAlzheimer’s disease mediated by phosphorylation of tau

33

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Juvenile AD with preceding UC

Case report

A juvenile case of Alzheimer’s disease with preceding ulcerative
colitisKoh Tadokoro, MD, PhD1); Yuki Taira, MD, PhD1); Yuko Kawahara, MD, PhD1);
Yoshio Omote, MD, PhD 1); Yusuke Fukui, PhD1); Yumiko Nakano, MD, PhD1);
Taijun Yunoki, MD, PhD1); Mami Takemoto, MD, PhD1); Ryuta Morihara, MD, PhD1);
Takeshi Ikeuchi, MD, PhD2); Koji Abe, MD, PhD1); Toru Yamashita, MD, PhD1)

1) Department of Neurology, Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University, Okayama2) Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata

Abstract:

A 59-year-old man, who began to suffer from ulcerative colitis at the age of 58, developed gradual cognitive decline and wasreferred to our clinic when he was 60 years old. Cerebrospinal fluid analysis revealed a decrease in the Aβ42 and Aβ42/Aβ40

ratio. He showed mild bilateral medial temporal lobar atrophy and decreased blood flow in the bilateral temporal lobe andposterior cingulate gyrus. A genetic test revealed that the APOE ε4 was homozygous but no mutations were found in APP , PSEN1 ,or PSEN2 genes. Therefore, he was diagnosed with Alzheimer’s disease. Systemic inflammation of ulcerative colitis may haveaccelerated Alzheimer’s disease in the present case.

Key Words: Alzheimer’s disease, ApoE, inflammation, ulcerative colitis

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
E-mail: kohtdkr0511@gmail.com
Introduction

were continued to maintain remission. When he was 59 years

Alzheimer’s disease (AD) is the most common form ofold, he developed gradual cognitive decline and he wasdementia1). Most patients develop AD at the age of 65 years orreferred to our clinic when he was 60. He had difficulty inolder, whereas only 5 % develop AD when they are younger

understanding books, remembering people’s names, andthan 65 years of age 2). Although AD is pathologicallymanaging his own company. His mother also developed AD

characterized by amyloid plaques and neurofibrillary tangles,

when she was 76 years old. On the other hand, neither his

chronic inflammation plays an important role in thefather, who died at the age of 70 due to heart disease, nor histhat is characterized by diffuse mucosal inflammation of thehighest educational background was a graduate diploma from adevelopment of AD3). Ulcerative colitis (UC) is a chronic disease

older brothers (67 and 65 years old), developed dementia. The

colon , but occasionally there are extraintestinaltechnical college. He was an occasional drinker and had a4)complications, including to the brain and vascular system.

smoking history (16 pack-years) between the ages of 18 andHere, we report a juvenile case of AD with a preceding history

30.

of UC.

     His physical findings were unremarkable. His visuospatial

ability was normal, and he did not present constructional

Case report

apraxia. Cognitive assessment revealed a cognitive decline with

A 58-year-old man consulted a doctor when he noticed aa mini-mental state examination (MMSE) score of 25/30 and abloody stool and unintended weight loss of 1 kg within one

Montreal cognitive assessment (MoCA) score of 18/30, inmonth. Although his serum analysis was unremarkable, awhich his short-term memory was severely disturbed. Inmononuclear cell infiltration of the large intestine. He waswere also impaired. Serum analysis showed a normal whitecolonoscopy revealed coarse mucosa (Fig. 1A) andaddition, his encoding, calculation, attention and orientation

diagnosed with UC. Following treatment with mesalazine andblood cell count of 5,830/µL, C-reactive protein (CRP) content

probiotics, his symptoms remitted. Mesalazine and probiotics

of 0.04 mg/dL, and an erythrocyte sedimentation rate (ESR) of

34 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Koh Tadokoro et al.
2/3 mm. Vitamins and thyroid hormones were also normal, andexacerbated systemic inflammation in the present patient.

hemagglutination test were negative. Cerebrospinal fluid (CSF)

and symptomatic UC developed early onset AD at the age of 59.

protein (69 mg/dL), normal total tau (269 pg/mL),development of AD.

pg/mL), decreased Aβ42 (388 pg/mL) (normal range > 500

Acknowledgements

a serologic test for syphilis and a T. pallidum antibody

In conclusion, the present patient with homozygous APOE ε4analysis revealed a normal cell count (2/µL), mildly elevated

Systemic inflammation of UC may have accelerated thephosphorylated tau (44.6 pg/mL), amyloid beta (Aβ) 40 (6,208

pg/mL ), and a lower Aβ42/Aβ40 ratio (0.063) (normal
5)

We appreciate the patient’s cooperation. This work was

range > 0.0925)). Magnetic resonance imaging (MRI) showed

partly supported by a Grant-in-Aid for Scientific Research (C)specific regional analysis system for Alzheimer’s disease

Young Research 20K19666, 21K15190, by Grants-in-Aid from

I-iodoamphetamine (IMP) single photon emission computed

Agency for Medical Research and Development, and by Grants-

mild bilateral medial temporal lobar atrophy with a voxel-based

20K09370, 20K12044, Challenging Research 21K19572,( VSRAD) value of 0.73 (Fig. 1B, C, arrowheads).
123

the Research Committees (Toba K, and Tsuji S) from the Japan

tomography (SPECT) demonstrated decreased blood flow in thein-Aid from the Japan Agency for Medical Research andbilateral temporal lobe and posterior cingulate gyrus (Fig. 1D,

Development JP21dk0207045 to TI.

patient’s consent, a genetic test was performed. It revealed that

Disclosures: None.

APP , PSEN1 , or PSEN2 genes.

Referencesarrowheads). He was thus diagnosed with juvenile AD. With the

APOE ε4 was homozygous, and no mutations were found in1)		Hishikawa N, Fukui Y, Sato K, et al. Characteristic features

Discussionof cognitive, affective and daily living functions of late-

The present patient developed juvenile AD at the age of 59.

elderly dementia. Geriatl Gerontol Int. 2016; 16: 458-465.

APOE ε4 was homozygous, and he developed UC a year before2) 	Zhu XC, Tan L, Wang HF, et al. Rate of early onset

the onset of AD.

Alzheimer’s disease: a systematic review and meta-

Chronic inflammation contributes considerably to thepathology of AD

6,7)

analysis. Ann Transl Med. 2015; 3: 38.

. Not only neuroinflammation, but also3) 	Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat

systemic inflammation, promotes AD-related pathology8,9).

TJ, Medeiros R. Inflammation: the link between

Subjects with UC show elevated serum inflammatory cytokines

comorbidities, genetics, and Alzheimer’s disease. J

such as interleukin-1β (IL-1β), IL-6, IL-8 and tumor necrotic

Neuroinflammation. 2018; 15: 276.

factor α (TNFα)10), and commonly display extraintestinal4) 	Langan RC, Gotsch PB, Krafczyk MA, Skillinge DD.

manifestations (25-40 %)11), suggesting systemic inflammation

Ulcerative colitis: diagnosis and treatment. Am Famof UC. Furthermore, several inflammatory proteins such as

Physician. 2007; 76: 1323-1330.

matrix metalloproteinase 10 (MMP10), chemokine (C-X-C

5) 	Palmqvist S, Zetterberg H, Mattsson N, et al. Detailed

motif ) ligand 9 (CXCL9), and monocyte chemotactic protein 1

comparison of amyloid PET and CSF biomarkers for(MCP-1) were upregulated, even in the preclinical stage ofidentifying early Alzheimer disease. Neurology. 2015; 85:

UC . Histological inflammation can be observed, even in

1240-1249.

12)

patients with normal CRP and ESR13). In addition, patients with6) 	Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM,

considerably promotes AD pathology15). A population-based

mechanism in Alzheimer’s disease. Alzheimers Dement.

dementia in inflammatory bowel disease, including UC (risk7) 	Shi X, Ohta Y, Liu X, et al. Acute anti-inflammatory markers

ApoE ε4 is a major genetic risk factor of AD. ApoE ε4disease model. J Alzheimers Dis. 2019; 68: 1667-1675.

UC have an increased risk of early atherosclerosis14), which

Salazar AM, Lamb BT. Inflammation as a central

cohort study demonstrated a higher risk of developing

2018; 4:575-590.

rate = 6.19)16).

ITIH4 and AHSG in mice brain of a novel Alzheimer’s

exacerbates AD pathology through multiple mechanisms such8) 	Holmes C, Cunningham C, Zotova E, et al. Systemic

as decreased amyloid β clearance, blood brain barrier

inflammation and disease progression in Alzheimer

dysfunction, and neuroinflammation . ApoE ε4 lowers age at

disease. Neurology. 2009; 73: 768-774.

17)

the onset of AD, but only 10 % of patients develop AD before9)		Walker KA, Ficek BN, Westbrook R. Understanding the role

they are 60, even among APOE ε4 carriers18). Therefore,of systemic inflammation in Alzheimer’s disease. ACS Chemcomplications in UC may have accelerated the development of

Neurosci. 2019; 10: 3340-3342.

AD in the present patient carrying a homozygous APOE ε410) Chen P, Zhou G, Lin J, et al. Serum biomarkers for, suggesting that ApoE ε4 may have directly11) Levine JS, Burakoff R. Extraintestinal manifestations ofgene. On the other hand, the APOE ε4 allele increases the risk

of UC

19)

inflammatory bowel disease. Front Med. 2020; 7: 123.

35

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Juvenile AD with preceding UC16) Zhang B, Wang HE, Bai YM, et al. Inflammatory bowel

inflammatory bowel disease. Gastroenterol Hepatol. 2011;

disease is associated with higher dementia risk: a

7: 235-241.

nationwide longitudinal study. Gut. 2021; 70: 85-91.

12) Bergemalm D, Andersson E, Hultdin J, et al. Systemic17) Kloske CM, Wilcock DM. The important interface between

inflammation in preclinical ulcerative colitis.

apolipoprotein E and neuroinflammation in Alzheimer’s

Gastroenterology. 2021; 161: 1526-1539.

disease. Front Immunol. 2020; 11: 754.

13) Solem CA, Loftus EV, Jr., Tremaine WJ, Harmsen WS,

Zinsmeister AR, Sandborn WJ. Correlation of C-reactive18) Sando SB, Melquist S, Cannon A, et al. APOE epsilon 4

radiographic activity in inflammatory bowel disease.

disease; a case control study from central Norway. BMC

lowers age at onset and is a high risk factor for Alzheimer’s

protein with clinical, endoscopic, histologic, andNeurol. 2008; 8: 9.

Inflamm Bowel Dis. 2005; 11: 707-712.

19) Al-Meghaiseeb ES, Al-Otaibi MM, Al-Robayan A, et al.

14) Papa A, Danese S, Urgesi R, et al. Early atherosclerosis in

Genetic association of apolipoprotein E polymorphisms

patients with inflammatory bowel disease. Eur Rev Med

with inflammatory bowel disease. World J Gastroenterol.

Pharmacol Sci. 2006; 10: 7-11.

2015; 21: 897-904.

15) Zhai Y, Yamashita T, Nakano Y, et al. Chronic cerebral

hypoperfusion accelerates Alzheimer’s disease pathology

with cerebrovascular remodeling in a novel mouse model. J
Alzheimers Dis. 2016; 53: 893-905.

Fig. 1(A) Colonoscopy, showing coarse mucosa of the patient’s rectum. (B, C) Brain MRI T1 weighted image, revealing mild bilateral medial temporal lobar atrophy (rt.
dominant, arrowheads). (D) IMP SPECT image, demonstrating decreased blood flow in the bilateral temporal lobe andposterior cingulate gyrus (lt. dominant, arrowheads).

36

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

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
It is my great honor to take over and become the 4th

The purposes of the activities of this society include to study

president of the Japanese Society for Vascular Cognitivethe vascular factors related to the occurrence and progression

Impairment from Dr. Ryuichi Morishita. This society has beenof various types of dementia, and integration of researchers inmembers of each committee, academic members, secretariats,

addition, doctors and researchers in the fields such as

developed with great support of the former presidents,

the basic and clinical fields to promote research activities. In

and other colleagues, and will be further activated byneurology, cardiology, geriatrics, psychiatry, and neurosurgery,increasing the number of academic members. We will makecarry out activities from a wide range of perspectives beyond

every effort to grow into an academic society that is widely

their specialties. We are developing unique activities that arerecognized by the general public. We would be grateful if you

not recognized in other academic societies.

could continue to support our society.

The Vas-Cog Journal has been fully renewed as English

This society was initially established as the Japan Vas-Cog

version since the 5th issue published in 2019, and has aJapanese Society for Vascular Cognitive Impairment also

academic activity reports. Further investigations are being

2021, the number of academic members is 200, and it isin PubMed Central (PMC) in the future. At the annual meeting

auditors. So far, we have held a total of 11 annual meetings,

from different specialized fields gather together to have active

Study Group in April 2010, and has been renamed to thecontent such as peer-reviewed papers, case reports, andknown as Vas-Cog Japan in October 2014. As of December

promoted by the journal editorial board to publish our papers

composed of 65 councilors, 26 directors, 2 advisors and 2

held in every summer, researchers, doctors, and medical staff

and in September 2015, we held the Vas-Cog World (7thdiscussions.

International Conference) jointly with the annual meeting of

Vascular risk factors such as lifestyle-related diseases haveour society.

been previously discussed in the pathophysiology of vascular

Japan is facing an unprecedented level of super-aging

dementia, however, many vascular factors are also clarified tosociety in the world, and the number of patients with dementia

be involved in the pathogenesis of Alzheimer’s disease, which is

is increasing rapidly. According to estimates by research inclassified as a neurodegenerative disease. We believe thatover) are considered to have dementia, and it is estimated thatthe pathophysiology of dementia such as Alzheimer’s disease2012, 4.62 million people (15% of the elderly aged 65 andacademic activities at this society will lead to the elucidation of

the number of people with dementia will reach about 7 million

and the establishment of effective preventive and therapeuticin 2025. Therefore, it is strongly desired to improve

interventions, which in turn will lead to great social

environment for dementia patients and their families, and tocontributions. I think that the activities of this society fit welldevelop research on early diagnostic tools and effectivewith the academic needs of specialists and professionals intreatments for dementia.

many fields. We sincerely look forward to your participation.

37

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Reports of the Vas-Cog Japan 2021

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

Department of Neurology
Tokai University School of Medicine

Masataka Sata

Shunya Takizawa

The 11th annual meeting of the Japanese society forcausing dementia. The special lectures were given by Prof.

on August 28th, 2021 (Saturday) on WEB. The meeting, which

Yamashita from Kobe University. Educational lectures were

Takayoshi Shimohata from Gifu University and Prof. Tomoya

vascular cognitive impairment (Vas-Cog Japan 2021) was held

given by Prof. Koji Abe from National Center Hospital, National

was originally scheduled in September, 2020, was postponed

Center of Neurology and Psychiatry and Prof. Yuishin Izumi

for one year due to COVID-19 pandemic. The meeting was heldfrom Tokushima University. We had three symposia “Frontierscompletely via WEB, where all participates presented andin researches in cerebrovascular blood flow and metabolism

discussed on remote. We would like to express our deep

related to vascular dementia,” “Dementia and cardiovascularappreciation for your participation and support. The meetingachieved a big success with a total of 146 participantsdiseases” and “Protective and exacerbating factors in vascular

medicine, cardiology, metabolic diseases and pharmacology.

young investigators from vascular and neurological medicine.

dementia.”   We also had two special symposia organized byincluding many doctors and researchers on neurology, geriatricIn Young Investigator’s Award session, we had excellent 8

presentations. The first prize was awarded to Dr Yuki Ito from

Accumulating evidence suggests that life-style related

Osaka University. In addition, we had 19 general oraldiseases, such as hypertension, diabetes, and dyslipidemia, arepresentations. We thank all participants for your greatrisk factors not only for cardiovascular diseases but also fordementia. Thus, we organized this meeting to facilitatecontributions, and hope to meet you again in the VasCog Japandementia to communicate each other to understand recent

is over.

2022 meeting, hopefully on site when the COVID-19 pandemic

opportunity for the expert researchers in atherosclerosis andadvances in both areas. The main theme of the meeting is“Dementia practice from vascular and neurological medicine”.

We focused on the close relationship between the vasculardiseases and the pathogenesis of neuronal degeneration38

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Welcome to Vas-Cog 2022
Theme: Cerebral small vessel disease and cognitive impairment,
frailty, sarcopenia

Department of Neurology. Tokyo Women’s
Medical University

Department of Geriatric Medicine Kyorin
University School of Medicine

Kazuo Kitagawa

Koichi Kozaki
Frailty and sarcopenia are the process of being disabled in

It is our honor to host the 11th annual meeting of theJapanese Society for Vascular Cognitive Impairment (Vas-Cog

the old age. Frailty is defined by 5-domains; body weight loss,

August 6th, 2022 in Tokyo with co-chairs of Professor

inactivity. Sarcopenia is defined by muscle weakness, physicaldetestable COVID-19 infection at this time February 2022, weboth frailty and sarcopenia are in part related to cerebral small

physical weakness, slowness, and exhaustion, and physicalJapan 2022). 11th annual meeting is scheduled to be held

weakness and muscle loss. Recent findings are showing that

Kitagawa and Kozaki. Although we are under the threat ofand large vessel disease.

are hoping that the conference will be held face-to-face inTogether, cerebral small vessel disease is a morbid condition

August 2022. This time we are planning to have a meeting withthe theme of “Cerebral small vessel disease and cognitive

causing cognitive impairment, dementia, frailty, andvessel disease has been showing us a lot of things, especially ahave a great time exchanging opinion with participants face-to-

impairment or possibly with frailty and sarcopenia, both arethis important issue. We would like all the members to submit

sarcopenia. We would like to revisit this important issue, andimpairment”. Recent progress in the field of cerebral small

face. We hope 2022 Vas-Cog conference will shed the light onclose relation of cerebral small vessel disease with cognitive

an abstract, attend the meeting and make active discussion

major cause of disability in the older adults.

next year.  Please join us!

Cerebral small vessel disease is closely related to lifestyle-related diseases such as hypertension, diabetes, dyslipidemia,

and others. Cerebral small vessel disease is in part a cause of

lacunar infarction and ischemic white matter lesion, so-called“leukoaraiosis”. Lacunar infarction and ischemic white matterlesion can be the cause of vascular dementia in the form of“small-vessel type” in the NINDS-AIREN criteria. Recent

evidence shows cerebral microbleeds, cortical microinfarction

and amyloid angiopathy are also included in cerebral smallvessel disease.

39

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Meeting report of Vas-Cog Asia 10 from India
Koji Abe, MD, PhD

The first Vas-Cog Asia President

Vas-Cog Asia society is an independent society with 24

I would like to celebrate the great success of Vas-Cog Asia

10, which was held on the completely web-based style indirectors from most Asian countries and   many active

jointing with Asia-Pacific Stroke Conference (APSC). Even undervascular factors in Alzheimer’s disease and related dementia,

members, which is dedicated to elucidate the mechanism ofChennai of India on December 9 afternoon (2021) always

and to contribute potential therapy for dementia people in Asia.

CORONA pandemic, APSC2021 received 154 abstracts, 107

Many vascular risk factors (VRFs) are related to cognitivefrom India, followed by 22 from Indonesia, 6 China, 3decline and affective-emotional changes in dementia patients

Singapore, 2 Japan, and so on. An unexpected pandemic of

CORONA (Covid-19) beginning 2020 January in Wuhan (China)

especially in elder or eldering countries in Asia.

years (2020 and 2021). However, we welcomed many

(November 25, 2022) under direction of our President Tsong-and Indonesia (photo). There were variety of important(Okayama). Vas-Cog World was also run virtually on September

Dementia (ACD) was one hot topic in this Vas-Cog Asia 10.

actively join the forthcoming Vas-Cog meetings to present and

Next Vas-Cog Asia 11 anniversary will be held in Taipei

forced our APSC+Vas-Cog Asia to organize on the web for 2

Hai Lee (Taipei) and Secretary General Toru Yamashita

participants from Japan, India, Taiwan, Korea, China, Thailand,

7-8 2021 from New Castle (UK). All of you are welcome topresentations in the present conference. After-CORONA

discuss on vascular factors of all type dementia.

Many basic science, translational research, clinical trials andevidence were discussed especially on the aspects of

Alzheimer’s disease (AD), vascular dementia (VD), behavioral
and psychiatric symptoms of dementia (BPSD), and theirimportant vascular involvement.

40

February 4, 2022

 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Reports of Vas-Cog Japan Council Meeting
Yoshio Ikeda, MD, PhD

Department of Neurology, Gunma University
Graduate School of Medicine*	Due to the absence of the leader of board for COI, theThe 12th board and council meeting of the Japanese Society

committee report and suggestions on the Code of Ethics wasfor Vascular Cognitive Impairment was held together with 20

decided to be discussed by e-mail.

board members, 2 auditors and 28 councilors on the WEB, on*	The leader of board for finance, Dr. Yoshio Ikeda, reported

the 20th of August 2021. The representative director andthat the number of member increase was only 6 in fiscal

committee members reported the topics shown below and all

2020, therefore, an increase of members will lead to a stableproceedings were approved by members.

income due to membership fees. We hope that the［Membership］

introduction of the web system will increase the rate ofpayment of membership fees. I would like future presidents

193 regular members (As of August 15, 2021)

of annual meeting to ask for participation of non-member［Report from each committee leader］

speakers, and selection of YIA candidates from both basic
and clinical research fields. I would like the directors and*	The leader of board for increasing membership and public

councilors to encourage young researchers/doctors to join in

relations, Dr. Kazuo Kitagawa, reported that a committee will

our society.

be held to discuss the solution to increase membership, andto promote effective publicity of Vas-Cog Japan.

*	The leader of board for academic organization promotion, Dr.

［Plans for future meetings］

becoming an academic organization is the fact that more

Osaki Bright Core Hall

Katsuya Urakami, reported that the biggest hurdle for

1. The 12th Meeting (6th of August 2022)
Chairmen: Dr. Kazuo Kitagawa and Dr. Koichi Kozaki

than half of the papers published in the Vas-Cog Journal

2. Refer to the last page for subsequent schedules.

must been peer-reviewed. Based on the active discussions by
the members of this committee, the name of the committee

should be revised as the ARIKATA committee rather than theacademic organization promotion. We would like to continue

to work on the issue of becoming an academic organization.

This does not mean to become an incorporation or a

subcommittee of the Japanese Association of Medical
Sciences. Based on the result that more than half of theparticipants agreed to this proposal, revision of thecommittee’s name was approved.

*	The chief editor of the academic magazine, Dr. Toshiki
Mizuno, reported that the current journal was published inJuly 2021. Three papers published in this issue have been all
peer-reviewed. As a future goal, we would like the papers inthe Vas-Cog Journal to be published in PMC (formerly
PubMed Central). If they become searchable in PMC, theincrease of membership from Asian countries and young

researchers could be expected. We would like to ask for thecooperation of the directors and councilors to submit papers

in the Vas-Cog Journal. In order to improve the income andexpenditure status of the society, we would like to makeefforts to sell booklets or charge for downloading.

41

JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

42 JAPANESE SOCIETY OF VASCULAR COGNITIVE IMPAIRMENT（2022 NO.8）

Editor’s Note
Masafumi Ihara, MD, PhD

Director of NeurologyNational Cerebral and Cardiovascular Center
The 8th issue of Vas-Cog Journal includes 6 outstanding

I would like to deeply appreciate every support from thereview articles, a case report, and a welcome message of thepresident, editorial board members, and secretariat of thisKitagawa and Professor Koichi Kozaki on August 6, 2022 insustainable advance within this academically exciting field.

meeting have been increasing, reflecting public attention on

pandemic, we believe we can progress hand-in-hand toward a

VAS-COG Japan 2022, which will be hosted by Professor Kazuo

wonderful Society, and hope our efforts will facilitate

Tokyo. Year by year, participants in VAS-COG Japan annual

Despite the unprecedented disaster caused by COVID-19

disease-modifying therapy for dementia and importance ofpromising future.

vascular risk factor management for preventing dementia

progression. Besides physicians and medical researchers,

comedical staff, students, and pharmaceutical companies aremaking this meeting and the VAS-COG Japan Society

increasingly successful. I would like to express my sincere
gratitude to all the continuing efforts by VAS-COG Japanmembers. The VAS-COG Journal is now being transformed froma mere collection of meeting reports into a fully equippedinternational journal with open and spontaneous contributionsof original articles, reviews, and case reports. The editorial

board welcomes general submissions to the VAS-COG journal
on the topic of vascular dementia and related scientific fields.

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 -47