Language：English   Publishing type：Research paper (scientific journal)  

Objective: To investigate secular trends in the prevalence, incidence, and survival rate of dementia in a Japanese elderly population in a comprehensive manner. Methods: Five cross-sectional surveys of dementia were conducted among residents of a Japanese community, aged ≥65 years, in 1985, 1992, 1998, 2005, and 2012. We also established 2 cohorts consisting of the residents of this age group without dementia in 1988 (n = 803) and 2002 (n = 1,231), and each was followed for 10 years. Results: The age-standardized prevalence of all-cause dementia and Alzheimer disease (AD) increased with time (for all-cause dementia: 6.8% in 1985, 4.6% in 1992, 5.3% in 1998, 8.4% in 2005, and 11.3% in 2012, p for trend <0.01; for AD: 1.5%, 1.4%, 2.4%, 3.9%, and 7.2%, respectively, p for trend <0.01), while no secular change was observed for vascular dementia (VaD) (2.4%, 1.6%, 1.5%, 2.4%, and 2.4%, respectively, p for trend = 0.59). The age- and sex-adjusted incidence of all-cause dementia and AD, but not VaD, increased from the 1988 cohort to the 2002 cohort (for all-cause dementia: Adjusted hazard ratio [aHR] 1.68, 95% confidence interval [CI] 1.38-2.06; for AD: AHR 2.07, 95% CI 1.59-2.70; for VaD: AHR 1.18, 95% CI 0.83-1.69). The 5-year survival rate of all-cause dementia and AD improved from the 1988 cohort to the 2002 cohort (for all-cause dementia: 47.3% to 65.2%; for AD: 50.7% to 75.1%; all p < 0.01). Conclusions: The increased incidence and improved survival rate of AD could have resulted in the steep increase in AD prevalence in the Japanese elderly.

DOI： 10.1212/WNL.0000000000003932

Language：English   Publishing type：Research paper (scientific journal)  

Objectives To clarify the association between midlife and late-life smoking and risk of dementia. Design Prospective cohort study. Setting The Hisayama Study, Japan. Participants Japanese community-dwellers without dementia aged 65 to 84 (mean age 72) followed for 17 years (1988-2005) (N = 754), 619 of whom had participated in a health examination conducted in 1973-74 (mean age, 57) and were included in the midlife analysis. Measurements The risk estimates of smoking status on the development of dementia were computed using a Cox proportional hazards model. Results During follow-up, 252 subjects developed all-cause dementia; 143 had Alzheimer's disease (AD), and 76 had vascular dementia (VaD). In late life, the multivariable-adjusted risk of all-cause dementia was significantly greater in current smokers than in never smokers; similar associations were seen for all-cause dementia, AD, and VaD in midlife current smokers. Meanwhile, no significant association was observed between past smoking and risk of any type of dementia in late or midlife. Multivariable analysis showed that smokers in midlife and late life had significantly greater risks than lifelong nonsmokers of all-cause dementia (adjusted hazard ratio (aHR) = 2.28, 95% confidence interval (CI) = 1.49-3.49), AD (aHR = 1.98, 95% CI = 1.09-3.61), and VaD (aHR = 2.88, 95% CI = 1.34-6.20). Such associations were not observed for midlife smokers who quit smoking in late life. Conclusion Persistent smoking from mid- to late life is a significant risk factor for dementia and its subtypes in the general Japanese population.

DOI： 10.1111/jgs.13794

Language：English   Publishing type：Research paper (scientific journal)  

APOE is an established susceptibility gene for late-onset Alzheimer's disease (LOAD). Recent genome-wide association studies have identified many additional susceptibility genes for LOAD in populations of European descent. However, there is little information on whether or not genetic variants in these genes are associated with other ethnicities. To investigate the association of seven genes identified by genome-wide association studies, we carried out a case-control study using 825 LOAD cases and 2934 controls in the Japanese population. For the APOE gene, APOE-ε4 carriers had a 4.54-fold higher risk than APOE-ε4 noncarriers after adjusting for age and sex (P=4.6×10^-27). For other genes, the single-nucleotide polymorphism in the PICALM gene was significantly associated with LOAD (P=0.02, odds ratio=1.23). There was no significant interaction between PICALM and APOE-ε4 carrier status (P for interaction=0.68). Our data indicate that PICALM is also a susceptibility gene for LOAD in the Japanese population.

DOI： 10.1097/YPG.0b013e3283586215

Language：English   Publishing type：Research paper (scientific journal)  

Objective: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. Methods: A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. Results: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L. Conclusions: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

DOI： 10.1212/WNL.0b013e31822f0435

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To estimate the effects of the apolipoprotein E (APOE)-É4 allele on the development of dementia and to elucidate its usefulness in the risk prediction of dementia in Japanese. DESIGN: Prospective cohort study. SETTING: The Hisayama Study, in Japan. PARTICIPANTS: Five hundred twenty-three participants with deoxyribonucleic acid samples from a population of 1,073 community-dwelling participants without dementia aged 60 to 79. MEASUREMENTS: The risk estimates of the APOE-É4 allele on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). RESULTS: During 17 years of follow-up, 136 participants developed dementia, 81 of whom had AD and 39 VaD. After adjusting for age, sex, education, smoking, alcohol intake, systolic blood pressure, use of antihypertensive agents, glycosylated hemoglobin, serum total cholesterol, body mass index, and regular exercise, the risks of all-cause dementia and AD were significantly higher in APOE-É4 carriers than in noncarriers, but no such association was observed for VaD (all-cause dementia: hazard ratio (HR)=1.81, P=.004; AD: HR=3.42, P<.001; VaD: HR=1.08, P=.86). The area under the receiver operating characteristic curve was significantly greater when the APOE genotype was incorporated into a model with potential risk factors for AD (0.74 vs 0.68, P=.02). Other measures of model discrimination (net reclassification improvement: 0.18, P=.01; integrated discrimination improvement: 6.25, P<.001) also confirmed this improvement in AD risk assessment. CONCLUSION: The APOE-É4 allele is a risk factor for AD in the Japanese population. Information on APOE genotype improves AD risk assessment substantially beyond a model based on potential risk factors.

DOI： 10.1111/j.1532-5415.2011.03405.x

Language：English   Publisher：npj Aging  

We investigated associations of glycemic measures, and insulin resistance and secretion measures with hippocampal and subfield volumes. In this cross-sectional study, 7400 community-dwelling participants underwent brain MRI and health checkups between 2016 and 2018. Hemoglobin A1c (HbA1c), glycated albumin (GA), homeostasis model assessment for insulin resistance (HOMA-IR), and HOMA of percent β-cell function (HOMA-β) were evaluated. The associations of each measure with a smaller volume of the hippocampus and twelve hippocampal subfields were investigated. As a result, higher HbA1c or GA and lower HOMA-β levels were significantly associated with smaller volumes in multiple hippocampal subfields. Furthermore, even when we analyzed non-diabetic individuals, substantial associations remained between higher GA or lower HOMA-β levels and smaller volumes of the whole hippocampus or the fimbria. Our findings indicate that postprandial glucose fluctuations, postprandial hyperglycemia, and low insulin secretion have a specific effect on the development of smaller hippocampal volume, suggesting that primary prevention of diabetes and/or sufficient glucose control are important for the prevention of dementia.

DOI： 10.1038/s41514-024-00164-2

Web of Science

Scopus

PubMed

Language：English   Publisher：npj Genomic Medicine  

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.

DOI： 10.1038/s41525-024-00431-x

Web of Science

Scopus

PubMed

Language：English   Publisher：(一社)日本疫学会  

<Highlight>●preserved ratio impaired spirometry(PRISm)と認知症との関連は明らかにされていない。●本研究では、認知症のない65歳以上の日本人地域高齢住民1,202人を対象に、中央値5.0年間の追跡調査を行った。●PRISm群は、呼吸機能正常群と比べ認知症の発症リスクが約2倍であった。●PRISmは、認知症の発症リスクが高い集団であり、呼吸機能障害の重要なサブタイプといえる。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：GeroScience  

Sarcopenia has been reported to be associated with cognitive decline and the risk of dementia. However, few studies have addressed the association between sarcopenia and brain morphological changes in the general population. A total of 1373 community-dwelling participants aged ≥ 65 years underwent brain MRI. Sarcopenia was defined based on the Asian Working Group for Sarcopenia's criteria. The pattern of regional gray matter volume loss associated with sarcopenia were assessed using a voxel-based morphometry (VBM) analysis. Regional brain volumes, intracranial volumes (ICV), and white matter lesions volumes (WMLV) were also measured using FreeSurfer. An analysis of covariance was used to examine the associations of sarcopenia with regional brain volumes in proportion to ICV. Of the participants, 112 had sarcopenia. The participants with sarcopenia had significantly lower total brain volume/ICV and total gray matter volume/ICV and higher WMLV/ICV than those without sarcopenia after adjusting for confounders. In VBM, sarcopenia was associated with lower gray matter volume in the frontal lobe, insula, cingulate gyrus, hippocampus, amygdala, and basal ganglia. Using FreeSurfer, we confirmed that the participants with sarcopenia had significantly lower frontal, insular, cingulate, and hippocampal volumes than those without sarcopenia. The current study showed that participants with sarcopenia had significantly lower volume in the frontal lobe, insula, cingulate, and hippocampus and higher WMLV than participants without sarcopenia. As these brain regions are likely to play an important role in cognitive function, these changes may suggest a shared underlying mechanism for the progression of sarcopenia and cognitive decline.

DOI： 10.1007/s11357-024-01289-8

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Epidemiological Association  

<p><b>Background:</b> Studies on the association between preserved ratio impaired spirometry (PRISm) and dementia are limited. Indeed, PRISm has often been overlooked or ignored as an index of lung function impairment. Therefore, we investigated the association of PRISm with the risk for the development of dementia in an older Japanese population.</p><p><b>Methods:</b> A total of 1,202 community-dwelling, older Japanese participants aged ≥65 years without dementia were followed up for a median of 5.0 years. Participants were categorized by spirometry as follows: normal spirometry (FEV₁/FVC ≥0.70 and FEV₁ ≥80% predicted), PRISm (≥0.70 and <80%), airflow limitation (AFL) Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 (<0.70 and ≥80%), and AFL GOLD 2 to 4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using a Cox proportional hazards model.</p><p><b>Results:</b> During the follow-up period, 122 participants developed dementia. The age- and sex-adjusted incidences of dementia in the participants with normal spirometry, PRISm, AFL GOLD 1, and AFL GOLD 2 to 4 were 20.5, 37.0, 18.4, and 28.6 per 1,000 person-years, respectively. Participants with PRISm had a higher risk of dementia (HR 2.04; 95% CI, 1.19–3.49) than those with normal spirometry after adjusting for confounders. Moreover, both reduced FEV₁% predicted values and FVC% predicted values were associated with the risk of dementia.</p><p><b>Conclusion:</b> PRISm was associated with an increased risk of dementia in a general older Japanese population.</p>

DOI： 10.2188/jea.je20230207

Web of Science

Scopus

PubMed

CiNii Research

researchmap

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

We investigated the association of retinopathy with the risk of dementia in a general older Japanese population. A total of 1709 population-based residents aged 60 years or older without dementia were followed prospectively for 10 years (2007–2017). They underwent color fundus photography in 2007. Retinopathy was graded according to the Modified Airlie House Classification. Main outcome was the Incidence of dementia. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for the risk of dementia by the presence of retinopathy. During the follow-up period, 374 participants developed all-cause dementia. The cumulative incidence of dementia was significantly higher in those with retinopathy than those without (p &lt; 0.05). Individuals with retinopathy had significantly higher risk of developing dementia than those without after adjustment for potential confounding factors (HR 1.64, 95% CI 1.19–2.25). Regarding the components of retinopathy, the presence of microaneurysms was significantly associated with a higher multivariable-adjusted HR for incident dementia (HR 1.94, 95% CI 1.37–2.74). Our findings suggest that, in addition to systemic risk factors, retinal microvascular signs from fundus photography provide valuable information for estimating the risk of developing dementia.

DOI： 10.1038/s41598-024-62688-7

Web of Science

Scopus

PubMed

researchmap

Other Link： https://www.nature.com/articles/s41598-024-62688-7

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journals of Gerontology - Series A Biological Sciences and Medical Sciences  

Several population-based studies have reported that higher serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are associated with brain morphological changes. However, no population-based studies have examined the relationship between serum NT-proBNP and various regional brain volumes in detail. We here analyzed the brain MRI data of 1 201 community-dwelling Japanese aged ≥65 years. Regional gray matter volumes (GMV) and intracranial volume (ICV) were estimated by applying voxel-based morphometry (VBM) methods. The associations of serum NT-proBNP with regional GMV/ICV were examined by analysis of covariance. The regional gray matter atrophy patterns associated with elevated serum NT-proBNP levels were investigated using VBM without a priori regions of interest. The multivariable-adjusted means of the frontal, temporal, hippocampal, parahippocampal, and entorhinal GMV/ICV decreased significantly with elevated serum NT-proBNP levels (all p for trend and q values of false discovery rate correction < .05). In VBM, elevated serum NT-proBNP levels were correlated with atrophy of the bilateral hippocampi, bilateral amygdalas, bilateral parahippocampal gyri, bilateral entorhinal areas, bilateral fusiform gyri, left middle temporal gyrus, left inferior temporal gyrus, right central operculum, right posterior orbital gyrus, bilateral middle frontal gyri, anterior cingulate gyrus and bilateral medial frontal cortices. In a sensitivity analysis excluding 254 participants with mild cognitive impairment or dementia, serum NT-proBNP levels were correlated with atrophy of the bilateral hippocampi, bilateral amygdalas, bilateral parahippocampal gyri, bilateral fusiform gyri, and left middle frontal gyrus. Our data suggest that elevated serum NT-proBNP levels are associated with gray matter atrophy in brain regions that play an important role in cognitive function.

DOI： 10.1093/gerona/glae075

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Psychiatry and Clinical Neurosciences  

AIM: To assess the association between plasma amyloid β (Aβ) 42/40, phosphorylated tau (p-τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population. METHODS: A total of 1346 Japanese community-dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD-X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia. RESULTS: During the follow-up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non-Alzheimer dementia (non-AD). Lower plasma Aβ42/40 levels and higher plasma p-τ181 levels were significantly associated with developing AD but not non-AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non-AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia. CONCLUSION: Our findings suggest that plasma Aβ42/40 and p-τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all-cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low-invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.

DOI： 10.1111/pcn.13661

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：Neuropathology  

The hypothalamus is the region of the brain that integrates the neuroendocrine system and whole-body metabolism. Patients with Alzheimer's disease (AD) have been reported to exhibit pathological changes in the hypothalamus, such as neurofibrillary tangles (NFTs) and amyloid plaques (APs). However, few studies have investigated whether hypothalamic AD pathology is associated with clinical factors. We investigated the association between AD-related pathological changes in the hypothalamus and clinical pictures using autopsied brain samples obtained from deceased residents of a Japanese community. A total of 85 autopsied brain samples were semi-quantitatively analyzed for AD pathology, including NFTs and APs. Our histopathological studies showed that several hypothalamic nuclei, such as the tuberomammillary nucleus (TBM) and lateral hypothalamic area (LHA), are vulnerable to AD pathologies. NFTs are observed in various neuropathological states, including normal cognitive cases, whereas APs are predominantly observed in AD. Regarding the association between hypothalamic AD pathologies and clinical factors, the degree of APs in the TBM and LHA was associated with a lower body mass index while alive, after adjusting for sex and age at death. However, we found no significant association between hypothalamic AD pathology and the prevalence of hypertension, diabetes, or dyslipidemia. Our study showed that a lower BMI, which is a poor prognostic factor of AD, might be associated with hypothalamic AP pathology and highlighted new insights regarding the disruption of the brain–whole body axis in AD.

DOI： 10.1111/neup.12974

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

In recent years, the association between neuroinflammatory markers and dementia, especially Alzheimer's disease (AD), has attracted much attention. However, the evidence for the relationship between serum-hs-CRP and dementia including AD are inconsistent. Therefore, the relationships of serum high-sensitivity CRP (hs-CRP) with dementia including AD and with regions of interest of brain MRI were investigated. A total of 11,957 community residents aged 65 years or older were recruited in eight sites in Japan (JPSC-AD Study). After applying exclusion criteria, 10,085 participants who underwent blood tests and health-related examinations were analyzed. Then, serum hs-CRP levels were classified according to clinical cutoff values, and odds ratios for the presence of all-cause dementia and its subtypes were calculated for each serum hs-CRP level. In addition, the association between serum hs-CRP and brain volume regions of interest was also examined using analysis of covariance with data from 8614 individuals in the same cohort who underwent brain MRI. After multivariable adjustment, the odds ratios (ORs) for all-cause dementia were 1.04 (95% confidence interval [CI] 0.76-1.43), 1.68 (95%CI 1.08-2.61), and 1.51 (95%CI 1.08-2.11) for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L, and those for AD were 0.72 (95%CI 0.48-1.08), 1.76 (95%CI 1.08-2.89), and 1.61 (95%CI 1.11-2.35), for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L. Multivariable-adjusted ORs for all-cause dementia and for AD prevalence increased significantly with increasing serum hs-CRP levels (p for trend < 0.001 and p = 0.001, respectively). In addition, the multivariable-adjusted temporal cortex volume/estimated total intracranial volume ratio decreased significantly with increasing serum hs-CRP levels (< 1.0 mg/L 4.28%, 1.0-1.9 mg/L 4.27%, 2.0-2.9 mg/L 4.29%, ≥ 3.0 mg/L 4.21%; p for trend = 0.004). This study's results suggest that elevated serum hs-CRP levels are associated with greater risk of presence of dementia, especially AD, and of temporal cortex atrophy in a community-dwelling Japanese older population.

DOI： 10.1038/s41598-024-57922-1

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：npj Aging  

Several studies have found associations between poor oral health, particularly tooth loss and cognitivedecline. However, the specific brain regions affected by tooth loss and the probable causes remainunclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan.Between 2016 and 2018, 2454 residents aged ≥60 participated, covering 92.9% of the local agedemographics. This study used comprehensive approach by combining detailed dental examinations,dietary assessments, magnetic resonance imaging (MRI) analysis, and cognitive evaluations. Toothloss, even in cognitively normal individuals, is associated with parahippocampal gyrus atrophy andincreased WMH volume, both of which are characteristics of dementia. Tooth loss was associatedwith altered dietary patterns, notably a reduction in plant-based food intake and an increase in fatty,processed food intake. This study highlights a possible preventative pathway where oral health mayplay a significant role in preventing the early neuropathological shifts associated with dementia.

DOI： 10.1038/s41514-024-00146-4

Web of Science

Scopus

PubMed

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28807573

CiNii Research

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

日本人高齢者における軽度認知障害(MCI)と歩行速度の関連について検討した。2016～2018年にJPSC-ADに参加した65歳以上の日本人8233人(男性3540人、女性4693人、平均72.8±6.0歳)を対象とした。性別及び年齢グループにより層別化した後、参加者の歩行速度を5グループに分けた。その結果、歩行速度の低下はMCIのオッズ上昇と関連し、性別及び年齢により変化していた。また、歩行速度はMCIのスクリーニングツールとして有用であることが示された。

Language：English   Publisher：Psychogeriatrics  

Background: Studies have shown that decreased gait speed is associated with impaired cognitive function. However, whether this association is equivalent across ages or genders in the older population remains unclear. Thus, we examined the association between mild cognitive impairment (MCI) and gait speed emphasising the influence of age and gender. Methods: Overall, 8233 Japanese participants aged ≥65 years were enrolled in this cross-sectional study between 2016 and 2018. After stratification by gender and age group, the participants' gait speeds were divided into quintiles, and the difference in MCI prevalence at each gait speed quintile was calculated. Logistic regression analyses were performed to assess the odds of MCI for each quintile and to assess the influence of age and gender. Results: Males had a consistently higher prevalence of MCI than females. The odds of MCI were increased as gait speed decreased. Logistic regression analyses revealed that in the multivariable-adjusted model 2, the odds ratios (95% confidence interval; CI) for MCI were 2.02 (1.47–2.76) for females and 1.75 (1.29–2.38) for males in the slowest gait speed quintiles compared to the fastest quintile. In the stratified analyses, only males showed an age-dependent increase in the associations between gait speed and MCI, while females exhibited comparable associations across age groups. Conclusions: Reduced gait speed was associated with increased odds of MCI, and this association may vary according to gender and age. Therefore, gait speed could serve as a valuable screening tool for MCI, with gender- and age-dependent clinical implications.

DOI： 10.1111/psyg.13013

Web of Science

Scopus

PubMed

Language：English  

DOI： 10.1039/d3dt01644g

Web of Science

PubMed

Language：Japanese   Publisher：(一社)日本認知症学会  

researchmap

Language：Japanese   Publisher：(一社)日本認知症学会  

researchmap

Language：English   Publisher：Neurology  

Background and ObjectivesEpidemiologic evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study.MethodsDementia-free community-dwelling Japanese aged 65 years or older underwent brain MRI scans and a comprehensive health examination. Frequency of contact with noncohabiting relatives and friends was determined by asking a single question with 4 categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV), and white matter lesion volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms.ResultsWe included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared with that in the group with the highest frequency of social contact (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesion volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency group vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q values of false discovery rate correction <0.05). The relationships seemed to be partly mediated by depressive symptoms, which accounted for 15%-29% of the observed associations.DiscussionLower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

DOI： 10.1212/WNL.0000000000207602

Web of Science

Scopus

PubMed

Language：English   Publisher：Journal of Geriatric Psychiatry and Neurology  

Background: Enlarged perivascular spaces (EPVS) of the brain may be involved in dementia, such as Alzheimer’s disease and cerebral small vessel disease (CSVD). Hypertension has been reported to be a risk factor for dementia and CSVD, but the association between blood pressure (BP) and perivascular spaces is still unclear. The aim of this study was to determine the association between BP and EPVS volumes and to examine the interactions of relevant factors. Methods: A total of 9296 community-dwelling subjects aged ≥65 years participated in a brain magnetic resonance imaging and health status screening examination. Perivascular volume was measured using a software package based on deep learning that was developed in-house. The associations between BP and EPVS volumes were examined by analysis of covariance and multiple regression analysis. Results: Mean EPVS volumes increased significantly with rising systolic and diastolic BP levels (P for trend =.003, P for trend<.001, respectively). In addition, mean EPVS volumes increased significantly for every 1-mmHg-increment in systolic and diastolic BPs (both P values <.001). These significant associations were still observed in the sensitivity analysis after excluding subjects with dementia. Conclusions: The present data suggest that higher systolic and diastolic BP levels are associated with greater EPVS volumes in cognitively normal older people.

DOI： 10.1177/08919887231195235

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND OBJECTIVES: Epidemiological evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study. METHODS: Dementia-free community-dwelling Japanese aged ≥65 years underwent brain MRI scans and a comprehensive health examination. Frequency of contact with non-cohabiting relatives and friends was determined by asking a single question with four categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV) and white matter lesions volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms. RESULTS: We included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared to that in the group with the highest frequency (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesions volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q value of FDR correction <0.05). The relationships appeared to be partly mediated by depressive symptoms, which accounted for 15% to 29% of the observed associations. DISCUSSION: Lower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND OBJECTIVES: Epidemiological evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study. METHODS: Dementia-free community-dwelling Japanese aged ≥65 years underwent brain MRI scans and a comprehensive health examination. Frequency of contact with non-cohabiting relatives and friends was determined by asking a single question with four categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV) and white matter lesions volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms. RESULTS: We included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared to that in the group with the highest frequency (67.3&#37; vs 67.8&#37;), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesions volume increased significantly with lower frequency of social contact (0.30&#37; in the lowest frequency vs 0.26&#37; in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q value of FDR correction <0.05). The relationships appeared to be partly mediated by depressive symptoms, which accounted for 15&#37; to 29&#37; of the observed associations. DISCUSSION: Lower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

Language：English   Publisher：Frontiers in Pharmacology  

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

DOI： 10.3389/fphar.2023.1203349

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Psychiatry and Clinical Neurosciences  

AIM: To investigate the association of white matter lesions volume (WMLV) levels with dementia risk and the association between dementia risk and the combined measures of WMLV and either total brain atrophy or dementia-related gray matter atrophy in a general older population. METHODS: One thousand one hundred fifty-eight Japanese dementia-free community-residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years. WMLV were segmented using the Lesion Segmentation Toolbox. Total brain volume (TBV) and regional gray matter volume were estimated by voxel-based morphometry. The WMLV-to-intracranial brain volume ratio (WMLV/ICV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. Total brain atrophy, defined as the TBV-to-ICV ratio (TBV/ICV), and dementia-related regional brain atrophy defined based on our previous report were calculated. The association between dementia risk and the combined measures of WMLV/ICV and either total brain atrophy or the number of atrophied regions was also tested. RESULTS: During the follow-up, 113 participants developed dementia. The risks of dementia increased significantly with higher WMLV/ICV levels. In addition, dementia risk increased additively both in participants with higher WMLV/ICV levels and lower TBV/ICV levels and in those with higher WMLV/ICV levels and a higher number of dementia-related brain regional atrophy. CONCLUSION: The risk of dementia increased significantly with higher WMLV/ICV levels. An additive increment in dementia risk was observed with higher WMLV/ICV levels and lower TBV/ICV levels or a higher number of dementia-related brain regional atrophy, suggesting the importance of prevention or control of cardiovascular risk factors.

DOI： 10.1111/pcn.13533

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

高齢者集団における白質病変容積(WMLV)及び脳萎縮と認知症リスクの関係について検討した。福岡県久山町の認知症がない65歳以上の住民のうち、脳MRIを実施した1158人(男性512人、女性646人、平均73.6±6.2歳)を対象とした。WMLVをLesion Segmentation Toolboxを用いてセグメント化し、全脳容積(TBV)と局所灰白質容積をvoxel-based morphometryを用いて推定した。頭蓋内脳容積(ICV)に対するWMLVの比(WMLV/ICV)を計算し、WMLV/ICVと認知症リスクの関連をCox比例ハザードモデルにより推定した。ICVに対するTBVの比(TBV/ICV)で定義された全脳萎縮と、著者等の過去の報告で定義された認知症関連の脳局所萎縮を算出した。5年間の経過観察期間中に113人が認知症を発症した。認知症リスクはWMLV/ICVとともに有意に増加した。WMLV/ICVが大きくTBV/ICVが小さい住民と、WMLV/ICVが大きく認知症関連の脳局所萎縮の数が多い住民では認知症リスクが相加的に増加することが観察された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Kidney Medicine  

RATIONALE & OBJECTIVE: Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. STUDY DESIGN: Population-based cross-sectional study. SETTING & PARTICIPANTS: A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. EXPOSURES: UACR and eGFR levels. OUTCOMES: The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). ANALYTICAL APPROACH: The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. RESULTS: Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend = 0.009 and <0.001, respectively). Lower eGFR levels were significantly associated with lower TBV/ICV, but not clearly associated with WMLV/ICV. In addition, higher UACR levels, but not lower eGFR, were significantly associated with lower temporal cortex volume-to-TBV ratio and lower hippocampal volume-to-TBV ratio. LIMITATIONS: Cross-sectional study, misclassification of UACR or eGFR levels, generalizability to other ethnicities and younger populations, and residual confounding factors. CONCLUSIONS: The present study demonstrated that higher UACR was associated with brain atrophy, especially in the temporal cortex and hippocampus, and with increased WMLV. These findings suggest that chronic kidney disease is involved in the progression of morphologic brain changes associated with cognitive impairment.

DOI： 10.1016/j.xkme.2022.100593

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：Japanese Society of Biological Psychiatry  

DOI： 10.11249/jsbpjjpp.34.1_38

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Archives of Gerontology and Geriatrics  

BACKGROUND: To investigate the association of gait speed with regional brain volumes and the risk of incident dementia. METHODS: A total of 1112 dementia-free Japanese residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years (median). The participants were classified into the age- and sex-specific quartile levels of maximum gait speed. Regional gray matter volumes (GMV) and white matter hyperintensities volumes (WMHV) were measured by applying voxel-based morphometry methods. The cross-sectional association of maximum gait speed with regional GMV was examined using an analysis of covariance. We also estimated the association between maximum gait speed level and the risk of developing dementia using a Cox proportional hazards model. Mediation analyses were conducted to determine the contribution of regional brain volumes to the association between maximum gait speed and dementia. RESULTS: Lower maximum gait speed was significantly associated with lower GMV of the total brain, frontal lobe, temporal lobe, cingulate gyrus, insula, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum, and increased WMHV at baseline. During the follow-up, 108 participants developed dementia. The incidence rate of all dementias increased significantly with decreasing maximum gait speed after adjusting for potential confounders (P for trend = 0.03). The mediating effects of the GMV of the hippocampus, GMV of the insula, and WMHV were significant. CONCLUSIONS: Lower maximum gait speed was significantly associated with an increased risk of dementia. Reduced GMV of the hippocampus or insula, and an increase in WMHV was likely to be involved in this association.

DOI： 10.1016/j.archger.2022.104883

Web of Science

Scopus

PubMed

researchmap

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Several prospective Western studies have reported an inverse association of vegetable and fruit intake with dementia risk. However, there is limited epidemiologic evidence in Asians. This study investigated the association of intakes of vegetables, fruits, and their nutrients on the risk of incident dementia and its subtypes in a Japanese community.

Methods

A total of 1071 participants (452 men and 619 women) aged ≥60 years without dementia at baseline were prospectively followed up for 24 years. Intakes of vegetables, fruits, and nutrients were evaluated using a 70-item semiquantitative food frequency questionnaire at baseline and were categorized into quartiles separately by gender. The outcome measure was the development of dementia and its subtypes—namely, Alzheimer’s disease (AD) and vascular dementia (VaD). The risk estimates of incident dementia were computed using a Cox proportional hazards model.

Results

During the long-term follow-up period, 464 subjects developed dementia, of whom 286 had AD and 144 had VaD. Higher vegetable intake was associated gradually with lower risk of developing dementia and AD (both P-trend &lt; 0.05), but not VaD, after adjusting for confounders. Subjects allocated the highest quartile of vegetable intake had 27 and 31% lower risk of dementia and AD, respectively, than those with the lowest quartile. The risk of dementia decreased significantly with higher intakes of vitamin A, riboflavin, vitamin C, magnesium, calcium, and potassium (all P-trend &lt; 0.05). Subjects with higher total dietary fiber intake tended to be at decreased risk for total dementia (P-trend = 0.07). Meanwhile, there were no significant associations between fruit intake and the risk of dementia and its subtypes.

Conclusion

Higher intakes of vegetables and their constituent nutrients were associated with a lower risk of dementia in Japanese older adults. A diet rich in vegetables may be beneficial in reducing the dementia risk in Asians.

DOI： 10.1186/s12877-022-02939-2

Web of Science

Scopus

PubMed

researchmap

Other Link： https://link.springer.com/article/10.1186/s12877-022-02939-2/fulltext.html

Language：English   Publisher：Frontiers in Pharmacology  

Background: Alzheimer’s disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer’s Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), −0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer’s disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

DOI： 10.3389/fphar.2022.991982

Web of Science

Scopus

PubMed

Language：English   Publisher：Scientific reports  

Physical frailty has been associated with adverse outcomes such as dementia. However, the underlying structural brain abnormalities of physical frailty are unclear. We investigated the relationship between physical frailty and structural brain abnormalities in 670 cognitively unimpaired individuals (mean age 70.1 years). Total brain volume (TBV), hippocampal volume (HV), total white matter hypointensities volume (WMHV), and estimated total intracranial volume (eTIV) on the 3D T1-weighted images were automatically computed using FreeSurfer software. Participants were divided into two states of physical frailty (robust vs. prefrail) based on the revised Japanese version of the Cardiovascular Health Study criteria. The multivariable-adjusted mean values of the TBV-to-eTIV ratio was significantly decreased, whereas that of the WMHV-to-eTIV ratio was significantly increased in the prefrail group compared with the robust group. Slowness, one of the components of physical frailty, was significantly associated with reduced TBV-to-eTIV and HV-to-eTIV ratios, and slowness and weakness were significantly associated with an increased WMHV-to-eTIV ratio. Our results suggest that the prefrail state is significantly associated with global brain atrophy and white matter hypointensities. Furthermore, slowness was significantly associated with hippocampal atrophy.

DOI： 10.1038/s41598-022-16190-7

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

We examined the association of serum s-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH) (methionine metabolites), and their ratio on the risk of dementia and death in a community-dwelling population of older Japanese individuals. 1371 residents of Hisayama, Japan, aged 65 years or older and without dementia, were followed for a median of 10.2 years (2007-2017). We divided serum SAM, SAH, and SAM/SAH ratio into quartiles. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of serum SAM, SAH, and SAM/SAH ratio levels on the risk of a composite outcome of all-cause dementia or death, and each outcome. During the follow-up, 635 participants developed all-cause dementia and/or died, of which 379 participants developed dementia and 394 deaths occurred. The multivariable-adjusted HRs of the composite outcome decreased significantly with increasing serum SAM levels (P for trend = 0.01), while they increased significantly with higher serum SAH levels (P for trend = 0.03). Higher serum SAM/SAH ratio levels were significantly associated with a lower risk of the composite outcome (P for trend = 0.002), as well as with lower risk of each outcome. Our findings suggest that the balance of methionine metabolites may closely associate with the risk of dementia and death.

DOI： 10.1038/s41598-022-16242-y

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ophthalmology Science  

PURPOSE: To assess the association of inner retinal thickness with prevalent dementia and regional brain atrophy in a general older population of Japanese. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 1078 residents aged 65 years or older who participated in an eye examination, a comprehensive survey of dementia, and brain magnetic resonance imaging scanning in 2017. METHODS: The thicknesses of the inner retinal layers, namely, the ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL)-were measured by swept-source OCT (SS-OCT). The association of these retinal thicknesses with the risk of the presence of dementia was estimated using restricted cubic splines and logistic regression models. Regional brain volumes were estimated separately by applying 2 different methods: voxel-based morphometry (VBM) and analysis by FreeSurfer software. The associations of GC-IPL and RNFL thickness with each brain regional volume were analyzed using multiple regression analysis. MAIN OUTCOME MEASURE: Prevalent dementia and regional brain atrophy. RESULTS: Among the study participants, 61 participants (5.7%) were diagnosed with dementia. The likelihood of the presence of dementia significantly increased with lower GC-IPL thickness after adjusting for potential confounders (odds ratio, 1.62 [95% confidence interval, 1.30-2.01] per 1 standard deviation decrement in the GC-IPL thickness), but no significant association was observed with RNFL thickness. In the VBM analyses with the multivariable adjustment, lower GC-IPL thickness was significantly associated with lower volume of known brain regions related to cognitive functions (i.e., the hippocampus, amygdala, entorhinal area, and parahippocampal gyrus) and visual functions (i.e., the cuneus, lingual gyrus, and thalamus). Meanwhile, the volume of the thalamus significantly decreased with lower RNFL thickness, but none of the brain regions related to cognitive function exhibited a volume change in association with RNFL thickness. The sensitivity analysis using FreeSurfer analysis also showed that lower GC-IPL thickness was significantly associated with lower regional brain volume/intracranial volume of the hippocampus, amygdala, cuneus, lingual gyrus, and thalamus. CONCLUSIONS: Our findings suggest that the measurement of GC-IPL thickness by SS-OCT, which is a noninvasive, convenient, and reproducible method, might be useful for identifying high-risk individuals with dementia.

DOI： 10.1016/j.xops.2022.100157

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：日本心身医学会総会ならびに学術講演会事務局  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Diabetes Care  

OBJECTIVE: To examine the association between diabetes and gray matter atrophy patterns in a general older Japanese population. RESEARCH DESIGN AND METHODS: In 2012, a total of 1,189 community-dwelling Japanese aged ≥65 years underwent brain MRI scans. Regional gray matter volumes (GMV) and intracranial volume (ICV) were measured by applying voxel-based morphometry (VBM) methods. The associations of diabetes and related parameters with the regional GMV/ICV were examined using an ANCOVA. The regional gray matter atrophy patterns in the subjects with diabetes or elevated fasting plasma glucose (FPG) or 2 h postload glucose (2hPG) levels were investigated using VBM. RESULTS: Subjects with diabetes had significantly lower mean values of GMV/ICV in the frontal lobe, temporal lobe, insula, deep gray matter structures, and cerebellum than subjects without diabetes after adjusting for potential confounders. A longer duration of diabetes was also significantly associated with lower mean values of GMV/ICV in these brain regions. The multivariable-adjusted mean values of the temporal, insular, and deep GMV/ICV decreased significantly with elevating 2hPG levels, whereas higher FPG levels were not significantly associated with GMV/ICV of any brain regions. In the VBM analysis, diabetes was associated with gray matter atrophy in the bilateral superior temporal gyri, right middle temporal gyrus, left inferior temporal gyrus, right middle frontal gyrus, bilateral thalami, right caudate, and right cerebellum. CONCLUSIONS: The current study suggests that a longer duration of diabetes and elevated 2hPG levels are significant risk factors for gray matter atrophy in various brain regions.

DOI： 10.2337/dc21-1911

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the American Geriatrics Society  

BACKGROUND: Little is known about the influence of serum level of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is a soluble type of an innate immune receptor expressed on the microglia, on the association of the daily sleep duration with the risk of dementia. METHODS: A total of 1230 Japanese community-residents aged 60 and older without dementia were followed prospectively for 10 years (2002-2012). Serum sTREM2 levels were divided into two groups using the median value (334.8 pg/ml). Self-reported daily sleep duration was grouped into three categories of <5.0, 5.0-7.9, and ≥8.0 h. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of daily sleep duration on the risk of dementia according to serum sTREM2 levels. RESULTS: During the follow-up, 262 subjects developed dementia. In subjects with low serum sTREM2 levels, subjects with ≥8.0 h of daily sleep had a significantly greater risk of dementia (multivariable-adjusted HR 2.05 [95% CI 1.32-3.19]) than those with 5.0-7.9 h of daily sleep, but those with <5.0 h did not. In contrast, the risk of dementia increased significantly in subjects with both <5.0 (1.95 [1.03-3.68]) and ≥8.0 h of daily sleep (1.48 [1.06-2.07]) in the subjects with high serum sTREM2 levels. CONCLUSIONS: The influence of daily sleep duration on risk of dementia differed according to serum sTREM2 levels in the older Japanese population. Short daily sleep may be associated with greater risk of dementia only in subjects with a high serum sTREM2 level.

DOI： 10.1111/jgs.17634

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pain  

ABSTRACT: Chronic low back pain (CLBP) is the leading cause of years lived with disability. Recently, it has been reported that CLBP is associated with alterations in the central nervous system. The present study aimed to investigate the association between CLBP and regional brain atrophy in an older Japanese population. A total of 1106 community-dwelling participants aged ≥65 years underwent brain magnetic resonance imaging scans and a health examination in 2017 to 2018. We used the FreeSurfer software for the analysis of brain magnetic resonance imaging. Chronic pain was defined as subjective pain for ≥3 months. Participants were divided into 3 groups according to the presence or absence of chronic pain and the body part that mainly suffered from pain: a "no chronic pain (NCP)" group (n = 541), "CLBP" group (n = 189), and "chronic pain in body parts other than the lower back (OCP)" group (n = 376). The brain volumes of the ventrolateral and dorsolateral prefrontal cortex, the posterior cingulate gyrus, and the amygdala were significantly lower in the CLBP group than in the NCP group after adjustment for sociodemographic, physical, and lifestyle factors and depressive symptoms. In addition, the left superior frontal gyrus was identified as a significant cluster by the Query, Design, Estimate, Contrast interface. There were no significant differences in the brain volumes of pain-related regions between the NCP and the OCP groups. The present study suggests that CLBP is associated with lower brain volumes of pain-related regions in a general older population of Japanese.

DOI： 10.1097/j.pain.0000000000002612

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Brain Pathology  

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. β amyloid (Aβ) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aβ phase score (A2-3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V-VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.

DOI： 10.1111/bpa.13014

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neuropathology and Experimental Neurology  

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

DOI： 10.1093/jnen/nlab126

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Alzheimer's Disease  

BACKGROUND: Glucose dysmetabolism is an important risk factor for dementia. OBJECTIVE: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. METHODS: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer's disease (AD) and vascular dementia (VaD) were investigated. RESULTS: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08-1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %-6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19-2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00-1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. CONCLUSION: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

DOI： 10.3233/JAD-215153

Web of Science

Scopus

PubMed

researchmap

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurology, Neurosurgery and Psychiatry  

<sec><title>Objective</title>To assess the association of regional grey matter atrophy with dementia risk in a general older Japanese population.

</sec><sec><title>Methods</title>We followed 1158 dementia-free Japanese residents aged ≥65 years for 5.0 years. Regional grey matter volume (GMV) at baseline was estimated by applying voxel-based morphometry methods. The GMV-to-total brain volume ratio (GMV/TBV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. We assessed whether the predictive ability of a model based on known dementia risk factors could be improved by adding the total number of regions with grey matter atrophy among dementia-related brain regions, where the cut-off value for grey matter atrophy in each region was determined by receiver operating characteristic curves.

</sec><sec><title>Results</title>During the follow-up, 113 participants developed all-cause dementia, including 83 with Alzheimer’s disease (AD). Lower GMV/TBV of the medial temporal lobe, insula, hippocampus and amygdala were significantly/marginally associated with higher risk of all-cause dementia and AD (all p for trend ≤0.08). The risks of all-cause dementia and AD increased significantly with increasing total number of brain regions exhibiting grey matter atrophy (both p for trend <0.01). Adding the total number of regions with grey matter atrophy into a model consisting of known risk factors significantly improved the predictive ability for AD (Harrell’s c-statistics: 0.765–0.802; p=0.02).

</sec><sec><title>Conclusions</title>Our findings suggest that the total number of regions with grey matter atrophy among the medial temporal lobe, insula, hippocampus and amygdala is a significant predictor for developing dementia, especially AD, in the general older population.

</sec>

DOI： 10.1136/jnnp-2021-326611

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The identification of individuals at high risk of developing hypertension can be of great value to improve the efficiency of primary prevention strategies for hypertension. The objective of this study was to develop a risk prediction model for incident hypertension based on prospective longitudinal data from a general Japanese population. A total of 982 subjects aged 40-59 years without hypertension at baseline were followed up for 10 years (2002-12) for the incidence of hypertension. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or the use of antihypertensive agents. The risk prediction model was developed using a Cox proportional hazards model. A simple risk scoring system was also established based on the developed model. During the follow-up period (median 10 years, interquartile range 5-10 years), 302 subjects (120 men and 182 women) developed new-onset hypertension. The risk prediction model for hypertension consisted of age, sex, SBP, DBP, use of glucose-lowering agents, body mass index (BMI), parental history of hypertension, moderate-to-high alcohol intake, and the interaction between age and BMI. The developed model demonstrated good discrimination (Harrell's C statistic=0.812 [95&#37; confidence interval, 0.791-0.834]; optimism-corrected C statistic based on 200 bootstrap samples=0.804) and calibration (Greenwood-Nam-D'Agostino χ2 statistic=12.2). This risk prediction model is a useful guide for estimating an individual's absolute risk for hypertension and could facilitate the management of Japanese individuals at high risk of developing hypertension in the future.

DOI： 10.1038/s41440-021-00673-7

Language：English  

DOI： 10.1038/s41598-021-97918-9

Language：Japanese  

Language：Japanese  

Language：English  

DOI： 10.1111/pcn.13204

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The prevalence of sarcopenia defined using the Asian Working Group for Sarcopenia (AWGS) criteria in Asian communities has not been fully addressed. Moreover, few studies have addressed the influence of sarcopenia on mortality. METHODS: A total of 1,371 and 1,597 residents aged 65 years or older participated in health surveys in 2012 and 2017. Sarcopenia was determined using the AWGS definition. Factors associated with the presence of sarcopenia were assessed using a logistic regression model in participants in the 2012 survey. Subjects in the 2012 survey were followed-up prospectively for a median of 4.3 years. Mortality risk for subjects with sarcopenia was examined using the Cox proportional hazards model. RESULTS: The crude prevalence of sarcopenia was 7.4&#37; and 6.6&#37; in participants at the 2012 and 2017 surveys, respectively; there was no significant difference between surveys (P = 0.44). The prevalence of sarcopenia increased significantly with age in both sexes (both P for trend <0.001). Subjects with sarcopenia were more likely to exercise less regularly, to intake less total energy, and to exhibit a disability in activity of daily living than those without. The multivariable-adjusted hazard ratio for all-cause mortality was 2.20 (95&#37; confidence interval, 1.25-3.85) in subjects with sarcopenia, compared to those without. CONCLUSIONS: Approximately 7&#37; of older subjects had sarcopenia in a community-dwelling older Japanese population. Moreover, subjects with sarcopenia had an increased mortality risk. Our findings suggest that a public health strategy for sarcopenia is needed to extend healthy life expectancy.

DOI： 10.2188/jea.JE20190289

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Folate and vitamin B-12 are essential nutrients for normal cell growth and replication, but the association of serum folate and vitamin B-12 concentrations with mortality risk remains uncertain. OBJECTIVE: This study was performed to investigate the associations of serum folate and vitamin B-12 concentrations with mortality risk and test whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism modifies these associations. METHODS: A total of 3050 Japanese community residents aged ≥40 y were prospectively followed-up for mortality between 2002 and 2012. Cox proportional hazards models and restricted cubic splines were used to estimate HRs and 95&#37; CIs of mortality. RESULTS: During a median follow-up period of 10.2 y, 336 participants died. Higher serum folate concentrations were associated with lower risks of all-cause mortality [multivariable-adjusted HR: 0.73; 95&#37; CI: 0.56, 0.96 for the second tertile (8.8-12.2 nmol/L; median 10.4 nmol/L) and HR: 0.61; 95&#37; CI: 0.46, 0.80 for the third tertile (≥12.5 nmol/L; median 15.6 nmol/L) serum folate concentrations compared with the first tertile (≤8.6 nmol/L; median 7.0 nmol/L)]. This association remained significant in all sensitivity analyses. Spline analyses showed a steady decline in all-cause mortality risk with increasing serum folate concentrations up to 20-25 nmol/L. This association persisted regardless of the MTHFR C677T genotypes. For serum vitamin B-12, the multivariable-adjusted HR of 1.32 (95&#37; CI: 0.97, 1.79) of all-cause mortality was marginally significantly greater in the first tertile compared with the second tertile. This association was attenuated and nonsignificant after the exclusion of participants with a history of cardiovascular disease or cancer, or participants aged ≥85 y at baseline, or deaths in the first 3 y of follow-up. CONCLUSIONS: Serum folate concentrations were inversely associated with the risk of all-cause mortality in Japanese adults. Serum vitamin B-12 concentrations were not consistently associated with all-cause mortality risk after accounting for reverse-causation bias.

DOI： 10.1093/jn/nxaa382

Language：English   Publishing type：Research paper (scientific journal)  

AIMS/INTRODUCTION: To investigate the association between midlife or late-life diabetes and the development of sarcopenia in an older Japanese population. MATERIALS AND METHODS: A total of 824 Japanese residents aged 65 to 84 years without sarcopenia were followed up from 2012 to 2017. Sarcopenia was determined following the Asian Working Group for Sarcopenia definition. The time of diabetes diagnosis was classified as midlife or late-life diabetes by the age at first diagnosis of diabetes (< 65 or ≥ 65 years) based on annual health checkups data over the past 24 years. The duration of diabetes was categorized into three groups of < 10, 10-15, and > 15 years. The odds ratios of incident sarcopenia according to the diabetic status were estimated using a logistic regression analysis. RESULTS: During follow-up, 47 subjects developed sarcopenia. The multivariable-adjusted odds ratio for incident sarcopenia was significantly greater in subjects with diabetes at baseline than in those without it (odds ratio 2.51, 95&#37; confidence interval 1.26-5.00). Subjects with midlife diabetes had a significantly greater risk of incident sarcopenia, whereas no significant association between late-life diabetes and incident sarcopenia was observed. With a longer duration of diabetes, the risk of incident sarcopenia increased significantly (P for trend = 0.002). CONCLUSIONS: The present study suggests that midlife diabetes and a longer duration of diabetes are significant risk factors for incident sarcopenia in the older population. Preventing diabetes in midlife may reduce the risk of the development of sarcopenia in later life.

DOI： 10.1111/jdi.13550

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Biomarkers for predicting future development of atrial fibrillation (AF) have not been fully established in general populations. The aim of this study was to assess the predictive ability of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) for the development of AF. METHODS AND RESULTS: A total of 3126 community-dwelling Japanese subjects aged ≥ 40 years without a history of AF in 2002 were followed up for a median of 10.2 years. Serum NT-proBNP levels at baseline were divided into four categories (≤ 54, 55-124, 125-299, and ≥ 300 pg/mL) according to the current guidelines and prior reports. The hazard ratios for the development of AF were estimated using a Cox proportional hazards model. During the follow-up period, 153 subjects developed new-onset AF. The age- and sex-adjusted cumulative incidence of AF increased significantly with higher serum NT-proBNP levels (p < 0.001 for trend). The association remained significant after adjustment for known risk factors for AF and cardiovascular disease (hazard ratio [95&#37; confidence interval]: ≤ 54 pg/mL: 1.00 [reference]; 55-124 pg/mL: 1.72 [1.00-2.97]; 125-299 pg/mL: 3.95 [2.23-6.98]; ≥ 300 pg/mL: 8.51 [4.48-16.17]; p < 0.001 for trend). Furthermore, incorporation of serum NT-proBNP levels into the model consisting of known risk factors for AF and cardiovascular disease significantly improved the predictive ability for developing AF (Harrell's c-statistics: 0.828 to 0.844, p = 0.01; continuous net reclassification improvement: 0.41, p < 0.001; integrated discrimination improvement: 0.031, p < 0.001). CONCLUSIONS: Serum NT-proBNP levels can be a risk biomarker for predicting future development of AF in a general Japanese population.

DOI： 10.1016/j.ijcard.2020.06.018

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To investigate the association of loneliness and its component subscales with the risk of dementia in a general Japanese older population. METHOD: A total of 1,141 community-dwelling Japanese residents aged ≥65 years without dementia were prospectively followed up for a median 5.0 years. We evaluated any loneliness and its component subscales-namely, social and emotional loneliness-by using the 6-Item de Jong Gierveld Loneliness Scale. Cox proportional hazards models were used to estimate hazard ratios (HRs) of each loneliness type on the risk of dementia controlling for demographic factors, lifestyle factors, physical factors, social isolation factors, and depression. RESULTS: During the follow-up, 114 participants developed dementia. The age- and sex-adjusted incidence rate of dementia was significantly greater in participants with any loneliness and emotional loneliness than those without. The multivariable-adjusted HRs (95&#37; confidence intervals) of participants with any loneliness and emotional loneliness on incident dementia were 1.61 (1.08-2.40) and 1.65 (1.07-2.54), respectively, as compared to those without. However, there was no significant association between social loneliness and dementia risk. In subgroup analyses of social isolation factors, excess risks of dementia associated with emotional loneliness were observed in participants who had a partner, lived with someone, or rarely communicated with relatives or friends, but such association was not significant in participants who had no partner, lived alone, or frequently communicated with friends or relatives. DISCUSSION: The present study suggested that loneliness, especially emotional loneliness, was a significant risk factor for the development of dementia in the general older population in Japan.

DOI： 10.1093/geronb/gbaa196

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: We aimed to investigate the association of serum glycated albumin (GA) levels with the risk of cardiovascular disease (CVD) and its subtypes, including coronary heart disease (CHD) and stroke, in a general Japanese population. METHODS: A total of 2965 Japanese community-dwellers aged ≥40 years were followed prospectively for a median of 10.2 years (2002-2012). Serum GA was measured by the enzymatic method and divided into quartiles. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and their 95&#37; confidence intervals (CIs) of serum GA levels on CVD risk. RESULTS: During the follow-up, 213 subjects developed CVD; 95 had CHD, and 133 had stroke. The cumulative incidence of CVD, CHD, and stroke increased significantly with increasing serum GA levels (all p for trend <0.02). Compared with the lowest serum GA quartile (<13.6&#37;), the multivariable-adjusted HRs (95&#37; CI) of the highest quartile (≥15.7&#37;) were 2.33 (1.46-3.68) for CVD, 2.23 (1.11-4.50) for CHD, and 2.47 (1.38-4.40) for stroke. In addition, a subgroup analysis showed that CVD risk increased significantly with increasing levels of serum GA in both subjects with and without diabetes mellitus. The increasing trend of CVD risk for higher serum GA levels was also observed in subjects with low hemoglobin A1c levels (hemoglobin A1c <5.46&#37;). CONCLUSIONS: Our findings suggest that higher serum GA levels are significantly associated with the development of CVD and its subtypes, even among subjects without diabetes or those with normal hemoglobin A1c levels, in a general Japanese population.

DOI： 10.1016/j.atherosclerosis.2020.08.016

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9&#37; were male. The prevalence of dementia at baseline was 8.5&#37; in overall participants. However, it was 16.4&#37; among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.

DOI： 10.1186/s12199-020-00903-3

Language：English   Publishing type：Research paper (scientific journal)  

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53&#37; women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95&#37; CI, 1.22-1.95] and 1.37 [95&#37; CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95&#37; CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95&#37; CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.

DOI： 10.1161/JAHA.119.014659

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To estimate the lifetime cumulative incidence of dementia and its subtypes from a community-dwelling elderly population in Japan. METHODS: A total of 1,193 community-dwelling Japanese individuals without dementia, aged 60 years or older, were followed up prospectively for 17 years. The cumulative incidence of dementia was estimated based on a death- and dementia-free survival function and the hazard functions of dementia at each year, which were computed by using a Weibull proportional hazards model. The lifetime risk of dementia was defined as the cumulative incidence of dementia at the point in time when the survival probability of the population was estimated to be less than 0.5&#37;. RESULTS: During the follow-up, 350 participants experienced some type of dementia; among them, 191 participants developed Alzheimer disease (AD) and 117 developed vascular dementia (VaD). The lifetime risk of dementia was 55&#37; (95&#37; confidence interval, 49&#37;-60&#37;). Women had an approximately 1.5 times greater lifetime risk of dementia than men (65&#37; [57&#37;-72&#37;] vs 41&#37; [33&#37;-49&#37;]). The lifetime risks of developing AD and VaD were 42&#37; (35&#37;-50&#37;) and 16&#37; (12&#37;-21&#37;) in women vs 20&#37; (7&#37;-34&#37;) and 18&#37; (13&#37;-23&#37;) in men, respectively. CONCLUSION: Lifetime risk of all dementia for Japanese elderly was substantial at approximately 50&#37; or higher. This study suggests that the lifetime burden attributable to dementia in contemporary Japanese communities is immense.

DOI： 10.1212/WNL.0000000000009917

Language：English   Publishing type：Research paper (scientific journal)  

Objective To examine the association between serum total homocysteine levels (tHcy) and dementia risk. Methods A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia. Results During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 μmol/L), the multivariable-adjusted HRs (95% CI) of the highest quintile (≥11.5 μmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 μmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07). Conclusion High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.

DOI： 10.1136/jnnp-2019-322366

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Both chronic kidney disease and brain white matter hyperintensities (WMH) are known to be risk factors of dementia and mortality.Methods and Results:In 2012, 1,214 community-dwelling Japanese subjects aged ≥65 years underwent brain magnetic resonance imaging (MRI) scans and a comprehensive health examination. This study investigated associations of the urinary albumin : creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with the WMH volume to intracranial volume (WMHV : ICV) ratio, and the association of the combination of UACR and the WMHV : ICV ratio with cognitive decline and mortality risk. The geometric mean of the WMHV : ICV ratio was 0.223&#37; in the entire study population, and increased significantly with higher UACR levels after adjusting for potential confounding factors (0.213&#37; for normoalbuminuria, 0.248&#37; for microalbuminuria, and 0.332&#37; for macroalbuminuria; Ptrend=0.01). In contrast, there was no clear association between eGFR and the WMHV : ICV ratio. Compared with subjects with normoalbuminuria and a smaller WMHV : ICV ratio (<0.257&#37; [median]), subjects with albuminuria and a larger WMHV : ICV ratio (≥0.257&#37;) had higher probabilities of cognitive decline at baseline and all-cause death during the follow-up. CONCLUSIONS: This study suggests that subjects with albuminuria have a greater risk of WMH enlargement and that the combination of albuminuria and WMH enlargement increases the risk of cognitive decline and all-cause mortality in an elderly Japanese population.

DOI： 10.1253/circj.CJ-19-1069

Language：English   Publishing type：Research paper (scientific journal)  

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index–defined lower-normal weight (18.5-22.4 kg/m²), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m²) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

DOI： 10.1111/obr.12989

Language：English   Publishing type：Research paper (scientific journal)  

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

DOI： 10.1111/obr.12989

Language：English  

OBJECTIVE: To examine the association between serum total homocysteine levels (tHcy) and dementia risk. METHODS: A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia. RESULTS: During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 µmol/L), the multivariable-adjusted HRs (95&#37; CI) of the highest quintile (≥11.5 µmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 µmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07). CONCLUSION: High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.

DOI： 10.1136/jnnp-2019-322366

Language：English   Publishing type：Research paper (scientific journal)  

Background: Research links blood pressure variability (BPV) with stroke; however, the association with cerebral small-vessel disease (CSVD) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. Methods and Results: A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke (<4 weeks); exposure, BPV quantified by any metric over any duration; comparison, (1) low versus high or mean BPV and (2) people with versus without CSVD; and outcomes, (1) CSVD as subcortical infarct, lacunae, white matter hyperintensities, cerebral microbleeds, or enlarged perivascular spaces; and (2) standardized mean difference in BPV. A total of 27 articles were meta-analyzed, comprising 12 309 unique brain scans. A total of 31 odds ratios (ORs) were pooled, indicating that higher systolic BPV was associated with higher odds for CSVD (OR, 1.27; 95% CI, 1.14–1.42; I²=85%) independent of mean systolic pressure. Likewise, higher diastolic BPV was associated with higher odds for CSVD (OR, 1.30; 95% CI, 1.14–1.48; I²=53%) independent of mean diastolic pressure. There was no evidence of a pairwise interaction between systolic/diastolic and BPV/mean ORs (P=0.47), nor a difference between BPV versus mean pressure ORs (P=0.58). Fifty-four standardized mean differences were pooled and provided similar results for pairwise interaction (P=0.38) and difference between standardized mean differences (P=0.70). Conclusions: On the basis of the available studies, BPV was associated with CSVD independent of mean blood pressure. However, more high-quality longitudinal data are required to elucidate whether BPV contributes unique variance to CSVD morphological characteristics.

DOI： 10.1161/JAHA.119.013841

Language：English   Publishing type：Research paper (scientific journal)  

AIMS/INTRODUCTION: To investigate the association of alternative glycemic measures - namely, serum glycated albumin (GA), hemoglobin A1c (HbA1c ) and the GA : HbA1c ratio - with global brain and hippocampal atrophy in a general elderly Japanese population. MATERIALS AND METHODS: A total of 1,278 Japanese individuals aged ≥65 years in a community participated in brain magnetic resonance imaging scanning and screening examination of health status in 2012. We measured total brain volume (TBV), hippocampal volume (HV) and intracranial volume (ICV) using the data from the magnetic resonance imaging examination. The association of each glycemic measure with the ratios of TBV : ICV (an indicator of global brain atrophy) and HV : ICV (an indicator of hippocampal atrophy) was examined by analysis of covariance. RESULTS: The mean values of the TBV : ICV and HV : ICV ratios decreased significantly with elevating serum GA levels and GA : HbA1c ratio levels (all P for trend < 0.05), but not with higher HbA1c levels, after adjusting for age, sex, low education, systolic blood pressure, antihypertensive medication, diabetes mellitus, serum total cholesterol, electrocardiogram abnormalities, body mass index, smoking habits, alcohol drinking habits and regular exercise. These significant associations were still observed in the sensitivity analysis after excluding individuals with mild cognitive impairment and dementia. In addition, increased serum GA levels and the GA : HbA1c ratio levels, but not HbA1c , were closely associated with lower mean values of the TBV : ICV and HV : ICV ratios, irrespective of the presence or absence of diabetes mellitus. CONCLUSIONS: The present study suggests that higher serum GA and higher GA : HbA1c ratio are significantly associated with global brain and hippocampal atrophy.

DOI： 10.1111/jdi.13220

Language：English   Publishing type：Research paper (scientific journal)  

Background: The association between decline in handgrip strength from midlife to late life and dementia is unclear. Methods: Japanese community-dwellers without dementia aged 60 to 79 years (ie, individuals in late life; mean age, 68 years) were followed for 24 years (1988–2012) (n = 1,055); 835 of them had participated in a health examination in 1973–1974 (mean age, 53 years), and these earlier data were used for the midlife analysis. Using a Cox proportional hazards model, we estimated the risk conferred by a decline in handgrip strength over a 15-year period (1973–74 to 1988) from midlife to late life on the development of total dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) over the late-life follow-up period from 1988 to 2012. Results: During the follow-up, 368 subjects experienced total dementia. The age-and sex-adjusted incidence of total dementia increased significantly with greater decline in handgrip strength (increased or unchanged handgrip strength [≥+0%] 25.1, mildly decreased [−14 to −1%] 28.4, and severely decreased [≤−15%] 38.9 per 1,000 person-years). A greater decline in handgrip strength was significantly associated with higher risk of total dementia after adjusting for potential confounding factors; subjects with severely decreased handgrip strength had 1.51-fold (95% confidence interval, 1.14–1.99, P < 0.01) increased risk of total dementia compared to those with increased or unchanged handgrip strength. Similar significant findings were observed for AD, but not for VaD. Conclusions: Our findings suggest that a greater decline in handgrip strength from midlife to late life is an important indicator for late-life onset of dementia.

DOI： 10.2188/jea.JE20180137

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: We have conducted the pathological cohort study of autopsied cases of Hisayama residents to reveal a recent trend of dementia-related pathology. We noticed a trend of putaminal involvement of Alzheimer's disease (AD) with parkinsonism. Then, we investigated the accurate prevalence of neurological diseases with putaminal AD pathology in the general population. Methods: We examined a series of 291 autopsies in the Hisayama study and performed image analysis of immunohistochemistry for microtubule-associated protein tau (MAPT) and amyloid β. Results: Approximately 65.6% and 36.1% of cases showed putaminal MAPT and amyloid deposits, respectively. Diffuse deposits of them were mainly found in the AD cases. Putaminal MAPT was highly associated with AD-related pathological criteria. Four of 22 cases with severe putaminal MAPT deposition were documented as having developed parkinsonism. Discussion: Severe MAPT accumulation in the basal ganglia was closely related to the development of AD pathology and could occur most frequently in AD cases without comorbidities.

DOI： 10.1016/j.dadm.2019.04.008

Language：English   Publishing type：Research paper (scientific journal)  

Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer's disease: The Hisayama study.
Introduction: We have conducted the pathological cohort study of autopsied cases of Hisayama residents to reveal a recent trend of dementia-related pathology. We noticed a trend of putaminal involvement of Alzheimer's disease (AD) with parkinsonism. Then, we investigated the accurate prevalence of neurological diseases with putaminal AD pathology in the general population. Methods: We examined a series of 291 autopsies in the Hisayama study and performed image analysis of immunohistochemistry for microtubule-associated protein tau (MAPT) and amyloid β. Results: Approximately 65.6&#37; and 36.1&#37; of cases showed putaminal MAPT and amyloid deposits, respectively. Diffuse deposits of them were mainly found in the AD cases. Putaminal MAPT was highly associated with AD-related pathological criteria. Four of 22 cases with severe putaminal MAPT deposition were documented as having developed parkinsonism. Discussion: Severe MAPT accumulation in the basal ganglia was closely related to the development of AD pathology and could occur most frequently in AD cases without comorbidities.

DOI： 10.1016/j.dadm.2019.04.008

Language：English   Publishing type：Research paper (scientific journal)  

ObjectiveThe associations between trans fatty acids and dementia have been unclear. We investigated the prospective association between serum elaidic acid (trans 18:1 n-9) levels, as an objective biomarker for industrial trans fat, and incident dementia and its subtypes.MethodsIn total, 1,628 Japanese community residents aged 60 and older without dementia were followed prospectively from when they underwent a screening examination in 2002-2003 to November 2012 (median 10.3 years, interquartile range 7.2-10.4 years). Serum elaidic acid levels were measured using gas chromatography/mass spectrometry and divided into quartiles. The Cox proportional hazards model was used to estimate the hazard ratios for all-cause dementia, Alzheimer disease (AD), and vascular dementia by serum elaidic acid levels.ResultsDuring the follow-up, 377 participants developed some type of dementia (247 AD, 102 vascular dementia). Higher serum elaidic acid levels were significantly associated with greater risk of developing all-cause dementia (p for trend = 0.003) and AD (p for trend = 0.02) after adjustment for traditional risk factors. These associations remained significant after adjustment for dietary factors, including total energy intake and intakes of saturated and polyunsaturated fatty acids (both p for trend <0.05). No significant associations were found between serum elaidic acid levels and vascular dementia.ConclusionsThe findings suggest that higher serum elaidic acid is a possible risk factor for the development of all-cause dementia and AD in later life. Public health policy to reduce industrially produced trans fatty acids may assist in the primary prevention of dementia.

DOI： 10.1212/WNL.0000000000008464

Language：English   Publishing type：Research paper (scientific journal)  

Serum elaidic acid concentration and risk of dementia: The Hisayama study.
OBJECTIVE: The associations between trans fatty acids and dementia have been unclear. We investigated the prospective association between serum elaidic acid (trans 18:1 n-9) levels, as an objective biomarker for industrial trans fat, and incident dementia and its subtypes. METHODS: In total, 1,628 Japanese community residents aged 60 and older without dementia were followed prospectively from when they underwent a screening examination in 2002-2003 to November 2012 (median 10.3 years, interquartile range 7.2-10.4 years). Serum elaidic acid levels were measured using gas chromatography/mass spectrometry and divided into quartiles. The Cox proportional hazards model was used to estimate the hazard ratios for all-cause dementia, Alzheimer disease (AD), and vascular dementia by serum elaidic acid levels. RESULTS: During the follow-up, 377 participants developed some type of dementia (247 AD, 102 vascular dementia). Higher serum elaidic acid levels were significantly associated with greater risk of developing all-cause dementia (p for trend = 0.003) and AD (p for trend = 0.02) after adjustment for traditional risk factors. These associations remained significant after adjustment for dietary factors, including total energy intake and intakes of saturated and polyunsaturated fatty acids (both p for trend <0.05). No significant associations were found between serum elaidic acid levels and vascular dementia. CONCLUSIONS: The findings suggest that higher serum elaidic acid is a possible risk factor for the development of all-cause dementia and AD in later life. Public health policy to reduce industrially produced trans fatty acids may assist in the primary prevention of dementia.

DOI： 10.1212/WNL.0000000000008464

Language：English   Publishing type：Research paper (scientific journal)  

We examined the association between serum concentrations of β-alanine, a metabolite of carnosine and anserine, and the risk of dementia in a general population of elderly Japanese persons. In 2007, 1,475 residents of Hisayama, Japan, aged 60-79 years and without dementia were divided into 4 groups according to quartiles of serum β-alanine concentrations (quartile 1, lowest; quartile 4, highest) and followed for a median of 5.3 years. During follow-up, 117 subjects developed all-cause dementia (Alzheimer in 77 cases and vascular dementia in 31). The risk of all-cause dementia decreased with increasing serum β-alanine levels after adjustment for potential confounding factors (quartile 2, hazard ratio (HR) = 0.73 (95% confidence interval (CI): 0.45, 1.18); quartile 3, HR = 0.50 (95% CI: 0.28, 0.89); quartile 4, HR = 0.50 (95% CI: 0.27, 0.92); P = 0.01 for trend). A similar inverse association was observed for Alzheimer disease (quartile 2, HR = 0.78 (95% CI: 0.44, 1.38); quartile 3, HR = 0.53 (95% CI: 0.26, 1.06); quartile 4, HR = 0.53 (95% CI: 0.25, 1.10); P = 0.04 for trend) but not for vascular dementia. We found that higher serum β-alanine levels were significantly associated with lower risks of all-cause dementia and Alzheimer disease. Because serum β-alanine levels reflect intakes of carnosine/anserine, higher intakes of carnosine/anserine might be beneficial for the prevention of dementia.

DOI： 10.1093/aje/kwz116

Language：English   Publishing type：Research paper (scientific journal)  

NT-proBNP and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study.
Background Epidemiological evidence implies a link between heart disease and dementia. However, few prospective studies have assessed the association between serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and dementia. Methods and Results A total of 1635 community-dwelling Japanese elderly aged ≥60 years without dementia (57&#37; women, mean age±SD 70.8±7.7 years) were followed up for 10 years. Serum NT-proBNP levels were divided into 4 categories (≤54, 55-124, 125-299, and ≥300 pg/mL). The hazard ratios were estimated using a Cox proportional hazards model. During the follow-up period, 377 subjects developed all-cause dementia, 247 Alzheimer disease, and 102 vascular dementia. The age- and sex-adjusted incidence of all-cause dementia was 31.5 per 1000 person-years and increased significantly with higher serum NT-proBNP levels, being 16.4, 32.0, 35.7, and 45.5, respectively (P for trend <0.01). Subjects with serum NT-proBNP levels of ≥300 pg/mL had a significantly higher risk of all-cause dementia (hazard ratio=2.46, 95&#37; CI 1.63-3.71) than those with serum NT-proBNP levels of ≤54 pg/mL after adjusting for confounders. Similar risks were observed for Alzheimer disease and vascular dementia. Incorporation of the serum NT-proBNP level into a model with known risk factors for dementia significantly improved the predictive ability for incident dementia (c-statistics 0.780-0.787, P=0.02; net reclassification improvement 0.189, P=0.001; integrated discrimination improvement 0.011, P=0.003). Conclusions Higher serum NT-proBNP levels were significantly associated with an increased risk of dementia. Serum NT-proBNP could be a novel biomarker for predicting future risk of dementia in the general elderly population.

DOI： 10.1161/JAHA.118.011652

Language：English   Publishing type：Research paper (scientific journal)  

Background Epidemiological evidence implies a link between heart disease and dementia. However, few prospective studies have assessed the association between serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and dementia. Methods and Results A total of 1635 community-dwelling Japanese elderly aged ≥60 years without dementia (57% women, mean age±SD 70.8±7.7 years) were followed up for 10 years. Serum NT-proBNP levels were divided into 4 categories (≤54, 55-124, 125-299, and ≥300 pg/mL). The hazard ratios were estimated using a Cox proportional hazards model. During the follow-up period, 377 subjects developed all-cause dementia, 247 Alzheimer disease, and 102 vascular dementia. The age- and sex-adjusted incidence of all-cause dementia was 31.5 per 1000 person-years and increased significantly with higher serum NT-proBNP levels, being 16.4, 32.0, 35.7, and 45.5, respectively (P for trend <0.01). Subjects with serum NT-proBNP levels of ≥300 pg/mL had a significantly higher risk of all-cause dementia (hazard ratio=2.46, 95% CI 1.63-3.71) than those with serum NT-proBNP levels of ≤54 pg/mL after adjusting for confounders. Similar risks were observed for Alzheimer disease and vascular dementia. Incorporation of the serum NT-proBNP level into a model with known risk factors for dementia significantly improved the predictive ability for incident dementia (c-statistics 0.780-0.787, P=0.02; net reclassification improvement 0.189, P=0.001; integrated discrimination improvement 0.011, P=0.003). Conclusions Higher serum NT-proBNP levels were significantly associated with an increased risk of dementia. Serum NT-proBNP could be a novel biomarker for predicting future risk of dementia in the general elderly population.

DOI： 10.1161/JAHA.118.011652

Language：English   Publishing type：Research paper (scientific journal)  

Objective: We estimated secular trends in the prevalence of type 2 diabetes (T2DM) and prediabetes, and examined potential explanatory factors for these trends in a Japanese community. Methods: 4 cross-sectional examinations were conducted among subjects aged 40–79 years in 1988 (n = 2,490), 2002 (n = 2,856), 2007 (n = 2,761), and 2012 (n = 2,644). Glucose tolerance status was defined by a 75g oral glucose tolerance test. Results: The age-standardized prevalence of T2DM increased significantly in both sexes from 1988 to 2002, and thereafter it remained stable in men, and decreased nonsignificantly in women from 2002 to 2012. The age-standardized prevalence of prediabetes in men increased significantly between 1988 and 2002, but then decreased significantly. A similar trend was observed in women. The age-specific prevalence of T2DM increased greatly in men aged 60–79 years and women aged 70–79 years from 1988 to 2002, and then plateaued at a high level, while a significant decreasing trend was observed in women aged 40–49 years. The mean values of body mass index (BMI) increased steeply in these elderly subjects from 1988 to 2002, and remained at a high level, whereas those in middle-aged women decreased appreciably over the study period. Conclusions: Our findings suggest that in Japanese, there was no further increase in the prevalence of T2DM or prediabetes in either men or women in the 2000s. Secular change in the BMI level was likely to contribute to trends in the prevalence of T2DM, and thus the management of obesity may be important to reduce the prevalence of T2DM.

DOI： 10.1007/s13340-018-0380-0

Language：Others  

Trends in the prevalence of type 2 diabetes and prediabetes in a Japanese community, 1988-2012: the Hisayama Study.

DOI： 10.1007/s13340-018-0380-0

Language：English   Publishing type：Research paper (scientific journal)  

Background: Little is known about the association between dairy intake and risk of functional disability in the elderly. Objectives: We examined the influence of dairy intake on the development of declining functional capacity and activities of daily living (ADL) in a prospective cohort study of an elderly population. Methods: A total of 859 community-dwelling Japanese residents, aged ?65 y without functional disability, were followed up for 7 y. Functional capacity impairment was defined as a TokyoMetropolitan Institute of Gerontology Index of Competence score of ≥12, and ADL disability was defined as a Barthel Index score of ≥95. Dairy intake was evaluated using a 150-item semiquantitative food frequency questionnaire, grouped into quartiles. The RR of dairy intake on incident functional disabilitywas computed using a Poisson regression model. Results: The multivariable-Adjusted RR of impaired functional capacity decreased significantly with increasing dairy intake levels (RR [95% CI]: quartile 1, 1.00 [reference]; quartile 2, 0.85 [0.71, 1.02]; quartile 3, 0.81 [0.68, 0.98]; and quartile 4, 0.74 [0.61, 0.90]; P-Trend = 0.001). Regarding the three subscales of functional capacity, the inverse association between dairy intake and risk for impairment of intellectual activity and social role remained significant (P-Trend = 0.0009 and 0.02, respectively), but such an association was not observed for instrumental ADL. The multivariable-Adjusted risk of ADL disability also decreased weakly but significantly with elevating dairy intake (P-Trend=0.04). A similar association was seen for severity of functional disability (P-Trend = 0.002). However, the magnitude of these associations was attenuated after further adjustment for protein intake. Conclusion: Our findings suggest that higher dairy intake is associated with a lower risk of functional disability and its progression in the elderly, probably via an increase in protein intake.

DOI： 10.1093/ajcn/nqz040

Language：English   Publishing type：Research paper (scientific journal)  

Dairy consumption and risk of functional disability in an elderly Japanese population: the Hisayama Study.
BACKGROUND: Little is known about the association between dairy intake and risk of functional disability in the elderly. OBJECTIVES: We examined the influence of dairy intake on the development of declining functional capacity and activities of daily living (ADL) in a prospective cohort study of an elderly population. METHODS: A total of 859 community-dwelling Japanese residents, aged ≥65 y without functional disability, were followed up for 7 y. Functional capacity impairment was defined as a Tokyo Metropolitan Institute of Gerontology Index of Competence score of ≤12, and ADL disability was defined as a Barthel Index score of ≤95. Dairy intake was evaluated using a 150-item semiquantitative food frequency questionnaire, grouped into quartiles. The RR of dairy intake on incident functional disability was computed using a Poisson regression model. RESULTS: The multivariable-adjusted RR of impaired functional capacity decreased significantly with increasing dairy intake levels (RR [95&#37; CI]: quartile 1, 1.00 [reference]; quartile 2, 0.85 [0.71, 1.02]; quartile 3, 0.81 [0.68, 0.98]; and quartile 4, 0.74 [0.61, 0.90]; P-trend = 0.001). Regarding the three subscales of functional capacity, the inverse association between dairy intake and risk for impairment of intellectual activity and social role remained significant (P-trend = 0.0009 and 0.02, respectively), but such an association was not observed for instrumental ADL. The multivariable-adjusted risk of ADL disability also decreased weakly but significantly with elevating dairy intake (P-trend = 0.04). A similar association was seen for severity of functional disability (P-trend = 0.002). However, the magnitude of these associations was attenuated after further adjustment for protein intake. CONCLUSION: Our findings suggest that higher dairy intake is associated with a lower risk of functional disability and its progression in the elderly, probably via an increase in protein intake.

DOI： 10.1093/ajcn/nqz040

Language：English   Publishing type：Research paper (scientific journal)  

Aims/Introduction: The present study aimed to examine cross-sectional associations between objectively measured sedentary time and the prevalence of diabetes mellitus in a general Japanese population, and to elucidate possible mediating roles of diet, obesity and insulin resistance in this relationship. Materials and Methods: A total of 1,758 community-dwelling individuals aged 40–79 years wore an accelerometer for ≥7 days and underwent a comprehensive health examination in 2012. Diabetes mellitus was diagnosed by a 75-g oral glucose tolerance test. The associations of sedentary time with the presence of diabetes mellitus and the levels of the homeostasis model assessment of insulin resistance were estimated by logistic and linear regression models. Results: After adjustment for demographic and lifestyle factors including moderate-to-vigorous physical activity, participants who spent ≥10 h in sedentary time had a significantly higher odds ratio of the presence of diabetes than those who spent <6 h in sedentary time (odds ratio 1.84, 95% confidence interval 1.02–3.31). This significant association remained after adjusting for overall and central obesity (as measured by body mass index and waist circumference), but weakened after adjusting for dietary energy intake or homeostasis model assessment of insulin resistance. Sedentary time was positively associated with homeostasis model assessment of insulin resistance levels among non-diabetic participants after adjusted for obesity or energy intake (P for trend <0.01). Conclusions: Longer sedentary time was associated with a higher prevalence of diabetes mellitus in a general Japanese population. Insulin resistance appeared to be mainly involved in this association. These results highlight the importance of public health strategies targeting reductions in sedentary time for the primary prevention of diabetes mellitus.

DOI： 10.1111/jdi.12968

Language：Others  

Objectively measured sedentary time and diabetes mellitus in a general Japanese population: The Hisayama Study.

DOI： 10.1111/jdi.12968

Language：Others  

Association Between Serum β-alanine and Risk of Dementia: the Hisayama Study.

DOI： 10.1093/aje/kwz116

Language：Japanese  

LONG-TERM PHYSICAL ACTIVITY FROM MIDLIFE TO LATE-LIFE AND COGNITIVE DECLINE IN AN ELDERLY JAPANESE POPULATION : THE HISAYAMA STUDY

Language：English   Publishing type：Research paper (scientific journal)  

The aim of the present study was to examine the prevalence and causes of adult epilepsy in a general Japanese population. We examined a total of 3333 Japanese residents in the town of Hisayama aged ≥40 years in 2012-2013. The examination was performed mainly at the municipal center for health promotion, but some subjects were examined in their homes, hospitals, or nursing homes. Twenty-three subjects had a diagnosis of epilepsy. The prevalence (95% confidence interval [CI]) of epilepsy per 1000 was 6.9 (4.1-9.7) in total, 4.9 (1.3-8.5) in men, and 8.4 (4.3-12.5) in women (P = 0.23 between sexes). The prevalence of epilepsy was significantly higher in the elderly (aged ≥65 years; 10.3 per 1000 [95% CI 5.4-15.1]) than in the middle-aged (aged 40-64 years; 3.6 per 1000 [95% CI 0.7-6.4]; P = 0.02). The major cause of epilepsy was cerebrovascular diseases (n = 11; 48% of the epilepsy patients). More than half of the epilepsy patients experienced the first episode of seizure in older age (≥65 years; n = 13; 57%). The findings of this study suggest the clinical importance of the prevention of cerebrovascular diseases to reduce the burden of epilepsy in the future.

DOI： 10.1002/epi4.12295

Language：English   Publishing type：Research paper (scientific journal)  

Prevalence of adult epilepsy in a general Japanese population: The Hisayama study.
The aim of the present study was to examine the prevalence and causes of adult epilepsy in a general Japanese population. We examined a total of 3333 Japanese residents in the town of Hisayama aged ≥40 years in 2012-2013. The examination was performed mainly at the municipal center for health promotion, but some subjects were examined in their homes, hospitals, or nursing homes. Twenty-three subjects had a diagnosis of epilepsy. The prevalence (95&#37; confidence interval [CI]) of epilepsy per 1000 was 6.9 (4.1-9.7) in total, 4.9 (1.3-8.5) in men, and 8.4 (4.3-12.5) in women (P = 0.23 between sexes). The prevalence of epilepsy was significantly higher in the elderly (aged ≥65 years; 10.3 per 1000 [95&#37; CI 5.4-15.1]) than in the middle-aged (aged 40-64 years; 3.6 per 1000 [95&#37; CI 0.7-6.4]; P = 0.02). The major cause of epilepsy was cerebrovascular diseases (n = 11; 48&#37; of the epilepsy patients). More than half of the epilepsy patients experienced the first episode of seizure in older age (≥65 years; n = 13; 57&#37;). The findings of this study suggest the clinical importance of the prevention of cerebrovascular diseases to reduce the burden of epilepsy in the future.

DOI： 10.1002/epi4.12295

Language：English   Publishing type：Research paper (scientific journal)  

Serum Soluble Triggering Receptor Expressed on Myeloid Cells 2 as a Biomarker for Incident Dementia: The Hisayama Study.
OBJECTIVE: To investigate the association between serum soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble type of an innate immune receptor expressed on the microglia, and the risk of dementia. METHODS: A total of 1,349 Japanese community residents aged 60 and older without dementia were followed prospectively for 10 years (2002-2012). Serum sTREM2 levels were quantified by using an enzyme-linked immunosorbent assay and divided into quartiles. Cox proportional hazards model was used to estimate the hazard ratios (HRs) of serum sTREM2 levels on the risk of dementia. RESULTS: During the follow-up, 300 subjects developed all-cause dementia; 193 had Alzheimer's disease (AD), and 85 had vascular dementia (VaD). The age- and sex-adjusted incidences of all-cause dementia, AD, and VaD elevated significantly with higher serum sTREM2 levels (all p for trend < 0.012). These associations were not altered after adjustment for confounding factors, including high-sensitive C-reactive protein. Subjects with the highest quartile of serum sTREM2 levels had significantly higher multivariable-adjusted risks of developing all-cause dementia, AD, and VaD than those with the lowest quartile (HR = 2.03, 95&#37; confidence interval [CI] = 1.39-2.97, p < 0.001 for all-cause dementia; HR = 1.62, 95&#37; CI = 1.02-2.55, p = 0.04 for AD; HR = 2.85, 95&#37; CI = 1.35-6.02, p = 0.006 for VaD). No significant heterogeneity in the association of serum sTREM2 levels with the development of dementia was observed among the other risk factor subgroups (all p for heterogeneity > 0.11). INTERPRETATION: The present findings suggest a significant association between increased serum sTREM2 levels and the risk of developing all-cause dementia, AD, and VaD in the general elderly Japanese population. ANN NEUROL 2019;85:47-58.

DOI： 10.1002/ana.25385

Language：English   Publishing type：Research paper (scientific journal)  

Decline in handgrip strength from midlife to late-life is associated with dementia in a Japanese community: the Hisayama Study.
BACKGROUND: The association between decline in handgrip strength from midlife to late life and dementia is unclear. METHODS: Japanese community-dwellers without dementia aged 60 to 79 years (ie, individuals in late life; mean age, 68 years) were followed for 24 years (1988-2012) (n = 1,055); 835 of them had participated in a health examination in 1973-1974 (mean age, 53 years), and these earlier data were used for the midlife analysis. Using a Cox proportional hazards model, we estimated the risk conferred by a decline in handgrip strength over a 15-year period (1973-74 to 1988) from midlife to late life on the development of total dementia, Alzheimer's disease (AD), and vascular dementia (VaD) over the late-life follow-up period from 1988 to 2012. RESULTS: During the follow-up, 368 subjects experienced total dementia. The age- and sex-adjusted incidence of total dementia increased significantly with greater decline in handgrip strength (increased or unchanged handgrip strength [≥+0&#37;] 25.1, mildly decreased [-14 to -1&#37;] 28.4, and severely decreased [≤-15&#37;] 38.9 per 1,000 person-years). A greater decline in handgrip strength was significantly associated with higher risk of total dementia after adjusting for potential confounding factors; subjects with severely decreased handgrip strength had 1.51-fold (95&#37; confidence interval, 1.14-1.99, P < 0.01) increased risk of total dementia compared to those with increased or unchanged handgrip strength. Similar significant findings were observed for AD, but not for VaD. CONCLUSIONS: Our findings suggest that a greater decline in handgrip strength from midlife to late life is an important indicator for late-life onset of dementia.

DOI： 10.2188/jea.JE20180137

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgs.15558

Language：Others  

Reply to "Long sleep duration: An epiphenomenon or a risk for dementia?"

DOI： 10.1111/jgs.15558

Language：English   Publishing type：Research paper (scientific journal)  

Background: A body of empirical work demonstrates that wide fluctuations in a person's blood pressure across consecutive measures, known as blood pressure variability (BPV), hold prognostic value to predict stroke and transient ischemic attack. However, the magnitude of association between BPV and other neurological outcomes remains less clear. This systematic review aims to pool together data regarding BPV with respect to incident dementia, cognitive impairment, and cognitive function. Methods: Electronic databases (MEDLINE, EMBASE, and SCOPUS) will be searched for the key words blood pressure variability and outcomes of dementia, cognitive impairment, and cognitive function. Authors and reference lists of included studies will also be contacted to identify additional published and unpublished studies. Eligibility criteria are as follows: population - adult humans (over 18 years but with no upper age limit) without dementia at baseline, with or without elevated blood pressure, or from hypertensive populations (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or use of antihypertensive drug for hypertension) and from primary care, community cohort, electronic database registry, or randomized controlled trial (RCT); exposure - any metric of BPV (systolic, diastolic or both) over any duration; comparison - persons without dementia who do not have elevated BPV; and outcome - dementia, cognitive impairment, cognitive function at follow-up from standardized neurological assessment, or cognitive testing. Article screening will be undertaken by two independent reviewers with disagreements resolved through discussion. Data extraction will include original data specified as hazard ratios, odds ratios, correlations, regression coefficients, and original cell data if available. Risk of bias assessment will be undertaken by two independent reviewers. Meta-analytic methods will be used to synthesize the data collected relating to the neurological outcomes with Comprehensive Meta-Analysis Version 2.0 (Biostat Inc., Engelwood, NJ). Discussion: This systematic review aims to clarify whether BPV is associated with elevated risk for dementia, cognitive impairment, and cognitive function. An evaluation of the etiological links between BPV with incident dementia might inform evidence-based clinical practice and policy concerning blood pressure measurement and hypertension management. The review will identify sources of heterogeneity and may inform decisions on whether it is feasible and desirable to proceed with an individual participant data meta-analysis.

DOI： 10.1186/s13643-018-0811-9

Language：Others  

Association Between Daily Sleep Duration and Risk of Dementia and Mortality in a Japanese Community.

DOI： 10.1111/jgs.15446

Language：English   Publishing type：Research paper (scientific journal)  

Background: Epidemiological evidence suggests that fish consumption and intake of n-3 polyunsaturated fatty acids (PUFA)—namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—confer protection against depression. However, few studies have addressed the influence of the balance between n-3 PUFA and n-6 PUFA in the human body on depression. Methods: A total of 2,529 community-dwelling Japanese residents aged ≥ 40 years were assessed for depressive symptoms (defined as a score of 16 points or more on the Center for Epidemiologic Studies Depression Scale [CES-D]) in 2007. The serum arachidonic acid (AA) /EPA ratio and AA/DHA ratio were measured in frozen samples collected in 2002 and categorized into quartiles. The odds ratios (ORs) for the presence of depressive symptoms were calculated using a logistic regression model. Results: The prevalence of depressive symptoms was 4.3%. There was no significant association between either the serum AA/EPA ratio or AA/DHA ratio and the presence of depressive symptoms. However, subjects with the highest serum AA/EPA ratios (range: 3.28–13.3) had a 4.10 times (95%CI: 1.13–19.80) greater OR for the presence of depressive symptoms than those with the lowest ratios (0.30–1.65) after adjusting for confounding factors in the subgroup with high-sensitivity C-reactive protein (hs-CRP) ≥ 1.0 mg/L, while no clear association was observed in the subgroup with hs-CRP < 1.0 mg/L. Limitations: Reverse causality is possible due to the cross-sectional study design. Conclusions: Our findings suggest that a higher serum AA/EPA ratio is associated with a greater likelihood of depressive symptoms in subjects with systemic inflammation in the general Japanese population.

DOI： 10.1016/j.jad.2018.05.004

Language：English   Publishing type：Research paper (scientific journal)  

Background: Epidemiological evidence suggests that fish consumption and intake of n-3 polyunsaturated fatty acids (PUFA)—namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—confer protection against depression. However, few studies have addressed the influence of the balance between n-3 PUFA and n-6 PUFA in the human body on depression. Methods: A total of 2,529 community-dwelling Japanese residents aged ≥ 40 years were assessed for depressive symptoms (defined as a score of 16 points or more on the Center for Epidemiologic Studies Depression Scale [CES-D]) in 2007. The serum arachidonic acid (AA) /EPA ratio and AA/DHA ratio were measured in frozen samples collected in 2002 and categorized into quartiles. The odds ratios (ORs) for the presence of depressive symptoms were calculated using a logistic regression model. Results: The prevalence of depressive symptoms was 4.3&#37;. There was no significant association between either the serum AA/EPA ratio or AA/DHA ratio and the presence of depressive symptoms. However, subjects with the highest serum AA/EPA ratios (range: 3.28–13.3) had a 4.10 times (95&#37;CI: 1.13–19.80) greater OR for the presence of depressive symptoms than those with the lowest ratios (0.30–1.65) after adjusting for confounding factors in the subgroup with high-sensitivity C-reactive protein (hs-CRP) ≥ 1.0 mg/L, while no clear association was observed in the subgroup with hs-CRP &lt
1.0 mg/L. Limitations: Reverse causality is possible due to the cross-sectional study design. Conclusions: Our findings suggest that a higher serum AA/EPA ratio is associated with a greater likelihood of depressive symptoms in subjects with systemic inflammation in the general Japanese population.

DOI： 10.1016/j.jad.2018.05.004

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer’s disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aβ accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.

DOI： 10.1007/s00439-018-1906-z

Language：Others  

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer's disease.

DOI： 10.1007/s00439-018-1906-z

Language：English   Publishing type：Research paper (scientific journal)  

Background We investigated the prevalence of and risk factors for cerebral microbleeds (CMBs) in a cross-sectional study of a general population of Japanese elderly. Methods In 2012, brain MRI scanning at 1.5T and comprehensive health examination were conducted for 1281 residents aged 65 years or older. CMBs were defined as ovoid hypointensity lesions less than 10 mm in diameter on T2-weighted images and classified into deep/infratentorial or lobar CMBs. Age- and sex-specific and overall prevalence of CMBs were estimated, and the associations of traditional cardiovascular risk factors and APOE polymorphism with the presence of CMBs were examined using a logistic regression analysis. Results The crude prevalences of total, deep/infratentorial, and lobar CMBs were 18.7% (n = 240), 13.5% (n = 173), and 9.6% (n = 123), respectively. The prevalence of total CMBs was 23.0% in men and 15.5% in women and increased with aging in both sexes (both p for trend <0.01). Hypertension was significantly associated with the presence of both deep/infratentorial and lobar CMBs. Lower serum total cholesterol was a significant risk factor for deep/infratentorial CMBs, but not for lobar CMBs, while APOE ϵ4 carriers had a significantly higher likelihood only of lobar CMBs compared with noncarriers. Conclusions Our study suggests that approximately 1 of 5 Japanese elderly people have CMBs, and that risk factors for deep/infratentorial and lobar CMBs are different, indicating the distinct pathologic backgrounds of these lesions.

DOI： 10.1212/CPJ.0000000000000464

Language：Others  

Prevalence of and risk factors for cerebral microbleeds in a general Japanese elderly community.

DOI： 10.1212/CPJ.0000000000000464

Language：English   Publishing type：Research paper (scientific journal)  

Background: There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese. Methods: A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer–Lemeshow test in the validation cohort. Results: During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend < 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer–Lemeshow test P = 0.43) in the validation cohort. Conclusions: We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual’s risk of future gastric cancer.

DOI： 10.1007/s10120-017-0768-8

Language：English   Publishing type：Research paper (scientific journal)  

Background: There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese. Methods: A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer–Lemeshow test in the validation cohort. Results: During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend &lt
 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer–Lemeshow test P = 0.43) in the validation cohort. Conclusions: We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual’s risk of future gastric cancer.

DOI： 10.1007/s10120-017-0768-8

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Objective The aim of this study was to investigate the association between anthropometric measurements of sarcopenic obesity and all-cause mortality. Methods The study included 2309 Japanese-American men ages 71 to 93 y. Mortality data were available for up to 24 y of follow-up. Sarcopenic obesity defined by three patterns of obesity indexes (body mass index [BMI], percent body fat [%BF] and waist circumference [WC]) and skeletal muscle index estimated by anthropometric measurements. Results Of the 2309 participants, 2210 deaths were reported during the mean follow-up period of 11.7 y. Risk for death was significantly increased with sarcopenia after adjusting for baseline age, lifestyle variables, hypertension, diabetes, and cognitive scores (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.15–1.38). Risk for death was significantly decreased with obesity using WC and %BF to define obesity, but not BMI. Risk for death also was significantly increased in the sarcopenia group compared with the optimal group, regardless of which pattern of obesity indexes (BMI, %BF, and WC) was used. Risk for death was significantly increased in sarcopenic obesity defined by WC (HR, 1.19; 95% CI, 1.02–1.38), borderline in the BMI-defined group, and not significant in the %BF-defined group. Conclusion All-cause mortality was increased in men with sarcopenic obesity defined by WC, but not BMI and %BF. Sarcopenia was a stronger predictor of all-cause mortality in this cohort >70 y of age. These results suggest that anthropometric definitions for sarcopenia and sarcopenic obesity are clinically useful as a predictor of all-cause mortality.

DOI： 10.1016/j.nut.2017.09.003

Language：English   Publishing type：Research paper (scientific journal)  

Objective The aim of this study was to investigate the association between anthropometric measurements of sarcopenic obesity and all-cause mortality. Methods The study included 2309 Japanese-American men ages 71 to 93 y. Mortality data were available for up to 24 y of follow-up. Sarcopenic obesity defined by three patterns of obesity indexes (body mass index [BMI], percent body fat [&#37;BF] and waist circumference [WC]) and skeletal muscle index estimated by anthropometric measurements. Results Of the 2309 participants, 2210 deaths were reported during the mean follow-up period of 11.7 y. Risk for death was significantly increased with sarcopenia after adjusting for baseline age, lifestyle variables, hypertension, diabetes, and cognitive scores (hazard ratio [HR], 1.26
95&#37; confidence interval [CI], 1.15–1.38). Risk for death was significantly decreased with obesity using WC and &#37;BF to define obesity, but not BMI. Risk for death also was significantly increased in the sarcopenia group compared with the optimal group, regardless of which pattern of obesity indexes (BMI, &#37;BF, and WC) was used. Risk for death was significantly increased in sarcopenic obesity defined by WC (HR, 1.19
95&#37; CI, 1.02–1.38), borderline in the BMI-defined group, and not significant in the &#37;BF-defined group. Conclusion All-cause mortality was increased in men with sarcopenic obesity defined by WC, but not BMI and &#37;BF. Sarcopenia was a stronger predictor of all-cause mortality in this cohort &gt
70 y of age. These results suggest that anthropometric definitions for sarcopenia and sarcopenic obesity are clinically useful as a predictor of all-cause mortality.

DOI： 10.1016/j.nut.2017.09.003

Language：English   Publishing type：Research paper (scientific journal)  

Background--Epidemiologic evidence has emerged to reveal an association of albuminuria and low estimated glomerular filtration rate (eGFR) with dementia, but the findings are inconsistent. In addition, there are limited studies addressing the association between albuminuria and Alzheimer disease (AD). Methods and Results--A total of 1562 community-dwelling Japanese subjects aged ≥60 years without dementia were followed up for 10 years. The outcomes were incidence of all-cause dementia and its subtypes, namely, AD and vascular dementia (VaD). The hazard ratios for the outcomes were estimated according to urine albumin-creatinine ratio (UACR) and eGFR levels using a Cox proportional hazards model. During the follow-up, 358 subjects developed all-cause dementia (238 AD and 93 VaD). Higher UACR level was significantly associated with greater multivariable-adjusted risks of all-cause dementia (hazard ratios [95% confidence intervals]: 1.00 [reference], 1.12 [0.78-1.60], 1.65 [1.18-2.30], and 1.56 [1.11-2.19] for UACR of ≤6.9, 7.0-12.7, 12.8-29.9, and ≥30.0 mg/g, respectively), AD (1.00 [reference], 1.20 [0.77-1.86], 1.75 [1.16-2.64], and 1.58 [1.03-2.41], respectively), and VaD (1.00 [reference], 1.03 [0.46-2.29], 1.94 [0.96-3.95], and 2.19 [1.09-4.38], respectively). On the other hand, lower eGFR level was marginally associated with greater risk of VaD, but not AD. Subjects with UACR ≥12.8 mg/g and eGFR of < 60 mL/min per 1.73 m² had 3.3-fold greater risk of VaD than those with UACR < 12.8 mg/g and eGFR of ≥60 mL/min per 1.73 m². Conclusions--Albuminuria is a significant risk factor for the development of both AD and VaD in community-dwelling Japanese elderly. Moreover, albuminuria and low eGFR are mutually associated with a greater risk of VaD.

DOI： 10.1161/JAHA.117.006693

Language：English   Publishing type：Research paper (scientific journal)  

Background--Epidemiologic evidence has emerged to reveal an association of albuminuria and low estimated glomerular filtration rate (eGFR) with dementia, but the findings are inconsistent. In addition, there are limited studies addressing the association between albuminuria and Alzheimer disease (AD). Methods and Results--A total of 1562 community-dwelling Japanese subjects aged ≥60 years without dementia were followed up for 10 years. The outcomes were incidence of all-cause dementia and its subtypes, namely, AD and vascular dementia (VaD). The hazard ratios for the outcomes were estimated according to urine albumin-creatinine ratio (UACR) and eGFR levels using a Cox proportional hazards model. During the follow-up, 358 subjects developed all-cause dementia (238 AD and 93 VaD). Higher UACR level was significantly associated with greater multivariable-adjusted risks of all-cause dementia (hazard ratios [95&#37; confidence intervals]: 1.00 [reference], 1.12 [0.78-1.60], 1.65 [1.18-2.30], and 1.56 [1.11-2.19] for UACR of ≤6.9, 7.0-12.7, 12.8-29.9, and ≥30.0 mg/g, respectively), AD (1.00 [reference], 1.20 [0.77-1.86], 1.75 [1.16-2.64], and 1.58 [1.03-2.41], respectively), and VaD (1.00 [reference], 1.03 [0.46-2.29], 1.94 [0.96-3.95], and 2.19 [1.09-4.38], respectively). On the other hand, lower eGFR level was marginally associated with greater risk of VaD, but not AD. Subjects with UACR ≥12.8 mg/g and eGFR of &lt
60 mL/min per 1.73 m2 had 3.3-fold greater risk of VaD than those with UACR &lt
12.8 mg/g and eGFR of ≥60 mL/min per 1.73 m2. Conclusions--Albuminuria is a significant risk factor for the development of both AD and VaD in community-dwelling Japanese elderly. Moreover, albuminuria and low eGFR are mutually associated with a greater risk of VaD.

DOI： 10.1161/JAHA.117.006693

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App ^{NL-G-F/NL-G-F} and 3xTg-AD-H mouse models. Genes commonly altered in App ^{NL-G-F/NL-G-F} and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App ^{NL-G-F/NL-G-F} cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App ^{NL-G-F/NL-G-F} cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

DOI： 10.1038/s41598-017-17999-3

Language：English   Publishing type：Research paper (scientific journal)  

The ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cancer death in a Japanese community: The Hisayama Study
Background: Whether the intake of eicosapentaenoic acid (EPA) or arachidonic acid (AA) affects the risk of cancer remains unclear, and the association between the serum EPA:AA ratio and cancer risk has not been fully evaluated in general populations.
Methods: A total of 3098 community-dwelling subjects aged >= 40 years were followed up for 9.6 years (2002-2012). The levels of the serum EPA:AA ratio were categorized into quartiles (<0.29, 0.29-0.41, 0.42-0.60, and >0.60). The risk estimates were computed using a Cox proportional hazards model. The same analyses were conducted for the serum docosahexaenoic acid to arachidonic acid (DHA:AA) ratio and individual fatty acid concentrations.
Results: During the follow-up period, 121 subjects died of cancer. Age-and sex-adjusted cancer mortality increased with lower serum EPA:AA ratio levels (P trend<0.05). In the multivariable-adjusted analysis, the subjects in the first quartile of the serum EPA:AA ratio had a 1.93-fold (95&#37; confidence interval, 1.15-3.22) greater risk of cancer death than those in the fourth quartile. Lower serum EPA concentrations were marginally associated with higher cancer mortality (P trend<0.11), but the serum DHA or AA concentrations and the serum DHA:AA ratio were not (all P trend>0.37). With regard to site-specific cancers, lower serum EPA:AA ratio was associated with a higher risk of death from liver cancer. However, no such associations were detected for deaths from other cancers.
Conclusions: These findings suggest that decreased level of the serum EPA: AA ratio is a significant risk factor for cancer death in the general Japanese population. (C) 2017 Publishing services by Elsevier B.V.

DOI： 10.1016/j.je.2017.01.004

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (A beta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the A beta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App(NL-GF/NL-G-F) and 3xTg-AD-H mouse models. Genes commonly altered in App(NL-GF/NL-G-F) and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App(NL-GF/NL-G-F) cortex as A beta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App(NL-G-F/NL-G-F) cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2 , Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical A beta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

DOI： 10.1038/s41598-017-17999-3

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1212/WNL.0000000000004590

Language：English  

DOI： 10.1212/WNL.0000000000004590

Language：English   Publishing type：Research paper (scientific journal)  

Background: Few studies have investigated the association between serum vitamin D levels and mortality in general Asian populations.
Methods and Results: We examined the association of serum 1,25-dihydroxyvitamin D (1,25(OH) 2D) levels with the risk of all-cause and cause-specific death in an average 9.5-year follow-up study of 3,292 community-dwelling Japanese subjects aged >= 40 years (2002-2012). The multivariable-adjusted hazard ratio (HR) for all-cause death increased significantly with lower serum 1,25(OH)(2)D levels (HR 1.54 [95&#37; confidence interval, 1.18-2.01] for the lowest quartile, 1.31 [0.99-1.73] for the 2nd quartile, 0.94 [0.70-1.25] for the 3rd quartile, 1.00 [Ref.] for highest quartile; P for trend < 0.001). A similar association was observed for cardiovascular and respiratory infection death (both P for trend < 0.01), but not for cancer death or death from other causes. In the stratified analysis, the association between lower serum 1,25(OH)(2)D levels and the risk of respiratory infection death was stronger in subjects with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) than in those with eGFR = 60 mL/min/1.73 m(2); there was a significant heterogeneity in the association between eGFR levels (P for heterogeneity= 0.04).
Conclusions: The findings suggested that a lower serum 1,25(OH)(2)D level is a potential risk factor for all-cause death, especially cardiovascular and respiratory infection death, in the general Japanese population, and that lower serum 1,25(OH) 2D levels greatly increase the risk of respiratory infection death in subjects with kidney dysfunction.

DOI： 10.1253/circj.CJ-16-0954

Language：English   Publishing type：Research paper (scientific journal)  

Context and Objective: We investigated the associations of hemoglobin A_1c (HbA_1c), glycated albumin (GA), GA/HbA_1c ratio, and 1,5-anhydroglucitol (1,5-AG) with the development of Alzheimer's disease (AD). Design and Participants: A total of 1187 community-dwelling Japanese subjects aged ≥65 years without dementia were followed up for an average of 4.8 years. Results: The age- and sex-adjusted incidence of AD increased significantly with higher quartiles of GA/HbA_1c ratio, and a similar tendency was seen for GA, whereas no such association was observed for HbA_1c and 1,5-AG. After adjusting for potential confounding factors, positive association of GA/HbA_1c ratio with the risk of AD remained significant: the multivariable-adjusted hazard ratio (HR) was significantly higher in the third [HR = 2.11, 95% confidence interval (CI) = 1.16 to 3.82] and fourth (HR = 2.01, 95% CI = 1.09 to 3.68) quartile than in the first quartile. Among subjects with normal glucose tolerance, those with high GA/HbA_1c ratio had a higher risk of AD than those with low GA/HbA_1c ratio (HR = 1.82, 95% CI = 1.05 to 3.16), and a similar tendency was found in those with glucose intolerance (HR = 1.73, 95% CI = 0.96 to 3.13). No such associations were observed for HbA_1c, GA, and 1,5-AG, regardless of glucose tolerance status. Conclusions: Our findings suggest that elevated GA/HbA_1c ratio-but not HbA_1c, GA, or 1,5-AG level-is significantly associated with the risk of AD in subjects both with and without glucose intolerance. GA/HbA_1c ratio may be a useful biomarker for predicting incident AD.

DOI： 10.1210/jc.2017-00439

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several observational studies have reported that higher visit-to-visit blood pressure variability is a risk factor for cognitive impairment and dementia. However, no studies have investigated the association of day-to-day blood pressure variability assessed by home blood pressure measurement with the development of dementia.
METHODS: A total of 1674 community-dwelling Japanese elderly without dementia, >= 60 years of age, were followed up for 5 years (2007-2012). Home blood pressure was measured 3 times every morning for a median of 28 days. Day-to-day systolic (SBP) and diastolic blood pressure variabilities, calculated as coefficients of variation (CoV) of home SBP and diastolic blood pressure, were categorized into quartiles. The hazard ratios and their 95&#37; confidence intervals of the CoV levels of home blood pressure on the development of all-cause dementia, vascular dementia (VaD), and Alzheimer disease (AD) were computed with a Cox proportional hazards model.
RESULTS: During the follow-up, 194 subjects developed all-cause dementia; of these, 47 had VaD and 134 had AD. The age-and sexadjusted incidences of all-cause dementia, VaD, and AD increased significantly with increasing CoV levels of home SBP (all P for trend <0.05). These associations remained unchanged after adjustment for potential confounding factors, including home SBP. Compared with subjects in the first quartile of CoV levels of home SBP, the risks of the development of all-cause dementia, VaD, and AD were significantly higher in those in the fourth quartile (hazard ratio=2.27, 95&#37; confidence interval=1.45-3.55, P<0.001 for all-cause dementia; hazard ratio=2.79, 95&#37; confidence interval=1.04-7.51, P=0.03 for VaD; hazard ratio=2.22, 95&#37; confidence interval=1.31-3.75, P<0.001 for AD). Similar associations were observed for CoV levels of home diastolic blood pressure. Meanwhile, home SBP levels were significantly associated with the risk of VaD but not with the risks of all-cause dementia and AD. There was no interaction between home SBP levels and CoV levels of home SBP on the risk of each subtype of dementia.
CONCLUSIONS: Our findings suggest that increased day-to-day blood pressure variability is, independently of average home blood pressure, a significant risk factor for the development of all-cause dementia, VaD, and AD in the general elderly Japanese population.

DOI： 10.1161/CIRCULATIONAHA.116.025667

Language：English   Publishing type：Research paper (scientific journal)  

Context and Objective: We investigated the associations of hemoglobin A1c (HbA(1c)), glycated albumin (GA), GA/HbA(1c) ratio, and 1,5-anhydroglucitol (1,5-AG) with the development of Alzheimer's disease (AD).
Design and Participants: A total of 1187 community-dwelling Japanese subjects aged >= 65 years without dementia were followed up for an average of 4.8 years.
Results: The age-and sex-adjusted incidence of AD increased significantly with higher quartiles of GA/HbA(1c) ratio, and a similar tendency was seen for GA, whereas no such association was observed for HbA(1c) and 1,5-AG. After adjusting for potential confounding factors, positive association of GA/HbA(1c) ratio with the risk of AD remained significant: the multivariable-adjusted hazard ratio (HR) was significantly higher in the third [HR = 2.11, 95&#37; confidence interval (CI) = 1.16 to 3.82] and fourth (HR = 2.01, 95&#37; CI = 1.09 to 3.68) quartile than in the first quartile. Among subjects with normal glucose tolerance, those with high GA/HbA(1c) ratio had a higher risk of AD than those with low GA/HbA(1c) ratio (HR = 1.82, 95&#37; CI = 1.05 to 3.16), and a similar tendency was found in those with glucose intolerance (HR = 1.73, 95&#37; CI = 0.96 to 3.13). No such associations were observed for HbA(1c), GA, and 1,5-AG, regardless of glucose tolerance status.
Conclusions: Our findings suggest that elevated GA/HbA1c ratio-but not HbA(1c), GA, or 1,5-AG level-is significantly associated with the risk of AD in subjects both with and without glucose intolerance. GA/HbA(1c) ratio may be a useful biomarker for predicting incident AD.

DOI： 10.1210/jc.2017-00439

Language：English   Publishing type：Research paper (scientific journal)  

Background and Purpose-The influence of dietary protein intake on stroke risk is an area of interest. We investigated the association between dietary protein intake and stroke risk in Japanese, considering sources of protein. Methods-A total of 2400 subjects aged 40 to 79 years were followed up for 19 years. Dietary protein intake was estimated using a 70-item semiquantitative food frequency questionnaire. The risk estimates for incident stroke and its subtypes were calculated using a Cox proportional hazards model. Results-During the follow-up, 254 participants experienced stroke events; of these, 172 had ischemic stroke, and 58 had intracerebral hemorrhage. Higher total protein intake was significantly associated with lower risks of stroke and intracerebral hemorrhage (both P for trend <0.05). With regard to sources of protein, the risks of total stroke and ischemic stroke significantly decreased by 40% (95% confidence interval, 12%-59%) and 40% (5%-62%), respectively, in subjects with the highest quartile of vegetable protein intake compared with those with the lowest one. In contrast, subjects with the highest quartile of animal protein intake had a 53% (4%-77%) lower risk of intracerebral hemorrhage. Vegetable protein intake was positively correlated with intakes of soybean products, vegetable, and algae, whereas animal protein intake was positively correlated with intakes of fish, meat, eggs, and milk/dairy products. Both types of protein intakes were negatively correlated with intakes of rice and alcohol. Conclusions-Our findings suggest that higher dietary protein intake is associated with a reduced risk of stroke in the general Japanese population.

DOI： 10.1161/STROKEAHA.116.016059

Language：English  

DOI： 10.1038/nrneurol.2017.63

Language：English   Publishing type：Research paper (scientific journal)  

Background and Purpose-The influence of dietary protein intake on stroke risk is an area of interest. We investigated the association between dietary protein intake and stroke risk in Japanese, considering sources of protein.
Methods-A total of 2400 subjects aged 40 to 79 years were followed up for 19 years. Dietary protein intake was estimated using a 70-item semiquantitative food frequency questionnaire. The risk estimates for incident stroke and its subtypes were calculated using a Cox proportional hazards model.
Results-During the follow-up, 254 participants experienced stroke events; of these, 172 had ischemic stroke, and 58 had intracerebral hemorrhage. Higher total protein intake was significantly associated with lower risks of stroke and intracerebral hemorrhage (both P for trend <0.05). With regard to sources of protein, the risks of total stroke and ischemic stroke significantly decreased by 40&#37; (95&#37; confidence interval, 12&#37;-59&#37;) and 40&#37; (5&#37;-62&#37;), respectively, in subjects with the highest quartile of vegetable protein intake compared with those with the lowest one. In contrast, subjects with the highest quartile of animal protein intake had a 53&#37; (4&#37;-77&#37;) lower risk of intracerebral hemorrhage. Vegetable protein intake was positively correlated with intakes of soybean products, vegetable, and algae, whereas animal protein intake was positively correlated with intakes of fish, meat, eggs, and milk/dairy products. Both types of protein intakes were negatively correlated with intakes of rice and alcohol.
Conclusions-Our findings suggest that higher dietary protein intake is associated with a reduced risk of stroke in the general Japanese population.

DOI： 10.1161/STROKEAHA.116.016059

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: To clarify the effect of tooth loss on development of all-cause dementia and its subtypes in an elderly Japanese population. Design: Prospective cohort study. Setting: The Hisayama Study, Japan. Participants: Community-dwelling Japanese adults without dementia aged 60 and older (N = 1,566) were followed for 5 years (2007–2012). Measurements: Participants were classified into four categories according to baseline number of remaining teeth (≥20, 10–19, 1–9, 0). The risk estimates of the effect of tooth loss on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were computed using a Cox proportional hazards model. Results: During follow-up, 180 (11.5%) subjects developed all-cause dementia; 127 (8.1%) had AD, and 42 (2.7%) had VaD. After adjusting for potential confounders, there was a tendency for the multivariable-adjusted hazard ratio of all-cause dementia to increase with decrease in number of remaining teeth (P for trend =.04). The risk of all-cause dementia was 1.62 times as great in subjects with 10 to 19 teeth, 1.81 times as great in those with one to nine teeth, and 1.63 times as great in those with no teeth as in those with 20 teeth or more. An inverse association was observed between number of remaining teeth and risk of AD (P for trend =.08), but no such association was observed with risk of VaD (P for trend =.20). Conclusion: Tooth loss is associated with an increased risk of all-cause dementia and AD in the Japanese population.

DOI： 10.1111/jgs.14791

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To investigate secular trends in the prevalence, incidence, and survival rate of dementia in a Japanese elderly population in a comprehensive manner.
Methods: Five cross-sectional surveys of dementia were conducted among residents of a Japanese community, aged >= 65 years, in 1985, 1992, 1998, 2005, and 2012. We also established 2 cohorts consisting of the residents of this age group without dementia in 1988 (n = 803) and 2002 (n = 1,231), and each was followed for 10 years.
Results: The age-standardized prevalence of all-cause dementia and Alzheimer disease (AD) increased with time (for all-cause dementia: 6.8&#37; in 1985, 4.6&#37; in 1992, 5.3&#37; in 1998, 8.4&#37; in 2005, and 11.3&#37; in 2012, p for trend <0.01; for AD: 1.5&#37;, 1.4&#37;, 2.4&#37;, 3.9&#37;, and 7.2&#37;, respectively, p for trend,0.01), while no secular change was observed for vascular dementia (VaD) (2.4&#37;, 1.6&#37;, 1.5&#37;, 2.4&#37;, and 2.4&#37;, respectively, p for trend = 0.59). The age- and sex-adjusted incidence of all-cause dementia and AD, but not VaD, increased from the 1988 cohort to the 2002 cohort (for all-cause dementia: adjusted hazard ratio [aHR] 1.68, 95&#37; confidence interval [CI] 1.38-2.06; for AD: aHR 2.07, 95&#37; CI 1.59-2.70; for VaD: aHR 1.18, 95&#37; CI 0.83-1.69). The 5-year survival rate of all-cause dementia and AD improved from the 1988 cohort to the 2002 cohort (for all-cause dementia: 47.3&#37; to 65.2&#37;; for AD: 50.7&#37; to 75.1&#37;; all p, 0.01).
Conclusions: The increased incidence and improved survival rate of AD could have resulted in the steep increase in AD prevalence in the Japanese elderly.

DOI： 10.1212/WNL.0000000000003932

Language：English   Publishing type：Research paper (scientific journal)  

ObjectivesTo clarify the effect of tooth loss on development of all-cause dementia and its subtypes in an elderly Japanese population.
DesignProspective cohort study.
SettingThe Hisayama Study, Japan.
ParticipantsCommunity-dwelling Japanese adults without dementia aged 60 and older (N=1,566) were followed for 5years (2007-2012).
MeasurementsParticipants were classified into four categories according to baseline number of remaining teeth (20, 10-19, 1-9, 0). The risk estimates of the effect of tooth loss on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were computed using a Cox proportional hazards model.
ResultsDuring follow-up, 180 (11.5&#37;) subjects developed all-cause dementia; 127 (8.1&#37;) had AD, and 42 (2.7&#37;) had VaD. After adjusting for potential confounders, there was a tendency for the multivariable-adjusted hazard ratio of all-cause dementia to increase with decrease in number of remaining teeth (P for trend=.04). The risk of all-cause dementia was 1.62 times as great in subjects with 10 to 19 teeth, 1.81 times as great in those with one to nine teeth, and 1.63 times as great in those with no teeth as in those with 20 teeth or more. An inverse association was observed between number of remaining teeth and risk of AD (P for trend=.08), but no such association was observed with risk of VaD (P for trend=.20).
ConclusionTooth loss is associated with an increased risk of all-cause dementia and AD in the Japanese population.

DOI： 10.1111/jgs.14791

Language：English   Publishing type：Research paper (scientific journal)  

Background: Few studies have investigated the association between serum vitamin D levels and mortality in general Asian populations. Methods and Results: We examined the association of serum 1,25-dihydroxyvitamin D (1,25(OH)₂D) levels with the risk of all-cause and cause-specific death in an average 9.5-year follow-up study of 3,292 community-dwelling Japanese subjects aged ≥40 years (2002-2012). The multivariable-adjusted hazard ratio (HR) for all-cause death increased significantly with lower serum 1,25(OH)₂D levels (HR 1.54 [95% confidence interval, 1.18-2.01] for the lowest quartile, 1.31 [0.99-1.73] for the 2nd quartile, 0.94 [0.70-1.25] for the 3rd quartile, 1.00 [Ref.] for highest quartile; P for trend <0.001). A similar association was observed for cardiovascular and respiratory infection death (both P for trend <0.01), but not for cancer death or death from other causes. In the stratified analysis, the association between lower serum 1,25(OH)₂D levels and the risk of respiratory infection death was stronger in subjects with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² than in those with eGFR ≥60 mL/min/1.73 m²; there was a significant heterogeneity in the association between eGFR levels (P for heterogeneity=0.04). Conclusions: The findings suggested that a lower serum 1,25(OH)₂D level is a potential risk factor for all-cause death, especially cardiovascular and respiratory infection death, in the general Japanese population, and that lower serum 1,25(OH)²D levels greatly increase the risk of respiratory infection death in subjects with kidney dysfunction.

DOI： 10.1253/circj.CJ-16-0954

Language：English   Publishing type：Research paper (scientific journal)  

Background: Whether the intake of eicosapentaenoic acid (EPA) or arachidonic acid (AA) affects the risk of cancer remains unclear, and the association between the serum EPA:AA ratio and cancer risk has not been fully evaluated in general populations. Methods: A total of 3098 community-dwelling subjects aged ≥40 years were followed up for 9.6 years (2002-2012). The levels of the serum EPA:AA ratio were categorized into quartiles (< 0.29, 0.29-0.41, 0.42-0.60, and > 0.60). The risk estimates were computed using a Cox proportional hazards model. The same analyses were conducted for the serum docosahexaenoic acid to arachidonic acid (DHA:AA) ratio and individual fatty acid concentrations. Results: During the follow-up period, 121 subjects died of cancer. Age- and sex-adjusted cancer mortality increased with lower serum EPA:AA ratio levels (P trend < 0.05). In the multivariable-adjusted analysis, the subjects in the first quartile of the serum EPA:AA ratio had a 1.93-fold (95% confidence interval, 1.15-3.22) greater risk of cancer death than those in the fourth quartile. Lower serum EPA concentrations were marginally associated with higher cancer mortality (P trend < 0.11), but the serum DHA or AA concentrations and the serum DHA:AA ratio were not (all P trend > 0.37). With regard to site-specific cancers, lower serum EPA:AA ratio was associated with a higher risk of death from liver cancer. However, no such associations were detected for deaths from other cancers. Conclusions: These findings suggest that decreased level of the serum EPA:AA ratio is a significant risk factor for cancer death in the general Japanese population.

DOI： 10.1016/j.je.2017.01.004

Language：English   Publishing type：Research paper (scientific journal)  

Background: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years. Objectives: We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology. Methods: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. Results: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012). Conclusion: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology.

DOI： 10.3233/JAD-160521

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.18632/oncotarget.22993

Language：English   Publishing type：Research paper (scientific journal)  

Background: There is little information regarding whether the combination of Helicobacter pylori (H. pylori) antibody and serum pepsinogen (sPG), which is a marker of the degree of atrophic gastritis, has a discriminatory ability for detecting incident gastric cancer. We examined this issue in a long-term prospective cohort study of a Japanese population.
Methods: A total of 2446 Japanese community-dwelling individuals aged >= 40 years were stratified into four groups according to baseline H. pylori serological status and sPG: Group A (H. pylori[-], sPG[-]), Group B (H. pylori[+], sPG[-]), Group C (H. pylori[+], sPG[+]), and Group D (H. pylori[-], sPG[+]), and participants were followed up prospectively for 20 years.
Results: During the follow-up, 123 subjects developed gastric cancer. Compared with that in Group A, the cumulative incidence of gastric cancer was significantly increased in Groups B, C, and D, whereas no significant difference was found between Groups C and D. The multivariable-adjusted risk of gastric cancer was significantly increased in Group B (hazard ratio [HR], 4.08; 95&#37; confidence interval [CI], 1.62-10.28) and in Groups C and D combined (HR 11.1; 95&#37; CI, 4.45-27.46). When the multivariable model with H. pylori antibody was changed into that with the combination of H. pylori antibody and sPG, the C statistics for developing gastric cancer increased significantly (0.773 vs 0.732, P = 0.005), and the continuous net reclassification improvement value was 0.591 (P < 0.001).
Conclusions: Our findings suggest that the combination of H. pylori antibody and sPG is a useful tool for predicting the development of gastric cancer.

DOI： 10.2188/jea.JE20150258

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE To investigate the association between diabetes and brain or hippocampal atrophy in an elderly population. RESEARCH DESIGN AND METHODS A total of 1,238 community-dwelling Japanese subjects aged ≥65 years underwent brain MRI scans and a comprehensive health examination in 2012. Total brain volume (TBV), intracranial volume (ICV), and hippocampal volume (HV) were measured using MRI scans for each subject. We examined the associations between diabetes-related parameters and the ratios of TBV to ICV (an indicator of global brain atrophy), HV to ICV (an indicator of hippocampal atrophy), and HV to TBV (an indicator of hippocampal atrophy beyond global brain atrophy) after adjustment for other potential confounders. RESULTS Themultivariable-adjustedmean values of the TBV-to-ICV,HV-to-ICV, and HV-to-TBV ratios were significantly lower in the subjects with diabetes compared with those without diabetes (77.6%vs. 78.2%for the TBV-to-ICV ratio, 0.513%vs. 0.529%for the HV-to-ICV ratio, and 0.660% vs. 0.676% for the HV-to-TBV ratio; all P < 0.01). These three ratios decreased significantlywith elevated 2-h postload glucose (PG) levels (all P for trend <0.05) but not fasting plasma glucose levels. Longer duration of diabetes was significantly associated with lower TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios. The subjectswith diabetes diagnosed in midlife had significantly lower HV-to-ICV and HV-to-TBV ratios than those without and those diagnosed in late life. CONCLUSIONS Our data suggest that a longer duration of diabetes and elevated 2-h PG levels, a marker of postprandial hyperglycemia, are risk factors for brain atrophy, particularly hippocampal atrophy.

DOI： 10.2337/dc15-2800

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE
To investigate the association between diabetes and brain or hippocampal atrophy in an elderly population.
RESEARCH DESIGN AND METHODS
A total of 1,238 community-dwelling Japanese subjects aged >= 65 years underwent brain MRI scans and a comprehensive health examination in 2012. Total brain volume (TBV), intracranial volume (ICV), and hippocampal volume (HV) were measured using MRI scans for each subject. We examined the associations between diabetes-related parameters and the ratios of TBV to ICV (an indicator of global brain atrophy), HV to ICV (an indicator of hippocampal atrophy), and HV to TBV (an indicator of hippocampal atrophy beyond global brain atrophy) after adjustment for other potential confounders.
RESULTS
The multivariable-adjusted mean values of the TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios were significantly lower in the subjects with diabetes compared with those without diabetes (77.6&#37; vs. 78.2&#37; for the TBV-to-ICV ratio, 0.513&#37; vs. 0.529&#37; for the HV-to-ICV ratio, and 0.660&#37; vs. 0.676&#37; for the HV-to-TBV ratio; all P < 0.01). These three ratios decreased significantly with elevated 2-h postload glucose (PG) levels (all P for trend < 0.05) but not fasting plasma glucose levels. Longer duration of diabetes was significantly associated with lower TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios. The subjects with diabetes diagnosed in midlife had significantly lower HV-to-ICV and HV-to-TBV ratios than those without and those diagnosed in late life.
CONCLUSIONS
Our data suggest that a longer duration of diabetes and elevated 2-h PG levels, a marker of postprandial hyperglycemia, are risk factors for brain atrophy, particularly hippocampal atrophy.

DOI： 10.2337/dc15-2800

Language：English   Publishing type：Research paper (scientific journal)  

Objective - Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population. Approach and Results - A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80-2.04]; Q3, 1.48 [0.95-2.32]; and Q4, 1.85 [1.20-2.85]; P=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76-1.94]; Q3, 1.38 [0.87-2.17]; and Q4, 1.66 [1.05-2.60]; P=0.02 for trend). Conclusions - Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.

DOI： 10.1161/ATVBAHA.116.307291

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/neup.12298

Language：English   Publishing type：Research paper (scientific journal)  

Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study
We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4&#37; in group I, 22.4&#37; in group II, 32.1&#37; in group III, 30.1&#37; in group IV, 51.2&#37; in group V; P for trend < 0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2&#37;, 11.9&#37;, 17.3&#37;, 20.6&#37; and 33.1&#37;, respectively; P for trend < 0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases.

DOI： 10.1111/neup.12298

Language：English   Publishing type：Research paper (scientific journal)  

Objective Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population.
Approach and Results A total of 3005 community-dwelling Japanese aged 40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95&#37; confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95&#37; confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80-2.04]; Q3, 1.48 [0.95-2.32]; and Q4, 1.85 [1.20-2.85]; P=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95&#37; confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76-1.94]; Q3, 1.38 [0.87-2.17]; and Q4, 1.66 [1.05-2.60]; P=0.02 for trend).
Conclusions Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.

DOI： 10.1161/ATVBAHA.116.307291

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986–1991, 257 cases), II (1992–1997, 268 cases), III (1998–2004, 318 cases), IV (2005–2011, 296 cases) and V (2012–2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend <0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend <0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases.

DOI： 10.1111/neup.12298

Language：Japanese   Publishing type：Research paper (scientific journal)  

The association between diabetes and the risk of developing dementia has received much attention in epidemiological studies. An accurate population-based prospective cohort study has been conducted in the elderly population of the town of Hisayama in Japan since 1985 aiming to elucidate the secular trends in the prevalence of dementia and examine risk and protective factors for dementia in the Japanese population. The prevalence of all-cause dementia significantly increased from 1985 to 2012. In regard to subtypes of dementia, a similar trend was observed for Alzheimer's disease (AD). In a prospective study of risk factors for dementia in Hisayama elder residents without dementia, diabetes was identified as a significant risk factor for developing all-cause dementia, especially AD. Moreover, 2-hour post-load glucose levels were closely associated with increased risk of all-cause dementia, AD, and vascular dementia. In a pathological study of Hisayama residents, higher levels of 2-hour post-load glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with increased risk of neuritic plaques. The steep increase in the frequency of diabetes could lead to the increasing trend in the prevalence of dementia, especially AD, in the Japanese elderly.

DOI： 10.11477/mf.1416200500

Language：English  

DOI： 10.2337/dc15-2800

Language：Japanese  

Risk and protective factors for dementia

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the long-term influence of physical activity on the risk of dementia in an elderly Japanese population. A total of 803 community-dwelling elderly Japanese individuals without dementia aged ≥65 years were followed prospectively for 17 years. Physically active status was defined as engaging in exercise at least one or more times per week during leisure time, and participants were divided into an active group and an inactive group by the presence or absence of such physical activity. The risk estimates of physical activity on the development of all-cause dementia and its subtypes were computed using a Cox proportional hazards model. During the follow-up, 291 participants developed all-cause dementia. Of these, 165 had Alzheimer’s disease (AD), 93 had vascular dementia (VaD), and 47 had other dementia. Compared with the inactive group, the active group showed significantly lower crude incidence of AD (21.8 vs. 14.2 per 1000 person-years, p = 0.01), but no significant differences were observed for all-cause dementia (35.6 vs. 30.5, p = 0.17), VaD (11.3 vs. 9.8, p = 049), and other dementia (4.6 vs. 7.1, p = 0.15). After adjusting for potential confounders, the relationship between physical activity and risk of AD remained significant (adjusted hazard ratio 0.59, 95 % confidence interval 0.41–0.84, p = 0.003). Our findings suggest that physical activity reduces the long-term risk of dementia, especially AD, in the general Japanese population.

DOI： 10.1007/s10654-016-0125-y

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the long-term influence of physical activity on the risk of dementia in an elderly Japanese population. A total of 803 community-dwelling elderly Japanese individuals without dementia aged a parts per thousand yen65 years were followed prospectively for 17 years. Physically active status was defined as engaging in exercise at least one or more times per week during leisure time, and participants were divided into an active group and an inactive group by the presence or absence of such physical activity. The risk estimates of physical activity on the development of all-cause dementia and its subtypes were computed using a Cox proportional hazards model. During the follow-up, 291 participants developed all-cause dementia. Of these, 165 had Alzheimer's disease (AD), 93 had vascular dementia (VaD), and 47 had other dementia. Compared with the inactive group, the active group showed significantly lower crude incidence of AD (21.8 vs. 14.2 per 1000 person-years, p = 0.01), but no significant differences were observed for all-cause dementia (35.6 vs. 30.5, p = 0.17), VaD (11.3 vs. 9.8, p = 049), and other dementia (4.6 vs. 7.1, p = 0.15). After adjusting for potential confounders, the relationship between physical activity and risk of AD remained significant (adjusted hazard ratio 0.59, 95 &#37; confidence interval 0.41-0.84, p = 0.003). Our findings suggest that physical activity reduces the long-term risk of dementia, especially AD, in the general Japanese population.

DOI： 10.1007/s10654-016-0125-y

Language：English   Publishing type：Research paper (scientific journal)  

Objective Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a metaanalysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. Research Design and Methods A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. Results Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetesassociated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P <0.001). Conclusions Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

DOI： 10.2337/dc15-1588

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a metaanalysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia.
RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95&#37; CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses.
RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60&#37; increased risk of any dementia in both sexes (women: pooled RR 1.62 [95&#37; CI 1.45-1.80]; men: pooled RR 1.58 [95&#37; CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95&#37; CI 1.86-2.94) in women and 1.73 (95&#37; CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95&#37; CI 1.35-1.73) in women and 1.49 (95&#37; CI 1.31-1.69) in men. Overall, women with diabetes had a 19&#37; greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95&#37; CI 1.08-1.30]; P < 0.001).
CONCLUSIONS Individuals with type 2 diabetes are at similar to 60&#37; greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

DOI： 10.2337/dc15-1588

Language：English   Publishing type：Research paper (scientific journal)  

Background: There is little information regarding whether the combination of Helicobacter pylori (H. pylori) antibody and serum pepsinogen (sPG), which is a marker of the degree of atrophic gastritis, has a discriminatory ability for detecting incident gastric cancer. We examined this issue in a long-term prospective cohort study of a Japanese population. Methods: A total of 2446 Japanese community-dwelling individuals aged ≥40 years were stratified into four groups according to baseline H. pylori serological status and sPG: Group A (H. pylori[-], sPG[-]), Group B (H. pylori[+], sPG[-]), Group C (H. pylori[+], sPG[+]), and Group D (H. pylori[-], sPG[+]), and participants were followed up prospectively for 20 years. Results: During the follow-up, 123 subjects developed gastric cancer. Compared with that in Group A, the cumulative incidence of gastric cancer was significantly increased in Groups B, C, and D, whereas no significant difference was found between Groups C and D. The multivariable-adjusted risk of gastric cancer was significantly increased in Group B (hazard ratio [HR], 4.08; 95% confidence interval [CI], 1.62-10.28) and in Groups C and D combined (HR 11.1; 95% CI, 4.45-27.46). When the multivariable model with H. pylori antibody was changed into that with the combination of H. pylori antibody and sPG, the C statistics for developing gastric cancer increased significantly (0.773 vs 0.732, P = 0.005), and the continuous net reclassification improvement value was 0.591 (P < 0.001). Conclusions: Our findings suggest that the combination of H. pylori antibody and sPG is a useful tool for predicting the development of gastric cancer.

DOI： 10.2188/jea. JE20150258

Language：English   Publishing type：Research paper (scientific journal)  

Background: There is little information regarding whether the combination of Helicobacter pylori (H. pylori) antibody and serum pepsinogen (sPG), which is a marker of the degree of atrophic gastritis, has a discriminatory ability for detecting incident gastric cancer. We examined this issue in a long-term prospective cohort study of a Japanese population. Methods: A total of 2446 Japanese community-dwelling individuals aged ≥40 years were stratified into four groups according to baseline H. pylori serological status and sPG: Group A (H. pylori[-], sPG[-]), Group B (H. pylori[+], sPG[-]), Group C (H. pylori[+], sPG[+]), and Group D (H. pylori[-], sPG[+]), and participants were followed up prospectively for 20 years. Results: During the follow-up, 123 subjects developed gastric cancer. Compared with that in Group A, the cumulative incidence of gastric cancer was significantly increased in Groups B, C, and D, whereas no significant difference was found between Groups C and D. The multivariable-adjusted risk of gastric cancer was significantly increased in Group B (hazard ratio [HR], 4.08; 95% confidence interval [CI], 1.62-10.28) and in Groups C and D combined (HR 11.1; 95% CI, 4.45-27.46). When the multivariable model with H. pylori antibody was changed into that with the combination of H. pylori antibody and sPG, the C statistics for developing gastric cancer increased significantly (0.773 vs 0.732, P = 0.005), and the continuous net reclassification improvement value was 0.591 (P < 0.001). Conclusions: Our findings suggest that the combination of H. pylori antibody and sPG is a useful tool for predicting the development of gastric cancer.

DOI： 10.2188/jea.JE20150258

Language：English   Publishing type：Research paper (scientific journal)  

ObjectivesTo clarify the association between midlife and late-life smoking and risk of dementia.
DesignProspective cohort study.
SettingThe Hisayama Study, Japan.
ParticipantsJapanese community-dwellers without dementia aged 65 to 84 (mean age 72) followed for 17 years (1988-2005) (N = 754), 619 of whom had participated in a health examination conducted in 1973-74 (mean age, 57) and were included in the midlife analysis.
MeasurementsThe risk estimates of smoking status on the development of dementia were computed using a Cox proportional hazards model.
ResultsDuring follow-up, 252 subjects developed all-cause dementia; 143 had Alzheimer's disease (AD), and 76 had vascular dementia (VaD). In late life, the multivariable-adjusted risk of all-cause dementia was significantly greater in current smokers than in never smokers; similar associations were seen for all-cause dementia, AD, and VaD in midlife current smokers. Meanwhile, no significant association was observed between past smoking and risk of any type of dementia in late or midlife. Multivariable analysis showed that smokers in midlife and late life had significantly greater risks than lifelong nonsmokers of all-cause dementia (adjusted hazard ratio (aHR) = 2.28, 95&#37; confidence interval (CI) = 1.49-3.49), AD (aHR = 1.98, 95&#37; CI = 1.09-3.61), and VaD (aHR = 2.88, 95&#37; CI = 1.34-6.20). Such associations were not observed for midlife smokers who quit smoking in late life.
ConclusionPersistent smoking from mid- to late life is a significant risk factor for dementia and its subtypes in the general Japanese population.

DOI： 10.1111/jgs.13794

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. Design: To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-ε4 status to eliminate the established effect of APOE region. Results: Our data indicated that 18p11.32 (rs1992269, P =9.77× 10^-7), CNTNAP2 (rs802571, P= 1.26×10^-6), and 12q24.23 (rs11613092, P =6.85×10^-6) were suggestive loci for susceptibility to LOAD. Conclusion: We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.

DOI： 10.1097/YPG.0000000000000090

Language：English   Publishing type：Research paper (scientific journal)  

ObjectiveAlthough a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations.DesignTo discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-epsilon 4 status to eliminate the established effect of APOE region.ResultsOur data indicated that 18p11.32 (rs1992269, P=9.77x10(-7)), CNTNAP2 (rs802571, P=1.26x10(-6)), and 12q24.23 (rs11613092, P=6.85x10(-6)) were suggestive loci for susceptibility to LOAD.ConclusionWe identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.

DOI： 10.1097/YPG.0000000000000090

Language：English  

DOI： 10.1111/jgs.13163

Language：English   Publishing type：Research paper (scientific journal)  

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

DOI： 10.1093/cercor/bht101

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To determine the effect of milk and dairy intake on the development of all-cause dementia and its subtypes in an elderly Japanese population.
DESIGN: Prospective cohort study.
SETTING: The Hisayama Study, Japan.
PARTICIPANTS: Individuals aged 60 and older without dementia (N = 1,081).
MEASUREMENTS: Milk and dairy intake was estimated using a 70-item semiquantitative food frequency questionnaire grouped into quartiles. The risk estimates of milk and dairy intake on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were computed using a Cox proportional hazards model.
RESULTS: Over 17 years of follow-up, 303 subjects developed all-cause dementia; 166 had AD, and 98 had VaD. The age-and sex-adjusted incidence of all-cause dementia, AD, and VaD significantly decreased as milk and dairy intake level increased (P for trend = .03 for all-cause dementia, .04 for AD, .01 for VaD). After adjusting for potential confounders, the linear relationship between milk and dairy intake and development of AD remained significant (P for trend = .03), whereas the relationships with all-cause dementia and VaD were not significant. The risk of AD was significantly lower in the second, third, and fourth quartiles of milk and dairy intake than in the first quartile.
CONCLUSION: Greater milk and dairy intake reduced the risk of dementia, especially AD, in the general Japanese population.

DOI： 10.1111/jgs.12887

Language：English   Publishing type：Research paper (scientific journal)  

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

DOI： 10.1093/cercor/bht101

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgs.13163

Language：English   Publishing type：Research paper (scientific journal)  

Objectives To determine the effect of milk and dairy intake on the development of all-cause dementia and its subtypes in an elderly Japanese population. Design Prospective cohort study. Setting The Hisayama Study, Japan. Participants Individuals aged 60 and older without dementia (N = 1,081). Measurements Milk and dairy intake was estimated using a 70-item semiquantitative food frequency questionnaire grouped into quartiles. The risk estimates of milk and dairy intake on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were computed using a Cox proportional hazards model. Results Over 17 years of follow-up, 303 subjects developed all-cause dementia; 166 had AD, and 98 had VaD. The age- and sex-adjusted incidence of all-cause dementia, AD, and VaD significantly decreased as milk and dairy intake level increased (P for trend =.03 for all-cause dementia,.04 for AD,.01 for VaD). After adjusting for potential confounders, the linear relationship between milk and dairy intake and development of AD remained significant (P for trend =.03), whereas the relationships with all-cause dementia and VaD were not significant. The risk of AD was significantly lower in the second, third, and fourth quartiles of milk and dairy intake than in the first quartile. Conclusion Greater milk and dairy intake reduced the risk of dementia, especially AD, in the general Japanese population.

DOI： 10.1111/jgs.12887

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.atherosclerosis.2014.03.033

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1176/appi.neuropsych.13020031

Language：English   Publishing type：Research paper (scientific journal)  

Objective: We examined the association between the ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) or the docosahexaenoic acid (DHA)/AA and the development of cardiovascular disease in a general Japanese population. Methods: A total of 3103 community-dwelling Japanese individuals aged ≥40 years were followed up for an average of 5.1 years. Serum EPA/AA ratios were categorized into quartiles. The risk estimates were computed using a Cox proportional hazards model. Results: During the follow-up period, 127 subjects experienced cardiovascular events. Age- and sex-adjusted incidence rates of cardiovascular disease increased with lower serum EPA/AA ratios in individuals with high-sensitivity C-reactive protein (HS-CRP) of ≥1.0mg/L ( p for trend=0.006), whereas no clear association was observed in those with HS-CRP of <1.0mg/L (p for trend=0.27). The multivariable-adjusted risk of cardiovascular disease increased significantly, by 1.52 times (95% confidence interval 1.12-2.04) per 0.20 decrement in serum EPA/AA ratio in subjects with HS-CRP of ≥1.0mg/L. A lower serum EPA/AA ratio was significantly associated with an increased risk of coronary heart disease, but there was no evidence of an association with stroke. The magnitude of the influence of the serum EPA/AA ratio on the cardiovascular risk increased significantly with elevating HS-CRP levels taken as a continuous variable (p for heterogeneity=0.007). However, no such association was observed for DHA/AA ratio. Conclusion: Our findings suggest that a lower serum EPA/AA ratio is associated with a greater risk of cardiovascular disease, especially coronary heart disease, among subjects with higher HS-CRP levels in the general Japanese population.

DOI： 10.1016/j.atherosclerosis.2013.09.023

Language：English   Publishing type：Research paper (scientific journal)  

Objective: We examined the association between the ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) or the docosahexaenoic acid (DHA)/AA and the development of cardiovascular disease in a general Japanese population. Methods: A total of 3103 community-dwelling Japanese individuals aged ≥40 years were followed up for an average of 5.1 years. Serum EPA/AA ratios were categorized into quartiles. The risk estimates were computed using a Cox proportional hazards model. Results: During the follow-up period, 127 subjects experienced cardiovascular events. Age- and sex-adjusted incidence rates of cardiovascular disease increased with lower serum EPA/AA ratios in individuals with high-sensitivity C-reactive protein (HS-CRP) of ≥1.0mg/L ( p for trend=0.006), whereas no clear association was observed in those with HS-CRP of &lt
1.0mg/L (p for trend=0.27). The multivariable-adjusted risk of cardiovascular disease increased significantly, by 1.52 times (95&#37; confidence interval 1.12-2.04) per 0.20 decrement in serum EPA/AA ratio in subjects with HS-CRP of ≥1.0mg/L. A lower serum EPA/AA ratio was significantly associated with an increased risk of coronary heart disease, but there was no evidence of an association with stroke. The magnitude of the influence of the serum EPA/AA ratio on the cardiovascular risk increased significantly with elevating HS-CRP levels taken as a continuous variable (p for heterogeneity=0.007). However, no such association was observed for DHA/AA ratio. Conclusion: Our findings suggest that a lower serum EPA/AA ratio is associated with a greater risk of cardiovascular disease, especially coronary heart disease, among subjects with higher HS-CRP levels in the general Japanese population. © 2013 Elsevier Ireland Ltd.

DOI： 10.1016/j.atherosclerosis.2013.09.023

Language：English   Publishing type：Research paper (other academic)  

We have proposed an automated method for three-dimensional (3D) measurement of cerebral cortical thicknesses based on fuzzy membership maps derived from magnetic resonance (MR) images for evaluation of Alzheimer's disease (AD). The cerebral cortical thickness was three-dimensionally measured on each cortical surface voxel by using a localized gradient vector trajectory in a fuzzy membership map. The proposed method could be useful for the 3D measurement of the cerebral cortical thickness on individual cortical surface voxels as an atrophy feature in AD.

DOI： 10.1109/EMBC.2013.6611198

Language：English   Publishing type：Research paper (scientific journal)  

Background: Uncertainty still surrounds the association between metabolic syndrome (MetS) and depression. We aimed to evaluate the association between MetS and elevated depressive symptoms in a general Japanese population. Methods. This is a cross-sectional survey of 3,113 community-dwelling individuals aged 40 years or over. MetS was defined according to the joint interim statement. MetS was diagnosed when a subject had three or more of the following components: 1) central obesity (waist circumference ≥90 cm for men, ≥80 cm in for women); 2) elevated blood pressure (≥130/85 mmHg or current use of antihypertensive medication); 3) hypertriglyceridemia (≥1.7 mmol/L); 4) low HDL cholesterol (< 1.0 mmol/L for men, < 1.3 mmol/L for women); and 5) elevated fasting plasma glucose (≥5.55 mmol/L or current use of antidiabetic medication). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The age- and multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using a logistic regression model. Results: Elevated depressive symptoms were observed in 4.3% of male and 6.3% of female participants. In men, the age-adjusted prevalence of elevated depressive symptoms was significantly higher in subjects with MetS than in those without (7.1% versus 3.6%, p = 0.04). The prevalence of elevated depressive symptoms rose progressively as the number of MetS components increased (3.5%, 3.6%, 5.8%, and 9.2% in male subjects with 0-1, 2, 3, and ≥4 components, respectively; p = 0.02 for trend). This association remained significant even after adjustment for age, marital status, history of cardiovascular disease, smoking habit, alcohol intake, and regular exercise. In women, on the other hand, there was no clear association between MetS and depressive symptoms. Conclusions: MetS was associated with elevated depressive symptoms in a general population of Japanese men.

DOI： 10.1186/1471-2458-13-862

Language：English   Publishing type：Research paper (scientific journal)  

Background: Uncertainty still surrounds the association between metabolic syndrome (MetS) and depression. We aimed to evaluate the association between MetS and elevated depressive symptoms in a general Japanese population.
Methods: This is a cross-sectional survey of 3,113 community-dwelling individuals aged 40 years or over. MetS was defined according to the joint interim statement. MetS was diagnosed when a subject had three or more of the following components: 1) central obesity (waist circumference >= 90 cm for men, >= 80 cm in for women); 2) elevated blood pressure (>= 130/85 mmHg or current use of antihypertensive medication); 3) hypertriglyceridemia (>= 1.7 mmol/L); 4) low HDL cholesterol (< 1.0 mmol/L for men, < 1.3 mmol/L for women); and 5) elevated fasting plasma glucose (>= 5.55 mmol/L or current use of antidiabetic medication). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The age- and multivariable-adjusted odds ratio (OR) and 95&#37; confidence interval (CI) were estimated using a logistic regression model.
Results: Elevated depressive symptoms were observed in 4.3&#37; of male and 6.3&#37; of female participants. In men, the age- adjusted prevalence of elevated depressive symptoms was significantly higher in subjects with MetS than in those without (7.1&#37; versus 3.6&#37;, p = 0.04). The prevalence of elevated depressive symptoms rose progressively as the number of MetS components increased (3.5&#37;, 3.6&#37;, 5.8&#37;, and 9.2&#37; in male subjects with 0-1, 2, 3, and >= 4 components, respectively; p = 0.02 for trend). This association remained significant even after adjustment for age, marital status, history of cardiovascular disease, smoking habit, alcohol intake, and regular exercise. In women, on the other hand, there was no clear association between MetS and depressive symptoms.
Conclusions: MetS was associated with elevated depressive symptoms in a general population of Japanese men.

DOI： 10.1186/1471-2458-13-862

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1212/CPJ.0b013e3182a1ba12

Language：English   Publishing type：Research paper (scientific journal)  

Background: To our knowledge, there are no previous reports that assessed the association between dietary patterns and risk of dementia in Asian populations.
Objective: We investigated dietary patterns and their potential association with risk of incident dementia in a general Japanese population.
Design: A total of 1006 community-dwelling Japanese subjects without dementia, aged 60-79 y, were followed up for a median of 15 y. The reduced rank regression procedure was used to efficiently determine their dietary patterns. Estimated risk conferred by a particular dietary pattern on the development of dementia was computed by using a Cox proportional hazards model.
Results: Seven dietary patterns were extracted; of these, dietary pattern 1 was correlated with high intakes of soybeans and soybean products, vegetables, algae, and milk and dairy products and a low intake of rice. During the follow-up, 271 subjects developed all-cause dementia. Of these individuals, 144 subjects had Alzheimer disease (AD), and 88 subjects had vascular dementia (VaD). After adjustment for potential confounders, risks of development of all-cause dementia, AD, and VaD were reduced by 0.66 (95&#37; Cl: 0.46, 0.95), 0.65 (95&#37; Cl: 0.40, 1.06), and 0.45 (95&#37; CI: 0.22, 0.91), respectively, in subjects in the highest quartile of score for dietary pattern 1 compared with subjects in the lowest quartile.
Conclusion: Our findings suggest that a higher adherence to a dietary pattern characterized by a high intake of soybeans and soybean products, vegetables, algae, and milk and dairy products and a low intake of rice is associated with reduced risk of dementia in the general Japanese population. Am J Clin Nutr 2013;97:1076-82.

DOI： 10.3945/ajcn.112.045575

Language：English   Publishing type：Research paper (scientific journal)  

Background: To our knowledge, there are no previous reports that assessed the association between dietary patterns and risk of dementia in Asian populations. Objective: We investigated dietary patterns and their potential association with risk of incident dementia in a general Japanese population. Design: A total of 1006 community-dwelling Japanese subjects without dementia, aged 60-79 y, were followed up for a median of 15 y. The reduced rank regression procedure was used to efficiently determine their dietary patterns. Estimated risk conferred by a particular dietary pattern on the development of dementia was computed by using a Cox proportional hazards model. Results: Seven dietary patterns were extracted; of these, dietary pattern 1 was correlated with high intakes of soybeans and soybean products, vegetables, algae, and milk and dairy products and a low intake of rice. During the follow-up, 271 subjects developed allcause dementia. Of these individuals, 144 subjects had Alzheimer disease (AD), and 88 subjects had vascular dementia (VaD). After adjustment for potential confounders, risks of development of allcause dementia, AD, and VaD were reduced by 0.66 (95% CI: 0.46, 0.95), 0.65 (95% CI: 0.40, 1.06), and 0.45 (95% CI: 0.22, 0.91), respectively, in subjects in the highest quartile of score for dietary pattern 1 compared with subjects in the lowest quartile. Conclusion: Our findings suggest that a higher adherence to a dietary pattern characterized by a high intake of soybeans and soybean products, vegetables, algae, and milk and dairy products and a low intake of rice is associated with reduced risk of dementia in the general Japanese population.

DOI： 10.3945/ajcn.112.045575

Language：English   Publishing type：Research paper (scientific journal)  

APOE is an established susceptibility gene for late-onset Alzheimer's disease (LOAD). Recent genome-wide association studies have identified many additional susceptibility genes for LOAD in populations of European descent. However, there is little information on whether or not genetic variants in these genes are associated with other ethnicities. To investigate the association of seven genes identified by genome-wide association studies, we carried out a case-control study using 825 LOAD cases and 2934 controls in the Japanese population. For the APOE gene, APOE-epsilon 4 carriers had a 4.54-fold higher risk than APOE-epsilon 4 noncarriers after adjusting for age and sex (P = 4.6 x 10(-27)). For other genes, the single-nucleotide polymorphism in the PICALM gene was significantly associated with LOAD (P = 0.02, odds ratio = 1.23). There was no significant interaction between PICALM and APOE-epsilon 4 carrier status (P for interaction = 0.68). Our data indicate that PICALM is also a susceptibility gene for LOAD in the Japanese population. Psychiatr Genet 22:290-293 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/YPG.0b013e3283586215

Language：English   Publishing type：Research paper (scientific journal)  

Objectives To investigate whether higher intake of potassium, calcium, and magnesium reduces the risk of incident dementia. Design Prospective cohort study. Setting The Hisayama Study, in Japan. Participants One thousand eighty-one community-dwelling Japanese individuals without dementia aged 60 and older. Measurements A 70-item semiquantitative food frequency questionnaire was used to assess potassium, calcium, and magnesium intakes. Hazard ratios (HRs) for the development of all-cause dementia and its subtypes were estimated using Cox proportional hazards model. Results During a 17-year follow-up, 303 participants experienced all-cause dementia; of these, 98 had vascular dementia (VaD), and 166 had Alzheimer's disease (AD). The multivariable-adjusted HRs for the development of all-cause dementia were 0.52 (95% confidence interval [CI] = 0.30-0.91), 0.64 (95% CI = 0.41-1.00), and 0.63 (95% CI = 0.40-1.01) for the highest quartiles of potassium, calcium, and magnesium intake, respectively, compared with the corresponding lowest quartiles. Similarly, the HRs for the development of VaD were 0.20 (95% CI = 0.07-0.56), 0.24 (95% CI = 0.11-0.53), and 0.26 (95% CI = 0.11-0.61) for the highest quartiles of potassium, calcium, and magnesium intake, respectively. There was no evidence of a linear association between these mineral intakes and the risk of AD. Conclusion Higher self-reported dietary intakes of potassium, calcium, and magnesium reduce the risk of all-cause dementia, especially VaD, in the general Japanese population.

DOI： 10.1111/j.1532-5415.2012.04061.x

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Objectives To investigate whether higher intake of potassium, calcium, and magnesium reduces the risk of incident dementia. Design Prospective cohort study. Setting The Hisayama Study, in Japan. Participants One thousand eighty-one community-dwelling Japanese individuals without dementia aged 60 and older. Measurements A 70-item semiquantitative food frequency questionnaire was used to assess potassium, calcium, and magnesium intakes. Hazard ratios (HRs) for the development of all-cause dementia and its subtypes were estimated using Cox proportional hazards model. Results During a 17-year follow-up, 303 participants experienced all-cause dementia; of these, 98 had vascular dementia (VaD), and 166 had Alzheimer's disease (AD). The multivariable-adjusted HRs for the development of all-cause dementia were 0.52 (95&#37; confidence interval [CI] = 0.300.91), 0.64 (95&#37; CI = 0.411.00), and 0.63 (95&#37; CI = 0.401.01) for the highest quartiles of potassium, calcium, and magnesium intake, respectively, compared with the corresponding lowest quartiles. Similarly, the HRs for the development of VaD were 0.20 (95&#37; CI = 0.070.56), 0.24 (95&#37; CI = 0.110.53), and 0.26 (95&#37; CI = 0.110.61) for the highest quartiles of potassium, calcium, and magnesium intake, respectively. There was no evidence of a linear association between these mineral intakes and the risk of AD. Conclusion Higher self-reported dietary intakes of potassium, calcium, and magnesium reduce the risk of all-cause dementia, especially VaD, in the general Japanese population.

DOI： 10.1111/j.1532-5415.2012.04061.x

Language：English   Publishing type：Research paper (scientific journal)  

Objective: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia.
Methods: A total of 1,017 community-dwelling dementia-free subjects aged >= 60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia.
Results: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95&#37; confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95&#37; CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95&#37; CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of >= 11.1 mmol/L.
Conclusions: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD. Neurology (R) 2011;77:1126-1134

Language：English   Publishing type：Research paper (scientific journal)  

The associations between blood pressure and dementia have been inconclusive. We followed up a total of 668 community-dwelling Japanese individuals without dementia, aged 65 to 79 years, for 17 years and examined the associations of late-life and midlife hypertension with the risk of vascular dementia and Alzheimer disease using the Cox proportional hazards model. During the follow-up, 76 subjects experienced vascular dementia and 123 developed Alzheimer disease. The age-and sex-adjusted incidence of vascular dementia significantly increased with elevated late-life blood pressure levels (normal: 2.3, prehypertension: 8.4, stage 1 hypertension: 12.6, and stage 2 hypertension: 18.9 per 1000 person-years; P(trend)<0.001), whereas no such association was observed for Alzheimer disease (P(trend)=0.88). After adjusting for potential confounding factors, subjects with prehypertension and stage 1 or stage 2 hypertension had 3.0-fold, 4.5-fold, and 5.6-fold greater risk of vascular dementia, respectively, compared with subjects with normal blood pressure. Likewise, there was a positive association of midlife blood pressure levels with the risk of vascular dementia but not with the risk of Alzheimer disease. Compared with those without hypertension in both midlife and late life, subjects with midlife hypertension had an approximate to 5-fold greater risk of vascular dementia, regardless of late-life blood pressure levels. Our findings suggest that midlife hypertension and late-life hypertension are significant risk factors for the late-life onset of vascular dementia but not for that of Alzheimer disease in a general Japanese population. Midlife hypertension is especially strongly associated with a greater risk of vascular dementia, regardless of late-life blood pressure levels. (Hypertension. 2011;58:22-28.). Online Data Supplement

DOI： 10.1161/HYPERTENSIONAHA.110.163055

Language：English   Publishing type：Research paper (scientific journal)  

The associations between blood pressure and dementia have been inconclusive. We followed up a total of 668 community-dwelling Japanese individuals without dementia, aged 65 to 79 years, for 17 years and examined the associations of late-life and midlife hypertension with the risk of vascular dementia and Alzheimer disease using the Cox proportional hazards model. During the follow-up, 76 subjects experienced vascular dementia and 123 developed Alzheimer disease. The age- and sex-adjusted incidence of vascular dementia significantly increased with elevated late-life blood pressure levels (normal: 2.3, prehypertension: 8.4, stage 1 hypertension: 12.6, and stage 2 hypertension: 18.9 per 1000 person-years; P_trend<0.001), whereas no such association was observed for Alzheimer disease (P_trend=0.88). After adjusting for potential confounding factors, subjects with prehypertension and stage 1 or stage 2 hypertension had 3.0-fold, 4.5-fold, and 5.6-fold greater risk of vascular dementia, respectively, compared with subjects with normal blood pressure. Likewise, there was a positive association of midlife blood pressure levels with the risk of vascular dementia but not with the risk of Alzheimer disease. Compared with those without hypertension in both midlife and late life, subjects with midlife hypertension had an ≈5-fold greater risk of vascular dementia, regardless of late-life blood pressure levels. Our findings suggest that midlife hypertension and late-life hypertension are significant risk factors for the late-life onset of vascular dementia but not for that of Alzheimer disease in a general Japanese population. Midlife hypertension is especially strongly associated with a greater risk of vascular dementia, regardless of late-life blood pressure levels.

DOI： 10.1161/HYPERTENSIONAHA.110.163055

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To estimate the effects of the apolipoprotein E (APOE)-epsilon 4 allele on the development of dementia and to elucidate its usefulness in the risk prediction of dementia in Japanese.
DESIGN: Prospective cohort study.
SETTING: The Hisayama Study, in Japan.
PARTICIPANTS: Five hundred twenty-three participants with deoxyribonucleic acid samples from a population of 1,073 community-dwelling participants without dementia aged 60 to 79.
MEASUREMENTS: The risk estimates of the APOE-epsilon 4 allele on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). RESULTS: During 17 years of follow-up, 136 participants developed dementia, 81 of whom had AD and 39 VaD. After adjusting for age, sex, education, smoking, alcohol intake, systolic blood pressure, use of antihypertensive agents, glycosylated hemoglobin, serum total cholesterol, body mass index, and regular exercise, the risks of all-cause dementia and AD were significantly higher in APOE-e4 carriers than in noncarriers, but no such association was observed for VaD (all-cause dementia: hazard ratio (HR) = 1.81, P = .004; AD: HR = 3.42, P <. 001; VaD: HR = 1.08, P = .86). The area under the receiver operating characteristic curve was significantly greater when the APOE genotype was incorporated into a model with potential risk factors for AD (0.74 vs 0.68, P = .02). Other measures of model discrimination (net reclassification improvement: 0.18, P = .01; integrated discrimination improvement: 6.25, P <. 001) also confirmed this improvement in AD risk assessment.
CONCLUSION: The APOE-epsilon 4 allele is a risk factor for AD in the Japanese population. Information on APOE genotype improves AD risk assessment substantially beyond a model based on potential risk factors. J Am Geriatr Soc 59:1074-1079, 2011.

DOI： 10.1111/j.1532-5415.2011.03405.x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1176/appi.neuropsych.18.4.557

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：つくば国際会議場   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：アクロス福岡国際会議場   Country：Japan  

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡   Country：Japan  

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：松山市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場   Country：Japan  

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：北九州国際会議場   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：コクヨショールーム   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京カンファレンスセンター品川   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2024.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.6 - 2023.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2021.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都市   Country：Japan  

Event date： 2021.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋市   Country：Japan  

Event date： 2021.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜市   Country：Japan  

Event date： 2021.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋市   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡市   Country：Japan  

Event date： 2020.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2020.12

Language：Japanese  

Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.8

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡市   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：仙台   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京都   Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京都   Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：佐賀市   Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：岡山市   Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2016.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Kumamoto   Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：松山市   Country：Japan  

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：つくば市   Country：Japan  

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：福岡市   Country：Japan  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：English  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

本邦4地域に在住する地域高齢住民を対象とした認知症の地域悉皆調査の成績によると,2022～2023年における軽度認知障害(MCI)の有病率(性年齢調整後)は15.5%であった.MCIはあくまでその時点における状態であり,認知症にprogressionしたり,正常にreversionしたりする.地域住民の追跡調査におけるMCIから正常へのreversion率や認知症へのprogression率はそれぞれ10～46%,4～38%であり,MCIと診断されても生活習慣病の管理に加えて余暇時の運動や社会活動への参加など健康的なライフスタイルが認知機能低下のリスク低減につながることが示唆された.(著者抄録)

Language：English   Publisher：日本脳血管・認知症学会  

Language：Japanese   Publisher：医歯薬出版(株)  

アルツハイマー病(AD)は,認知症のなかで最も頻度の高い神経変性疾患である.ADの発症において,常染色体優性遺伝ADはわずか1%にすぎず,そのほとんどが複数の感受性遺伝子とさまざまな環境因子が関与する複合病態であることがわかっている.既報の研究から,ADの最も強力な遺伝的危険因子であるAPOE-ε4対立遺伝子を有していても高い教育,禁煙,多様性に富む健康的な食習慣が,その遺伝的リスクを低減することが示唆される.さらに既報の遺伝的危険因子を用いたポリジェニックリスクスコア(PRS)と環境要因の遺伝-環境相互作用について検討した報告から,遺伝的リスクが高い状態であっても健康的な生活習慣の意識と実践により,認知症の発症リスクが修飾できる可能性がある.さらなる基礎・臨床研究を通じて認知症の遺伝的リスクに応じたリスク低減の方法が開発され,その予防法が社会実装されることに期待したい.(著者抄録)

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publisher：(株)アークメディア  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

認知症の疫学研究は,循環器疾患や悪性腫瘍の疫学研究に比べ,その疾患特異的な特徴や社会的偏見から研究数は少ない.欧米を中心とした認知症の追跡調査の成績から認知症発症と関連する因子として,高血圧,糖尿病,高コレステロール血症,喫煙,飲酒,うつ病,孤独感,睡眠,運動習慣,食習慣が挙げられる.認知症の発症リスクを低減してその社会的負担の増大を抑制するためには,中年期から生活習慣病の予防とその適切な管理に加えて健康的な生活習慣を心がけることが大切である.(著者抄録)

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)世論時報社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：大道学館出版部  

Language：Japanese   Publisher：(株)医学出版  

国内外の前向きコホート研究の成績から,糖尿病は認知症発症の危険因子であることが示唆される.福岡県久山町で継続中の疫学調査の成績を用いて両者の関係を検討した結果,糖尿病は認知症,とくにアルツハイマー型認知症発症の有意な危険因子だった.血糖レベル別の検討では,空腹時血糖値と認知症発症の関連は認められなかったが,糖負荷後2時間血糖値の上昇と認知症発症の間に有意な正の関連が認められた.また,剖検脳を用いた検討では,生前の糖尿病関連因子(糖負荷後2時間血糖値や空腹時インスリン値など)の上昇は老人斑沈着と有意に関連した.さらに,頭部MRIを用いた脳画像研究では,糖負荷後2時間血糖値の上昇と糖尿病の罹病期間の延長が海馬や側頭葉などの認知症に関わる脳部位の容積低下と有意に関連していた.認知症の社会的負担を軽減するために,糖尿病の予防とその適切な管理が重要と考えられる.(著者抄録)

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

軽度認知障害(MCI)の調査は対象集団の選定により結果が大きく異なる.本邦8地域に在住する地域高齢住民を対象としたコホート研究の成績によると,2016～2018年におけるMCI(non-amnestic含む)の粗有病率は17.0%であった.地域住民の追跡調査におけるMCIから正常へのreversion率や認知症へのprogression率はそれぞれ10～44%,4～38%であり,MCIと診断されても生活習慣病の管理に加えて余暇時の運動や社会活動への参加など,健康的なライフスタイルが認知機能低下のリスク低減につながることが示唆された.(著者抄録)

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(株)ライフ・サイエンス  

認知症の発症リスクを低減し、その社会的負担を軽減することは喫緊の課題である。生活習慣病や生活習慣と認知症の関係を検討した国内外の追跡研究の成績によると、高血圧(特に中年期)、糖尿病、喫煙習慣は認知症発症の有意な危険因子であった。一方、運動習慣や多様性に富む食習慣を有する人では、認知症の発症リスクが有意に低かった。これらの疫学データの知見より、認知症の発症リスクを低減する上で、禁煙、定期的な運動、多様性に富む食習慣などの健康的な生活習慣を心掛けるとともに、高血圧や糖尿病などの生活習慣病の予防とその適切な管理を行うことが重要であると考えられる。(著者抄録)

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

地域高齢住民における認知症の有病率・発症率・予後の時代的変化 久山町研究

Language：Japanese  

認知症の新規発症を減らすためにできることは何か? 生活習慣病や生活習慣との関連 久山町研究

Language：Japanese  

連続剖検例にて神経原線維変化型認知症と診断された認知症例の臨床的特徴 久山町研究

Language：Japanese  

地域住民における糖尿病有病率の時代的変化、1988-2012年 久山町研究

Language：Japanese  

【実施診療のための最新認知症学-検査・治療・予防・支援-】 認知症予防 久山町研究から考える認知症予防

Language：Japanese  

地域在住非糖尿病者における座位時間とインスリン抵抗性の関連 久山町研究

Language：Japanese  

地域高齢者における中年期から老年期の握力低下と認知症発症の関連 久山町研究

Language：Japanese  

地域高齢者における中年期から老年期までの握力変化と認知症発症の関連 久山町研究

Language：Japanese  

老年期の脂肪量および除脂肪体重が認知症発症におよぼす影響 久山町研究

Language：Japanese  

久山町研究からみた認知症の予防

Language：Japanese  

地域住民におけるNT-proBNPの変化率と総死亡および死因別死亡との関連 久山町研究

Language：Japanese  

地域住民における血糖関連指標とアルツハイマー病発症との関連 久山町研究

Language：Japanese  

剖検にて神経原線維変化型認知症が判明した老年期認知症の1例

Language：Japanese  

未病予防の幹となる生活のなかの運動の包括的位置づけ 地域住民における運動と生活習慣病の疫学 久山町研究

Language：Japanese  

未病と認知症の一次予防 福岡県久山町における認知症の疫学 久山町研究

Language：Japanese  

地域高齢者における歯の喪失が認知症発症に及ぼす影響の検討 久山町研究

Language：Japanese  

地域高齢住民における微小脳出血の有病率とその危険因子 久山町研究

Language：Japanese  

地域住民における座位時間と糖尿病の関連 久山町研究

Language：English  

The association between diabetes and the risk of developing dementia has received much attention in epidemiological studies. An accurate population-based prospective cohort study has been conducted in the elderly population of the town of Hisayama in Japan since 1985 aiming to elucidate the secular trends in the prevalence of dementia and examine risk and protective factors for dementia in the Japanese population. The prevalence of all-cause dementia significantly increased from 1985 to 2012. In regard to subtypes of dementia, a similar trend was observed for Alzheimer's disease (AD). In a prospective study of risk factors for dementia in Hisayama elder residents without dementia, diabetes was identified as a significant risk factor for developing all-cause dementia, especially AD. Moreover, 2-hour post-load glucose levels were closely associated with increased risk of all-cause dementia, AD, and vascular dementia. In a pathological study of Hisayama residents, higher levels of 2-hour post-load glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with increased risk of neuritic plaques. The steep increase in the frequency of diabetes could lead to the increasing trend in the prevalence of dementia, especially AD, in the Japanese elderly.

Language：Japanese  

【アルツハイマー型認知症診療のBreakthrough】 生活習慣病とアルツハイマー型認知症

Language：Japanese  

一般住民におけるアルブミン尿と認知症発症の関係 久山町研究

Language：Japanese  

地域高齢者における野菜・果実の摂取と認知機能の関係 久山町研究

Language：Japanese  

【認知症】 疫学 Alzheimer病の危険因子・防御因子
Alzheimer病(AD)は加齢と密接に関連する神経変性疾患である.久山町研究を含む国内外の追跡調査の成績によると,アポリポタンパクE(APOE-ε4),糖尿病,喫煙,うつ症状はAD発症の有意な危険因子であった.一方,運動および和食+野菜+牛乳・乳製品という食事パターンとAD発症の間に,有意な負の関連が存在した.つまり,加齢や遺伝的要因に基づくADのリスクは,生活習慣病の予防や生活習慣の是正によって軽減できる可能性がある.(著者抄録)

Language：Japanese  

【認知症の早期発見と予防・治療-認知症500万人時代に求められるもの】 ライフスタイルと認知症

Language：Japanese  

運動疫学研究の今とこれから 久山町研究における運動疫学

DOI： 10.7600/jspfsm.65.50

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese  

【生活習慣病-新しい展開】 見直された生活習慣病と疾患 生活習慣病と認知症

Language：Japanese  

これからの認知症治療を考える(基礎・臨床) 家庭血圧の日間変動と認知症発症との関連 久山町研究

Language：Japanese  

地域高齢住民における認知症の疫学 久山町研究

Language：Japanese  

地域高齢者における糖尿病と頭部MRI上の海馬萎縮との関係 久山町研究

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese  

握力の経年変化が総死亡および死因別死亡に与える影響 久山町研究

Language：Japanese  

地域高齢住民における認知症発症率の時代的変化とその要因の検討 久山町研究

Language：Japanese  

地域高齢者における乳・乳製品摂取が生活機能障害と日常生活動作障害の発生に及ぼす影響 久山町研究

Language：English  

DOI： 10.1111/jgs.13163

Language：Japanese  

歯周病・糖尿病・アルツハイマー病の負のスパイラルを断ち切る 口腔からの健康寿命延伸戦略 アルツハイマー病脳における糖尿病関連遺伝子の発現異常とその意義 久山町研究

Language：Japanese  

地域住民におけるヘマトクリットレベルが心血管病発症に及ぼす影響 久山町研究

Language：Japanese  

地域住民におけるヘモグロビンA1cレベルと心血管病発症の関係 久山町研究

Language：English  

DOI： 10.1016/j.atherosclerosis.2014.03.033

Language：Japanese  

地域高齢住民における食事パターンが認知症発症に与える影響 久山町研究

Language：Japanese  

蛋白質エネルギー比率と脳卒中発症との関連 久山町研究

Language：Japanese  

Glucose Tolerance Status and Risk of Dementia in the Community : the Hisayama Study

Language：Japanese  

わが国において継続中の認知症疫学研究 久山町研究 生活習慣病と認知症

Language：Japanese  

生活習慣病と認知症 久山町研究

Language：Japanese  

地域住民における乳・乳製品の摂取量と認知症発症との関連 久山町研究

Language：Japanese  

地域高齢者が生涯に認知症を発症する確率の検討 久山町研究

Language：Japanese  

定期的な運動習慣が認知症発症に及ぼす影響 久山町研究

Language：Japanese  

地域一般住民におけるカルシウム、マグネシウム、カリウムの摂取量と認知症発症の関連 久山町研究

Language：Japanese  

地域一般住民における耐糖能レベルと認知症発症の関係 久山町研究

Language：Japanese  

地域住民における耐糖能レベルが認知症発症におよぼす影響 久山町研究

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc.