Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Tomoyuki Ohara Last modified date:2021.07.19

Lecturer / 医学部 医学科 臨床医学 / Neuro-Psychiatry / Kyushu University Hospital


Papers
1. Toshiharu Ninomiya, Tomoyuki Ohara, Yoichiro Hirakawa, Daigo Yoshida, Yasufumi Doi, Jun Hata, Shigenobu Kanba, Toru Iwaki, Yutaka Kiyohara, Midlife and Late-Life Blood Pressure and Dementia in Japanese Elderly The Hisayama Study, HYPERTENSION, 10.1161/HYPERTENSIONAHA.110.163055, 58, 1, 22-U58, 2011.07, 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.
2. T. Ohara, Y. Doi, T. Ninomiya, Y. Hirakawa, J. Hata, T. Iwaki, S. Kanba, Y. Kiyohara, Glucose tolerance status and risk of dementia in the community The Hisayama Study, NEUROLOGY, 77, 12, 1126-1134, 2011.09, 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. Neurology (R) 2011;77:1126-1134.
3. Tomoyuki Ohara, Toshiharu Ninomiya, Michiaki Kubo, Yoichiro Hirakawa, Yasufumi Doi, Jun Hata, Toru Iwaki, Shigenobu Kanba, Yutaka Kiyohara, Apolipoprotein Genotype for Prediction of Alzheimer's Disease in Older Japanese: The Hisayama Study, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/j.1532-5415.2011.03405.x, 59, 6, 1074-1079, 2011.06, 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..
4. Mio Ozawa, Toshiharu Ninomiya, Tomoyuki Ohara, Yoichiro Hirakawa, Yasufumi Doi, Jun Hata, Kazuhiro Uchida, Tomoko Shirota, Takanari Kitazono, Yutaka Kiyohara, Self-Reported Dietary Intake of Potassium, Calcium, and Magnesium and Risk of Dementia in the Japanese: The Hisayama Study, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/j.1532-5415.2012.04061.x, 60, 8, 1515-1520, 2012.08, 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] = 0.300.91), 0.64 (95% CI = 0.411.00), and 0.63 (95% 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% CI = 0.070.56), 0.24 (95% CI = 0.110.53), and 0.26 (95% 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..
5. Tomoyuki Ohara, Toshiharu Ninomiya, Yoichiro Hirakawa, Kyota Ashikawa, Akira Monji, Yutaka Kiyohara, Shigenobu Kanba, Michiaki Kubo, Association study of susceptibility genes for late-onset Alzheimer's disease in the Japanese population, PSYCHIATRIC GENETICS, 10.1097/YPG.0b013e3283586215, 22, 6, 290-293, 2012.12, 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..
6. Atsuko Sekita, Hisatomi Arima, Toshiharu Ninomiya, Tomoyuki Ohara, Yasufumi Doi, Yoichiro Hirakawa, Masayo Fukuhara, Jun Hata, Koji Yonemoto, Yukiko Ga, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Elevated depressive symptoms in metabolic syndrome in a general population of Japanese men: a cross-sectional study, BMC PUBLIC HEALTH, 10.1186/1471-2458-13-862, 13, 862, 2013.09, 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..
7. Mio Ozawa, Toshiharu Ninomiya, Tomoyuki Ohara, Yasufumi Doi, Kazuhiro Uchida, Tomoko Shirota, Koji Yonemoto, Takanari Kitazono, Yutaka Kiyohara, Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study, AMERICAN JOURNAL OF CLINICAL NUTRITION, 10.3945/ajcn.112.045575, 97, 5, 1076-1082, 2013.05, 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% Cl: 0.46, 0.95), 0.65 (95% Cl: 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. Am J Clin Nutr 2013;97:1076-82..
8. Toshiharu Ninomiya, Masaharu Nagata, Jun Hata, Yoichiro Hirakawa, Mio Ozawa, Daigo Yoshida, Tomoyuki Ohara, Hiro Kishimoto, Naoko Mukai, Masayo Fukuhara, Takanari Kitazono, Yutaka Kiyohara, Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: The Hisayama Study, Atherosclerosis, 10.1016/j.atherosclerosis.2013.09.023, 231, 2, 261-267, 2013.12, 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. © 2013 Elsevier Ireland Ltd..
9. Mio Ozawa, Tomoyuki Ohara, Toshiharu Ninomiya, Jun Hata, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Kazuhiro Uchida, Tomoko Shirota, Takanari Kitazono, Yutaka Kiyohara, Milk and Dairy Consumption and Risk of Dementia in an Elderly Japanese Population: The Hisayama Study, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/jgs.12887, 62, 7, 1224-1230, 2014.07, 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..
10. Mio Ozawa, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, DIETARY FACTORS AND INCIDENCE OF DEMENTIA: COX REGRESSION ANALYSIS WITH SPECIAL EMPHASIS ON THE NUMBER OF EVENTS RESPONSE, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/jgs.13163, 62, 12, 2467-2468, 2014.12.
11. Masaaki Hokama, Sugako Oka, Julio Leon, Toshiharu Ninomiya, Hiroyuki Honda, Kensuke Sasaki, Toru Iwaki, Tomoyuki Ohara, Tomio Sasaki, Frank M. LaFerla, Yutaka Kiyohara, Yusaku Nakabeppu, Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study, CEREBRAL CORTEX, 10.1093/cercor/bht101, 24, 9, 2476-2488, 2014.09, 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..
12. Tomoyuki Ohara, Toshiharu Ninomiya, Jun Hata, Mio Ozawa, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Toru Iwaki, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Midlife and Late-Life Smoking and Risk of Dementia in the Community: The Hisayama Study, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/jgs.13794, 63, 11, 2332-2339, 2015.11, 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% 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.
ConclusionPersistent smoking from mid- to late life is a significant risk factor for dementia and its subtypes in the general Japanese population..
13. Atsushi Hirano, Tomoyuki Ohara, Atsushi Takahashi, Masayuki Aoki, Yuta Fuyuno, Kyota Ashikawa, Takashi Morihara, Masatoshi Takeda, Kouzin Kamino, Etsuko Oshima, Yuko Okahisa, Nobuto Shibata, Heii Arai, Hiroyasu Akatsu, Masashi Ikeda, Nakao Iwata, Toshiharu Ninomiya, Akira Monji, Takanari Kitazono, Yutaka Kiyohara, Michiaki Kubo, Shigenobu Kanba, A genome-wide association study of late-onset Alzheimer's disease in a Japanese population, PSYCHIATRIC GENETICS, 10.1097/YPG.0000000000000090, 25, 4, 139-146, 2015.08, 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..
14. Saion Chatterjee, Sanne A. E. Peters, Mark Woodward, Silvia Mejia Arango, G. David Batty, Nigel Beckett, Alexa Beiser, Amy R. Borenstein, Paul K. Crane, Mary Haan, Linda B. Hassing, Kathleen M. Hayden, Yutaka Kiyohara, Eric B. Larson, Chung-Yi Li, Toshiharu Ninomiya, Tomoyuki Ohara, Ruth Peters, Tom C. Russ, Sudha Seshadri, Bjorn H. Strand, Rod Walker, Weili Xu, Rachel R. Huxley, Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia, DIABETES CARE, 10.2337/dc15-1588, 39, 2, 300-307, 2016.02, 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 diabetes-associated 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 similar to 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..
15. Honda H, Sasaki K, Hamasaki H, Shijo M, Koyama S, Ohara T, Ninomiya T, Kiyohara Y, Suzuki SO, Iwaki T, Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12298, 36, 4, 383-387, 2016.08.
16. Hiro Kishimoto, Tomoyuki Ohara, Jun Hata, Toshiharu Ninomiya, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Fumie Ikeda, Masayo Fukuhara, Shuzo Kumagai, Shigenobu Kanba, Takanari Kitazono, Yutaka Kiyohara, The long-term association between physical activity and risk of dementia in the community: the Hisayama Study, EUROPEAN JOURNAL OF EPIDEMIOLOGY, 10.1007/s10654-016-0125-y, 31, 3, 267-274, 2016.03, 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 % 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..
17. Jun Hata, Naoko Mukai, Masaharu Nagata, Tomoyuki Ohara, Daigo Yoshida, Hiro Kishimoto, Mao Shibata, Yoichiro Hirakawa, Motoyoshi Endo, Tetsuro Ago, Takanari Kitazono, Yuichi Oike, Yutaka Kiyohara, Toshiharu Ninomiya, Serum Angiopoietin-Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community: The Hisayama Study, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/ATVBAHA.116.307291, 36, 8, 1686-1691, 2016.08, 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..
18. Naoki Hirabayashi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Mao Shibata, Seiji Goto, Yoshihiko Furuta, Fumio Yamashita, Kazufumi Yoshihara, Takanari Kitazono, Nobuyuki Sudo, Yutaka Kiyohara, Toshiharu Ninomiya, Elevated 2-Hour Post-load Glucose Levels and Longer Duration of Diabetes Are Risk Factors for Hippocampal Atrophy in Elderly Japanese: The Hisayama Study, DIABETES, 10.2337/dc15-2800, 65, A361-A361, 2016.06.
19. Fumie Ikeda, Kentaro Shikata, Jun Hata, Masayo Fukuhara, Yoichiro Hirakawa, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Daigo Yoshida, Koji Yonemoto, Motohiro Esaki, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Combination of Helicobacter pylori Antibody and Serum Pepsinogen as a Good Predictive Tool of Gastric Cancer Incidence: 20-Year Prospective Data From the Hisayama Study, JOURNAL OF EPIDEMIOLOGY, 10.2188/jea.JE20150258, 26, 12, 629-636, 2016.12, 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..
20. Naoki Hirabayashi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Mao Shibata, Seiji Gotoh, Yoshihiko Furuta, Fumio Yamashita, Kazufumi Yoshihara, Takanari Kitazono, Nobuyuki Sudo, Yutaka Kiyohara, Toshiharu Ninomiya, Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study, DIABETES CARE, 10.2337/dc15-2800, 39, 9, 1543-1549, 2016.09, 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% 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 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..
21. Tomoyuki Ohara, Jun Hata, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Toru Iwaki, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Toshiharu Ninomiya, Trends in dementia prevalence, incidence, and survival rate in a Japanese community, NEUROLOGY, 10.1212/WNL.0000000000003932, 88, 20, 1925-1932, 2017.05, 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..
22. Kenji Takeuchi, Tomoyuki Ohara, Michiko Furuta, Toru Takeshita, Yukie Shibata, Jun Hata, Daigo Yoshida, Yoshihisa Yamashita, Toshiharu Ninomiya, Tooth Loss and Risk of Dementia in the Community: the Hisayama Study, JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 10.1111/jgs.14791, 65, 5, E95-E100, 2017.05, 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%) 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).
ConclusionTooth loss is associated with an increased risk of all-cause dementia and AD in the Japanese population..
23. Nagata M, Hata J, Hirakawa Y, Mukai N, Yoshida D, Ohara T, Kishimoto H, Kawano H, Kitazono T, Kiyohara Y, Ninomiya T, The ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cancer death in a Japanese community: The Hisayama Study., Journal of epidemiology, 10.1016/j.je.2017.01.004, 27, 12, 578-583, 2017.12.
24. Yu-Tzu Wu, Alexa S. Beiser, Monique M. B. Breteler, Laura Fratiglioni, Catherine Helmer, Hugh C. Hendrie, Hiroyuki Honda, M. Arfan Ikram, Kenneth M. Langa, Antonio Lobo, Fiona E. Matthews, Tomoyuki Ohara, Karine Peres, Chengxuan Qiu, Sudha Seshadri, Britt-Marie Sjolund, Ingmar Skoog, Carol Brayne, The changing prevalence and incidence of dementia over time - current evidence (vol 13, pg 327, 2017), NATURE REVIEWS NEUROLOGY, 10.1038/nrneurol.2017.63, 13, 6, 339-339, 2017.06.
25. Mio Ozawa, Daigo Yoshida, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Mao Shibata, Kazuhiro Uchida, Masashi Nagata, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Dietary Protein Intake and Stroke Risk in a General Japanese Population The Hisayama Study, STROKE, 10.1161/STROKEAHA.116.016059, 48, 6, 1478-+, 2017.06, 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..
26. Emi Oishi, Tomoyuki Ohara, Satoko Sakata, Masayo Fukuhara, Jun Hata, Daigo Yoshida, Mao Shibata, Toshio Ohtsubo, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Day-to-Day Blood Pressure Variability and Risk of Dementia in a General Japanese Elderly Population The Hisayama Study, CIRCULATION, 10.1161/CIRCULATIONAHA.116.025667, 136, 6, 516-+, 2017.08, 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% 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% confidence interval=1.45-3.55, P<0.001 for all-cause dementia; hazard ratio=2.79, 95% confidence interval=1.04-7.51, P=0.03 for VaD; hazard ratio=2.22, 95% 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..
27. Erika Castillo, Julio Leon, Guianfranco Mazzei, Nona Abolhassani, Naoki Haruyama, Takashi Saito, Takaomi Saido, Masaaki Hokama, Toru Iwaki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Kunihiko Sakumi, Frank M. LaFerla, Yusaku Nakabeppu, Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation, SCIENTIFIC REPORTS, 10.1038/s41598-017-17999-3, 7, 1, 17762, 2017.12, 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..
28. Kaoru Umehara, Naoko Mukai, Jun Hata, Yoichiro Hirakawa, Tomoyuki Ohara, Daigo Yoshida, Hiro Kishimoto, Takanari Kitazono, Sumio Hoka, Yutaka Kiyohara, Toshiharu Ninomiya, Association Between Serum Vitamin D and All-Cause and Cause-Specific Death in a General Japanese Population - The Hisayama Study -, CIRCULATION JOURNAL, 10.1253/circj.CJ-16-0954, 81, 9, 1315-+, 2017.09, 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% 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..
29. Naoko Mukai, Tomoyuki Ohara, Jun Hata, Yoichiro Hirakawa, Daigo Yoshida, Hiro Kishimoto, Masafumi Koga, Udai Nakamura, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Alternative Measures of Hyperglycemia and Risk of Alzheimer's Disease in the Community: The Hisayama Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 10.1210/jc.2017-00439, 102, 8, 3002-3010, 2017.08, 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% 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/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..
30. Tomoyuki Ohara, Toshiharu Ninomiya, AUTHOR RESPONSE: TRENDS IN DEMENTIA PREVALENCE, INCIDENCE, AND SURVIVAL RATE IN A JAPANESE COMMUNITY, NEUROLOGY, 10.1212/WNL.0000000000004590, 89, 18, 1930-1931, 2017.10.
31. Reply to "Long sleep duration: An epiphenomenon or a risk for dementia?".
32. Prevalence of and risk factors for cerebral microbleeds in a general Japanese elderly community..
33. 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..
34. Masahiro Iida, Fumie Ikeda, Jun Hata, Yoichiro Hirakawa, Tomoyuki Ohara, Naoko Mukai, Daigo Yoshida, Koji Yonemoto, Motohiro Esaki, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Development and validation of a risk assessment tool for gastric cancer in a general Japanese population, Gastric Cancer, 10.1007/s10120-017-0768-8, 21, 3, 383-390, 2018.05, 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..
35. Decline in handgrip strength from midlife to late-life is associated with dementia in a Japanese community: the Hisayama Study..
36. Kiyoshi Sanada, Randi Chen, Bradley Willcox, Tomoyuki Ohara, Aida Wen, Cody Takenaka, Kamal Masaki, Association of sarcopenic obesity predicted by anthropometric measurements and 24-y all-cause mortality in elderly men: The Kuakini Honolulu Heart Program, Nutrition, 10.1016/j.nut.2017.09.003, 46, 97-102, 2018.02, 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..
37. Mao Shibata, Tomoyuki Ohara, Daigo Yoshida, Jun Hata, Naoko Mukai, Hiroyuki Kawano, Shigenobu Kanba, Takanari Kitazono, Toshiharu Ninomiya, Association between the ratio of serum arachidonic acid to eicosapentaenoic acid and the presence of depressive symptoms in a general Japanese population: the Hisayama Study, Journal of Affective Disorders, 10.1016/j.jad.2018.05.004, 237, 73-79, 2018.09, 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..
38. Association Between Daily Sleep Duration and Risk of Dementia and Mortality in a Japanese Community..
39. Keita Takae, Jun Hata, Tomoyuki Ohara, Daigo Yoshida, Mao Shibata, Naoko Mukai, Yoichiro Hirakawa, Hiro Kishimoto, Kazuhiko Tsuruya, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Albuminuria increases the risks for both Alzheimer disease and vascular dementia in community-dwelling Japanese elderly: The hisayama study, Journal of the American Heart Association, 10.1161/JAHA.117.006693, 7, 2, 2018.01, 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..
40. Trends in the prevalence of type 2 diabetes and prediabetes in a Japanese community, 1988-2012: the Hisayama Study..
41. Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer's disease: The Hisayama study..
42. Serum elaidic acid concentration and risk of dementia: The Hisayama study..
43. Serum Soluble Triggering Receptor Expressed on Myeloid Cells 2 as a Biomarker for Incident Dementia: The Hisayama Study..
44. Prevalence of adult epilepsy in a general Japanese population: The Hisayama study..
45. Objectively measured sedentary time and diabetes mellitus in a general Japanese population: The Hisayama Study..
46. NT-proBNP and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study..
47. Dairy consumption and risk of functional disability in an elderly Japanese population: the Hisayama Study..
48. Association Between Serum β-alanine and Risk of Dementia: the Hisayama Study..
49. Sanmei Chen, Takanori Honda, Tomoyuki Ohara, Jun Hata, Yoichiro Hirakawa, Daigo Yoshida, Mao Shibata, Satoko Sakata, Emi Oishi, Yoshihiko Furuta, Takanari Kitazono, Toshiharu Ninomiya, Serum homocysteine and risk of dementia in Japan., Journal of neurology, neurosurgery, and psychiatry, 10.1136/jnnp-2019-322366, 2020.03, 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..
50. Tomoyuki Ohara, Yoshihiko Furuta, Naoki Hirabayashi, Jun Hata, Yoichiro Hirakawa, Takanori Honda, Daigo Yoshida, Mao Shibata, Takanari Kitazono, Toshiharu Ninomiya, Elevated serum glycated albumin and glycated albumin : hemoglobin A1c ratio were associated with hippocampal atrophy in a general elderly population of Japanese: The Hisayama Study., Journal of diabetes investigation, 10.1111/jdi.13220, 2020.01, 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..
51. Crystal ManYing Lee, Mark Woodward, G David Batty, Alexa S Beiser, Steven Bell, Claudine Berr, Espen Bjertness, John Chalmers, Robert Clarke, Jean-Francois Dartigues, Kendra Davis-Plourde, Stéphanie Debette, Emanuele Di Angelantonio, Catherine Feart, Ruth Frikke-Schmidt, John Gregson, Mary N Haan, Linda B Hassing, Kathleen M Hayden, Marieke P Hoevenaar-Blom, Jaakko Kaprio, Mika Kivimaki, Georgios Lappas, Eric B Larson, Erin S LeBlanc, Anne Lee, Li-Yung Lui, Eric P Moll van Charante, Toshiharu Ninomiya, Liv Tybjaerg Nordestgaard, Tomoyuki Ohara, Toshiaki Ohkuma, Teemu Palviainen, Karine Peres, Ruth Peters, Nawab Qizilbash, Edo Richard, Annika Rosengren, Sudha Seshadri, Martin Shipley, Archana Singh-Manoux, Bjorn Heine Strand, Willem A van Gool, Eero Vuoksimaa, Kristine Yaffe, Rachel R Huxley, Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia., Obesity reviews : an official journal of the International Association for the Study of Obesity, 10.1111/obr.12989, 21, 4, e12989, 2020.04, 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..
52. Tomoyuki Ohara, Yoshihiko Furuta, Naoki Hirabayashi, Jun Hata, Yoichiro Hirakawa, Takanori Honda, Daigo Yoshida, Mao Shibata, Takanari Kitazono, Toshiharu Ninomiya, Elevated serum glycated albumin and glycated albumin : hemoglobin A1c ratio were associated with hippocampal atrophy in a general elderly population of Japanese: the Hisayama Study, Journal of Diabetes Investigation, 10.1111/jdi.13220, 2020.01, Aims/Introduction: To investigate the association of alternative glycemic measures – namely, serum glycated albumin (GA), hemoglobin A1c and the GA : HbA1cratio – 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..
53. Takanori Honda, Tomoyuki Ohara, Masakazu Shinohara, Jun Hata, Ryuji Toh, Daigo Yoshida, Mao Shibata, Tatsuro Ishida, Yoichiro Hirakawa, Yasuhiro Irino, Satoko Sakata, Kazuhiro Uchida, Takanari Kitazono, Shigenobu Kanba, Ken Ichi Hirata, Toshiharu Ninomiya, Serum elaidic acid concentration and risk of dementia
The Hisayama Study, Neurology, 10.1212/WNL.0000000000008464, 93, 22, E2053-E2064, 2019.11, 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..
54. Takuya Nagata, Tomoyuki Ohara, Jun Hata, Satoko Sakata, Yoshihiko Furuta, Daigo Yoshida, Takanori Honda, Yoichiro Hirakawa, Tomomi Ide, Shigenobu Kanba, Takanari Kitazono, Hiroyuki Tsutsui, Toshiharu Ninomiya, NT-proBNP and Risk of Dementia in a General Japanese Elderly Population
The Hisayama Study, Journal of the American Heart Association, 10.1161/JAHA.118.011652, 8, 17, e011652, 2019.09, 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..
55. Tomoyuki Ohara, Jun Hata, Masashi Tanaka, Takanori Honda, Hajime Yamakage, Daigo Yoshida, Takayuki Inoue, Yoichiro Hirakawa, Toru Kusakabe, Mao Shibata, Tadashi Teraoka, Takanari Kitazono, Shigenobu Kanba, Noriko Satoh-Asahara, Toshiharu Ninomiya, Serum Soluble Triggering Receptor Expressed on Myeloid Cells 2 as a Biomarker for Incident Dementia
The Hisayama Study, Annals of Neurology, 10.1002/ana.25385, 85, 1, 47-58, 2019.01, 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% confidence interval [CI] = 1.39–2.97, p < 0.001 for all-cause dementia; HR = 1.62, 95% CI = 1.02–2.55, p = 0.04 for AD; HR = 2.85, 95% 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..
56. Jun Hata, Tomoyuki Ohara, Yoshinori Katakura, Kuniyoshi Shimizu, Shuntaro Yamashita, Daigo Yoshida, Takanori Honda, Yoichiro Hirakawa, Mao Shibata, Satoko Sakata, Takanari Kitazono, Satoru Kuhara, Toshiharu Ninomiya, Association between Serum β-Alanine and Risk of Dementia, American journal of epidemiology, 10.1093/aje/kwz116, 188, 9, 1637-1645, 2019.09, 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..
57. Naoko Mukai, Jun Hata, Yoichiro Hirakawa, Tomoyuki Ohara, Daigo Yoshida, Udai Nakamura, Takanari Kitazono, Toshiharu Ninomiya, Trends in the prevalence of type 2 diabetes and prediabetes in a Japanese community, 1988–2012
the Hisayama Study, Diabetology International, 10.1007/s13340-018-0380-0, 10, 3, 198-205, 2019.07, 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..
58. Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masahiro Shijo, Tomoyuki Ohara, Yozo Hatabe, Tsuyoshi Okamoto, Toshiharu Ninomiya, Toru Iwaki, Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer's disease
The Hisayama study, Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, 10.1016/j.dadm.2019.04.008, 11, 415-423, 2019.12, 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..
59. Yozo Hatabe, Mao Shibata, Tomoyuki Ohara, Emi Oishi, Daigo Yoshida, Takanori Honda, Jun Hata, Shigenobu Kanba, Takanari Kitazono, Toshiharu Ninomiya, Decline in handgrip strength from midlife to late-life is associated with dementia in a Japanese community
The Hisayama study, Journal of epidemiology, 10.2188/jea.JE20180137, 30, 1, 15-23, 2020.01, 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..
60. , Phillip J. Tully, Yuichiro Yano, Lenore J. Launer, Kazuomi Kario, Michiaki Nagai, Simon P. Mooijaart, Jurgen A.H.R. Claassen, Simona Lattanzi, Andrew D. Vincent, Christophe Tzourio, Kaarin J. Anstey, Nigel Beckett, Alexa S. Beiser, Jonathan Birns, Adam M. Brickman, Nicholas R. Burns, Mahir Cengiz, Suzanne Cosh, Rianne A.A. de Heus, Peter W. de Leeuw, Diana Dorstyn, Merrill F. Elias, J. Wouter Jukema, Masahiro Kikuya, Abraham A. Kroon, Rajiv Mahajan, Emer R. McGrath, Eric P. Moll van Charante, Toshiharu Ninomiya, Tomoyuki Ohara, Takayoshi Ohkubo, Emi Oishi, Ruth Peters, Edo Richard, Michihiro Satoh, Joseph Selvayanagam, Sudha Seshadri, David J. Stott, Stella Trompet, Willem A. van Gool, Tessa van Middelaar, Deborah A. Turnbull, Association Between Blood Pressure Variability and Cerebral Small-Vessel Disease
A Systematic Review and Meta-Analysis, Journal of the American Heart Association, 10.1161/JAHA.119.013841, 9, 1, 2020.01, 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..
61. Crystal Man Ying Lee, Mark Woodward, G. David Batty, Alexa S. Beiser, Steven Bell, Claudine Berr, Espen Bjertness, John Chalmers, Robert Clarke, Jean Francois Dartigues, Kendra Davis-Plourde, Stéphanie Debette, Emanuele Di Angelantonio, Catherine Feart, Ruth Frikke-Schmidt, John Gregson, Mary N. Haan, Linda B. Hassing, Kathleen M. Hayden, Marieke P. Hoevenaar-Blom, Jaakko Kaprio, Mika Kivimaki, Georgios Lappas, Eric B. Larson, Erin S. LeBlanc, Anne Lee, Li Yung Lui, Eric P. Moll van Charante, Toshiharu Ninomiya, Liv Tybjærg Nordestgaard, Tomoyuki Ohara, Toshiaki Ohkuma, Teemu Palviainen, Karine Peres, Ruth Peters, Nawab Qizilbash, Edo Richard, Annika Rosengren, Sudha Seshadri, Martin Shipley, Archana Singh-Manoux, Bjorn Heine Strand, Willem A. van Gool, Eero Vuoksimaa, Kristine Yaffe, Rachel R. Huxley, Association of anthropometry and weight change with risk of dementia and its major subtypes
A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia, Obesity Reviews, 10.1111/obr.12989, 21, 4, 2020.04, 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..
62. Sanmei Chen, Takanori Honda, Tomoyuki Ohara, Jun Hata, Yoichiro Hirakawa, Daigo Yoshida, Mao Shibata, Satoko Sakata, Emi Oishi, Yoshihiko Furuta, Takanari Kitazono, Toshiharu Ninomiya, Serum homocysteine and risk of dementia in Japan, Journal of Neurology, Neurosurgery and Psychiatry, 10.1136/jnnp-2019-322366, 91, 5, 540-546, 2020.05, 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..
63. Daigo Yoshida, Tomoyuki Ohara, Jun Hata, Mao Shibata, Yoichiro Hirakawa, Takanori Honda, Kazuhiro Uchida, Satoshi Takasugi, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Dairy consumption and risk of functional disability in an elderly Japanese population
The Hisayama Study, American Journal of Clinical Nutrition, 10.1093/ajcn/nqz040, 109, 6, 1664-1671, 2019.06, 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..
64. Tomoyuki Ohara, Toshiharu Ninomiya, Reply to “Long sleep duration
An epiphenomenon or a risk for dementia?”, Journal of the American Geriatrics Society, 10.1111/jgs.15558, 66, 11, 2225-2226, 2018.11.
65. Tomoyuki Ohara, Takanori Honda, Jun Hata, Daigo Yoshida, Naoko Mukai, Yoichiro Hirakawa, Mao Shibata, Hiro Kishimoto, Takanari Kitazono, Shigenobu Kanba, Toshiharu Ninomiya, Association Between Daily Sleep Duration and Risk of Dementia and Mortality in a Japanese Community, Journal of the American Geriatrics Society, 10.1111/jgs.15446, 66, 10, 1911-1918, 2018.10, Objectives: To investigate the association between daily sleep duration and risk of dementia and death in a Japanese elderly population. Design: Prospective cohort study. Setting: The Hisayama Study, Japan. Participants: Community-dwelling Japanese individuals aged 60 and older without dementia. Measurements: Self-reported daily sleep duration was grouped into 5 categories (<5.0, 5.0–6.9, 7.0–7.9, 8.0–9.9, ≥10.0 hours). The association between daily sleep duration and risk of dementia and death was determined using a Cox proportional hazards models. Results: During follow-up, 294 participants developed dementia, and 282 died. Age- and sex-adjusted incidence rates of dementia and all-cause mortality were significantly greater in subjects with daily sleep duration of less than 5.0 hours and 10.0 hours and more than in those with daily sleep duration of 5.0 to 6.9 hours. These associations remained unchanged after adjustment for potential confounding factors (<5.0 hours: hazard ratio (HR)=2.64, 95% confidence interval (CI)=1.38–5.05 for dementia; HR=2.29, 95% CI=1.15–4.56 for death; ≥10.0 hours: HR=2.23, 95% CI=1.42–3.49 for dementia; HR=1.67, 95% CI=1.07–2.60 for death). Similar U-shaped associations were observed for Alzheimer's disease and vascular dementia. With regard to the influence of hypnotic use on risk of dementia and death, subjects who used hypnotics and had any sleep duration had a risk of dementia that was 1.66 times as great and a risk of death that was 1.83 times as great as those who did not use hypnotics and had a daily sleep duration of 5.0 to 6.9 hours. Conclusion: Short and long daily sleep duration and hypnotic use are risk factors for dementia and death in Japanese elderly adults..
66. Tomoyuki Ohara, Jun Hata, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Toru Iwaki, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Toshiharu Ninomiya, Trends in dementia prevalence, incidence, and survival rate in a Japanese community, Neurology, 10.1212/WNL.0000000000003932, 88, 20, 1925-1932, 2017.05, 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..
67. Tomoyuki Ohara, Toshiharu Ninomiya, Author response
Trends in dementia prevalence, incidence, and survival rate in a Japanese community, Neurology, 10.1212/WNL.0000000000004590, 89, 18, 1930-1931, 2017.10.
68. Tomohiro Yubi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Yoichiro Hirakawa, Daigo Yoshida, Seiji Gotoh, Naoki Hirabayashi, Yoshihiko Furuta, Tetsuro Ago, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Prevalence of and risk factors for cerebral microbleeds in a general Japanese elderly community, Neurology: Clinical Practice, 10.1212/CPJ.0000000000000464, 8, 3, 223-231, 2018.06, 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..
69. Kiyoshi Sanada, Randi Chen, Bradley Willcox, Tomoyuki Ohara, Aida Wen, Cody Takenaka, Kamal Masaki, Association of sarcopenic obesity predicted by anthropometric measurements and 24-y all-cause mortality in elderly men
The Kuakini Honolulu Heart Program, Nutrition, 10.1016/j.nut.2017.09.003, 46, 97-102, 2018.02, 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..
70. Yumi Yamaguchi-Kabata, Takashi Morihara, Tomoyuki Ohara, Toshiharu Ninomiya, Atsushi Takahashi, Hiroyasu Akatsu, Yoshio Hashizume, Noriyuki Hayashi, Daichi Shigemizu, Keith A. Boroevich, Manabu Ikeda, Michiaki Kubo, Masatoshi Takeda, Tatsuhiko Tsunoda, 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, Human Genetics, 10.1007/s00439-018-1906-z, 137, 6-7, 521-533, 2018.07, 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..
71. Mao Shibata, Tomoyuki Ohara, Daigo Yoshida, Jun Hata, Naoko Mukai, Hiroyuki Kawano, Shigenobu Kanba, Takanari Kitazono, Toshiharu Ninomiya, Association between the ratio of serum arachidonic acid to eicosapentaenoic acid and the presence of depressive symptoms in a general Japanese population
the Hisayama Study, Journal of Affective Disorders, 10.1016/j.jad.2018.05.004, 237, 73-79, 2018.09, 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..
72. Phillip J. Tully, Deborah A. Turnbull, Kaarin J. Anstey, Nigel Beckett, Alexa S. Beiser, Jonathan Birns, Adam M. Brickman, Nicholas R. Burns, Suzanne Cosh, Peter W. De Leeuw, Diana Dorstyn, Merrill F. Elias, J. Wouter Jukema, Kazuomi Kario, Masahiro Kikuya, Abraham A. Kroon, Lenore J. Launer, Rajiv Mahajan, Emer R. McGrath, Simon P. Mooijaart, Eric P. Moll Van Charante, Michiaki Nagai, Toshiharu Ninomiya, Tomoyuki Ohara, Takayoshi Ohkubo, Emi Oishi, Ruth Peters, Edo Richard, Michihiro Satoh, Sudha Seshadri, David J. Stott, Willem A. Van Gool, Tessa Van Middelaar, Stella Trompet, Kristy Giles, Phoebe Drioli-Phillips, Umama Aaimir, Frank Connolly, Christophe Tzourio, The association between blood pressure variability (BPV) with dementia and cognitive function
A systematic review and meta-analysis protocol 11 Medical and Health Sciences 1117 Public Health and Health Services, Systematic Reviews, 10.1186/s13643-018-0811-9, 7, 1, 2018.10, 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..
73. Akihiro Tanaka, Jun Hata, Naoki Akamatsu, Naoko Mukai, Yoichiro Hirakawa, Daigo Yoshida, Hiro Kishimoto, Tomoyuki Ohara, Toshiki Mizuno, Sadatoshi Tsuji, Takanari Kitazono, Toshiharu Ninomiya, Prevalence of adult epilepsy in a general Japanese population
The Hisayama study, Epilepsia Open, 10.1002/epi4.12295, 4, 1, 182-186, 2019.03, 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..
74. Takanori Honda, Hiro Kishimoto, Naoko Mukai, Jun Hata, Daigo Yoshida, Yoichiro Hirakawa, Mao Shibata, Tomoyuki Ohara, Shuzo Kumagai, Toshiharu Ninomiya, Objectively measured sedentary time and diabetes mellitus in a general Japanese population
The Hisayama Study, Journal of Diabetes Investigation, 10.1111/jdi.12968, 10, 3, 809-816, 2019.05, 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..
75. Tomoyuki Ohara, Y. Doi, Toshiharu Ninomiya, Yoichiro Hirakawa, Jun Hata, Toru Iwaki, Shigenobu Kanba, Y. Kiyohara, Glucose tolerance status and risk of dementia in the community
The Hisayama Study, Neurology, 10.1212/WNL.0b013e31822f0435, 77, 12, 1126-1134, 2011.09, 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..
76. Tomoyuki Ohara, Akira Monji, Toshiaki Onitsuka, Toshihiko Maekawa, Yoji Hirano, Shogo Hirano, Sadayuki Hashioka, Takahiro Kato, Ichiro Yoshida, Shigenobu Kanba, Interictal psychosis after stroke with forced normalization [6], Journal of Neuropsychiatry and Clinical Neurosciences, 10.1176/appi.neuropsych.18.4.557, 18, 4, 557-559, 2006.09.
77. Tomoyuki Ohara, Toshiharu Ninomiya, Michiaki Kubo, Yoichiro Hirakawa, Yasufumi Doi, Jun Hata, Toru Iwaki, Shigenobu Kanba, Yutaka Kiyohara, Apolipoprotein genotype for prediction of Alzheimer's disease in older Japanese
The hisayama study, Journal of the American Geriatrics Society, 10.1111/j.1532-5415.2011.03405.x, 59, 6, 1074-1079, 2011.06, 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..
78. Tomoyuki Ohara, Toshiharu Ninomiya, Yoichiro Hirakawa, Kyota Ashikawa, Akira Monji, Yutaka Kiyohara, Shigenobu Kanba, Michiaki Kubo, Association study of susceptibility genes for late-onset Alzheimer's disease in the Japanese population, Psychiatric Genetics, 10.1097/YPG.0b013e3283586215, 22, 6, 290-293, 2012.12, 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..
79. Yu Tzu Wu, Alexa S. Beiser, Monique M.B. Breteler, Laura Fratiglioni, Catherine Helmer, Hugh C. Hendrie, Hiroyuki Honda, M. Arfan Ikram, Kenneth M. Langa, Antonio Lobo, Fiona E. Matthews, Tomoyuki Ohara, Karine Pérès, Chengxuan Qiu, Sudha Seshadri, Britt Marie Sjölund, Ingmar Skoog, Carol Brayne, The changing prevalence and incidence of dementia over time-current evidence, Nature Reviews Neurology, 10.1038/nrneurol.2017.63, 13, 6, 327-339, 2017.06, Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population..
80. Tomoyuki Ohara, Toshiharu Ninomiya, Jun Hata, Mio Ozawa, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Toru Iwaki, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Midlife and late-life smoking and risk of dementia in the community
The Hisayama study, Journal of the American Geriatrics Society, 10.1111/jgs.13794, 63, 11, 2332-2339, 2015.11, 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..
81. Emi Oishi, Tomoyuki Ohara, Satoko Sakata, Masayo Fukuhara, Jun Hata, Daigo Yoshida, Mao Shibata, Toshio Ohtsubo, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Day-to-Day Blood Pressure Variability and Risk of Dementia in a General Japanese Elderly Population
The Hisayama Study, Circulation, 10.1161/CIRCULATIONAHA.116.025667, 136, 6, 516-525, 2017.08, 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% 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- A nd sex-adjusted 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% confidence interval=1.45-3.55, P<0.001 for all-cause dementia; hazard ratio=2.79, 95% confidence interval=1.04-7.51, P=0.03 for VaD; hazard ratio=2.22, 95% 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..
82. Fumie Ikeda, Kentaro Shikata, Jun Hata, Masayo Fukuhara, Yoichiro Hirakawa, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Daigo Yoshida, Koji Yonemoto, Motohiro Esaki, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Combination of helicobacter pylori antibody and serum pepsinogen as a good predictive tool of gastric cancer incidence
20-year prospective data from the hisayama study, Journal of epidemiology, 10.2188/jea.JE20150258, 26, 12, 629-636, 2016.01, 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..
83. Tomoyuki Ohara, Emi Oishi, Toshiharu Ninomiya, Day-to-day blood pressure variability and dementia, Oncotarget, 10.18632/oncotarget.22993, 8, 70, 114416-114417, 2017.01.
84. Toshiharu Ninomiya, Tomoyuki Ohara, Yoichiro Hirakawa, Daigo Yoshida, Yasufumi Doi, Jun Hata, Shigenobu Kanba, Toru Iwaki, Yutaka Kiyohara, Midlife and late-life blood pressure and dementia in japanese elderly
The hisayama study, Hypertension, 10.1161/HYPERTENSIONAHA.110.163055, 58, 1, 22-28, 2011.07, 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; Ptrend<0.001), whereas no such association was observed for Alzheimer disease (Ptrend=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..
85. Mio Ozawa, Toshiharu Ninomiya, Tomoyuki Ohara, Yoichiro Hirakawa, Yasufumi Doi, Jun Hata, Kazuhiro Uchida, Tomoko Shirota, Takanari Kitazono, Yutaka Kiyohara, Self-reported dietary intake of potassium, calcium, and magnesium and risk of dementia in the Japanese
The hisayama study, Journal of the American Geriatrics Society, 10.1111/j.1532-5415.2012.04061.x, 60, 8, 1515-1520, 2012.08, 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..
86. Shuichi Isomura, Akira Monji, Kensuke Sasaki, Shingo Baba, Toshiaki Onitsuka, Tomoyuki Ohara, Yoshito Mizoguchi, Takahiro Kato, Hideki Horikawa, Yoshihiro Seki, Shigenobu Kanba, FTD with catatonia-like signs that temporarily resolved with zolpidem, Neurology: Clinical Practice, 10.1212/CPJ.0b013e3182a1ba12, 3, 4, 354-357, 2013.08.
87. Mio Ozawa, Toshiharu Ninomiya, Tomoyuki Ohara, Yasufumi Doi, Kazuhiro Uchida, Tomoko Shirota, Koji Yonemoto, Takanari Kitazono, Yutaka Kiyohara, Dietary patterns and risk of dementia in an elderly Japanese population
The hisayama Study1-3, American Journal of Clinical Nutrition, 10.3945/ajcn.112.045575, 97, 5, 1076-1082, 2013.05, 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..
88. Atsuko Sekita, Hisatomi Arima, Toshiharu Ninomiya, Tomoyuki Ohara, Yasufumi Doi, Yoichiro Hirakawa, Masayo Fukuhara, Jun Hata, Koji Yonemoto, Yukiko Ga, Takanari Kitazono, Shigenobu Kanba, Yutaka Kiyohara, Elevated depressive symptoms in metabolic syndrome in a general population of Japanese men
A cross-sectional study, BMC Public Health, 10.1186/1471-2458-13-862, 13, 1, 2013.09, 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..
89. Hidetaka Arimura, Chiaki Tokunaga, Takashi Yoshiura, Tomoyuki Ohara, Yasuo Yamashita, Fukai Toyofuku, Automated measurement of cerebral cortical thickness based on fuzzy membership map derived from MR images for evaluation of Alzheimer's disease, 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2013 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2013, 10.1109/EMBC.2013.6611198, 7116-7119, 2013.10, 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..
90. Toshiharu Ninomiya, Masaharu Nagata, Jun Hata, Yoichiro Hirakawa, Mio Ozawa, Daigo Yoshida, Tomoyuki Ohara, Hiro Kishimoto, Naoko Mukai, Masayo Fukuhara, Takanari Kitazono, Yutaka Kiyohara, Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease
The Hisayama Study, Atherosclerosis, 10.1016/j.atherosclerosis.2013.09.023, 231, 2, 261-267, 2013.12, 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..
91. Akira Monji, Keisuke Motomura, Yoshito Mizoguchi, Tomoyuki Ohara, Shingo Baba, Takashi Yoshiura, Shigenobu Kanba, A case of late-onset bipolar disorder with severely abnormal behavior and neuroimaging observations very similar to those of frontotemporal dementia, Journal of Neuropsychiatry and Clinical Neurosciences, 10.1176/appi.neuropsych.13020031, 26, 1, 2014.
92. Mio Ozawa, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Response Letter, Journal of the American Geriatrics Society, 10.1111/jgs.13163, 62, 12, 2467-2468, 2014.01.
93. Mio Ozawa, Tomoyuki Ohara, Toshiharu Ninomiya, Jun Hata, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Kazuhiro Uchida, Tomoko Shirota, Takanari Kitazono, Yutaka Kiyohara, Milk and dairy consumption and risk of dementia in an elderly Japanese population
The hisayama study, Journal of the American Geriatrics Society, 10.1111/jgs.12887, 62, 7, 1224-1230, 2014.01, 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..
94. Toshiharu Ninomiya, Masaharu Nagata, Jun Hata, Yoichiro Hirakawa, Mio Ozawa, Daigo Yoshida, Tomoyuki Ohara, Hiro Kishimoto, Naoko Mukai, Masayo Fukuhara, Takanari Kitazono, Yutaka Kiyohara, Corrigendum to "Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease
The Hisayama Study" [Atherosclerosis 231 (2) (2013) 261-267], Atherosclerosis, 10.1016/j.atherosclerosis.2014.03.033, 234, 2, 344-345, 2014.01.
95. Hiro Kishimoto, Tomoyuki Ohara, Jun Hata, Toshiharu Ninomiya, Daigo Yoshida, Naoko Mukai, Masaharu Nagata, Fumie Ikeda, Masayo Fukuhara, Shuzo Kumagai, Shigenobu Kanba, Takanari Kitazono, Yutaka Kiyohara, The long-term association between physical activity and risk of dementia in the community
the Hisayama Study, European Journal of Epidemiology, 10.1007/s10654-016-0125-y, 31, 3, 267-274, 2016.03, 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..
96. Saion Chatterjee, Sanne A.E. Peters, Mark Woodward, Silvia Mejia Arango, G. David Batty, Nigel Beckett, Alexa Beiser, Amy R. Borenstein, Paul K. Crane, Mary Haan, Linda B. Hassing, Kathleen M. Hayden, Yutaka Kiyohara, Eric B. Larson, Chung Yi Li, Toshiharu Ninomiya, Tomoyuki Ohara, Ruth Peters, Tom C. Russ, Sudha Seshadri, Bjørn H. Strand, Rod Walker, Weili Xu, Rachel R. Huxley, Type 2diabetes as a risk factor for dementia in women compared with men
A pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia, Diabetes Care, 10.2337/dc15-1588, 39, 2, 300-307, 2016.02, 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..
97. Fumie Ikeda, Kentaro Shikata, Jun Hata, Masayo Fukuhara, Yoichiro Hirakawa, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Daigo Yoshida, Koji Yonemoto, Motohiro Esaki, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Combination of helicobacter pylori antibody and serum pepsinogen as a good predictive tool of gastric cancer incidence
20-year prospective data from the hisayama study, Journal of Epidemiology, 10.2188/jea. JE20150258, 26, 12, 629-636, 2016.01, 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..
98. Atsushi Hirano, Tomoyuki Ohara, Atsushi Takahashi, Masayuki Aoki, Yuta Fuyuno, Kyota Ashikawa, Takashi Morihara, Masatoshi Takeda, Kouzin Kamino, Etsuko Oshima, Yuko Okahisa, Nobuto Shibata, Heii Arai, Hiroyasu Akatsu, Masashi Ikeda, Nakao Iwata, Toshiharu Ninomiya, Akira Monji, Takanari Kitazono, Yutaka Kiyohara, Michiaki Kubo, Shigenobu Kanba, A genome-wide association study of late-onset Alzheimer's disease in a Japanese population, Psychiatric Genetics, 10.1097/YPG.0000000000000090, 25, 4, 139-146, 2015.08, 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..
99. Masaaki Hokama, Sugako Oka, Julio Leon, Toshiharu Ninomiya, Hiroyuki Honda, Kensuke Sasaki, Toru Iwaki, Tomoyuki Ohara, Tomio Sasaki, Frank M. LaFerla, Yutaka Kiyohara, Yusaku Nakabeppu, Altered expression of diabetes-related genes in Alzheimer's disease brains
The Hisayama study, Cerebral Cortex, 10.1093/cercor/bht101, 24, 9, 2476-2488, 2014.01, 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..
100. Hiroyuki Honda, Kensuke Sasaki, Hideomi Hamasaki, Masahiro Shijo, Sachiko Koyama, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Satoshi Suzuki, Toru Iwaki, Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study, Neuropathology, 10.1111/neup.12298, 36, 4, 383-387, 2016.08, 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..
101. Jun Hata, Naoko Mukai, Masaharu Nagata, Tomoyuki Ohara, Daigo Yoshida, Hiro Kishimoto, Mao Shibata, Yoichiro Hirakawa, Motoyoshi Endo, Tetsuro Ago, Takanari Kitazono, Yuichi Oike, Yutaka Kiyohara, Toshiharu Ninomiya, Serum Angiopoietin-Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community, Arteriosclerosis, Thrombosis, and Vascular Biology, 10.1161/ATVBAHA.116.307291, 36, 8, 1686-1691, 2016.08, 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..
102. Naoki Hirabayashi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Mao Shibata, Seiji Gotoh, Yoshihiko Furuta, Fumio Yamashita, Kazufumi Yoshihara, Takanari Kitazono, Nobuyuki Sudo, Yutaka Kiyohara, Toshiharu Ninomiya, Association between diabetes and hippocampal atrophy in Elderly Japanese
The Hisayama study, Diabetes Care, 10.2337/dc15-2800, 39, 9, 1543-1549, 2016.09, 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..
103. Masaharu Nagata, Jun Hata, Yoichiro Hirakawa, Naoko Mukai, Daigo Yoshida, Tomoyuki Ohara, Hiro Kishimoto, Hiroyuki Kawano, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, The ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cancer death in a Japanese community
The Hisayama Study, Journal of Epidemiology, 10.1016/j.je.2017.01.004, 27, 12, 578-583, 2017.01, 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..
104. Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Sachiko Koyama, Satoshi Suzuki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Toru Iwaki, Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population
The Hisayama Study, Journal of Alzheimer's Disease, 10.3233/JAD-160521, 55, 2, 613-624, 2017.01, 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..
105. Kaoru Umehara, Naoko Mukai, Jun Hata, Yoichiro Hirakawa, Tomoyuki Ohara, Daigo Yoshida, Hiro Kishimoto, Takanari Kitazono, Sumio Hoka, Yutaka Kiyohara, Toshiharu Ninomiya, Association between serum vitamin D and All-Cause and Cause-Specific death in a general Japanese population ― the hisayama study ―, Circulation Journal, 10.1253/circj.CJ-16-0954, 81, 9, 1315-1321, 2017.01, 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..
106. Kenji Takeuchi, Tomoyuki Ohara, Michiko Furuta, Toru Takeshita, Yukie Shibata, Jun Hata, Daigo Yoshida, Yoshihisa Yamashita, Toshiharu Ninomiya, Tooth Loss and Risk of Dementia in the Community
the Hisayama Study, Journal of the American Geriatrics Society, 10.1111/jgs.14791, 65, 5, e95-e100, 2017.05, 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..
107. Mio Ozawa, Daigo Yoshida, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Mao Shibata, Kazuhiro Uchida, Masashi Nagata, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Dietary Protein Intake and Stroke Risk in a General Japanese Population
The Hisayama Study, Stroke, 10.1161/STROKEAHA.116.016059, 48, 6, 1478-1486, 2017.06, 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..
108. Naoko Mukai, Tomoyuki Ohara, Jun Hata, Yoichiro Hirakawa, Daigo Yoshida, Hiro Kishimoto, Masafumi Koga, Udai Nakamura, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Alternative measures of hyperglycemia and risk of Alzheimer's disease in the community
The hisayama study, Journal of Clinical Endocrinology and Metabolism, 10.1210/jc.2017-00439, 102, 8, 3002-3010, 2017.08, Context and Objective: We investigated the associations of hemoglobin A1c (HbA1c), glycated albumin (GA), GA/HbA1c 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/HbA1c ratio, and a similar tendency was seen for GA, whereas no such association was observed for HbA1c and 1,5-AG. After adjusting for potential confounding factors, positive association of GA/HbA1c 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/HbA1c ratio had a higher risk of AD than those with low GA/HbA1c 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 HbA1c, GA, and 1,5-AG, regardless of glucose tolerance status. Conclusions: Our findings suggest that elevated GA/HbA1c ratio-but not HbA1c, GA, or 1,5-AG level-is significantly associated with the risk of AD in subjects both with and without glucose intolerance. GA/HbA1c ratio may be a useful biomarker for predicting incident AD..
109. Erika Castillo, Julio Leon, Guianfranco Mazzei, Nona Abolhassani, Naoki Haruyama, Takashi Saito, Takaomi Saido, Masaaki Hokama, Toru Iwaki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Sakumi Kunihiko, Frank M. Laferla, Yusaku Nakabeppu, Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation, Scientific Reports, 10.1038/s41598-017-17999-3, 7, 1, 2017.12, 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..
110. Keita Takae, Jun Hata, Tomoyuki Ohara, Daigo Yoshida, Mao Shibata, Naoko Mukai, Yoichiro Hirakawa, Hiro Kishimoto, Kazuhiko Tsuruya, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Albuminuria increases the risks for both Alzheimer disease and vascular dementia in community-dwelling Japanese elderly
The hisayama study, Journal of the American Heart Association, 10.1161/JAHA.117.006693, 7, 2, 2018.01, 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..
111. Masahiro Iida, Fumie Ikeda, Jun Hata, Yoichiro Hirakawa, Tomoyuki Ohara, Naoko Mukai, Daigo Yoshida, Koji Yonemoto, Motohiro Esaki, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Development and validation of a risk assessment tool for gastric cancer in a general Japanese population, Gastric Cancer, 10.1007/s10120-017-0768-8, 21, 3, 383-390, 2018.05, 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..