||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..
||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..
||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..
||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..
||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..
||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..
||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..
||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..
||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..
||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..