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Secular trends in the risk of recurrent stroke have been reported in several epidemiological studies worldwide, but this issue has not been investigated in general Japanese populations. We examined the trends in the 5-year risk of recurrent stroke over a half century using community-based prospective data in Japan.We established 4 cohort studies in 1961, 1974, 1988, and 2002. To examine the risk of recurrent stroke, participants who developed stroke during a 10-year follow-up period in each cohort were followed-up for 5 years from the date of first onset. A total of 154 (first sub-cohort: 1961-1971), 144 (second sub-cohort: 1974-1984), 172 (third sub-cohort: 1988-1998), and 146 (fourth sub-cohort: 2002-2012) participants from each cohort were enrolled in the present study. The 5-year cumulative risk of recurrent stroke was compared among the sub-cohorts using the Kaplan-Meier method and the age- and sex-adjusted Cox proportional hazards model.The risks of recurrent stroke after any stroke and ischemic stroke decreased significantly from the first to the third sub-cohort, but they did not clearly change from the third to the fourth sub-cohort. The risk of recurrent stroke after hemorrhagic stroke decreased mainly from the first to the second sub-cohort and there was no apparent decrease from the second to the fourth sub-cohort. These trends were substantially unchanged after adjusting for age and sex.In the Japanese community, the risk of recurrent stroke decreased mainly from the 1960s to 1990s, but there was no apparent decrease in recent years.

Aim To develop and validate a new risk prediction model for predicting the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in Japanese adults. Methods A total of 2,454 participants aged 40-84 years without a history of cardiovascular disease (CVD) were prospectively followed up for 24 years. An incident ASCVD event was defined as the first occurrence of coronary heart disease or atherothrombotic brain infarction. A Cox proportional hazards regression model was used to construct the prediction model. In addition, a simplified scoring system was translated from the developed prediction model. The model performance was evaluated using Harrell's C statistics, a calibration plot with the Greenwood-Nam-D'Agostino test, and a bootstrap validation procedure. Results During a median of a 24-year follow-up, 270 participants experienced the first ASCVD event. The predictors of the ASCVD events in the multivariable Cox model included age, sex, systolic blood pressure, diabetes, serum high-density lipoprotein cholesterol, serum low-density lipoprotein cholesterol, proteinuria, smoking habits, and regular exercise. The developed models exhibited good discrimination with negligible evidence of overfitting (Harrell's C statistics: 0.786 for the multivariable model and 0.789 for the simplified score) and good calibrations (the Greenwood-Nam-D'Agostino test: P=0.29 for the multivariable model, 0.52 for the simplified score). Conclusion We constructed a risk prediction model for the development of ASCVD in Japanese adults. This prediction model exhibits great potential as a tool for predicting the risk of ASCVD in clinical practice by enabling the identification of specific risk factors for ASCVD in individual patients.

To evaluate the longitudinal association between yogurt product intake and oral health in a population-based study.This study included 1967 Japanese residents aged 40-79 years who underwent dental examinations in 2012. Among them, 1469 participants were followed up in 2017 for the incidence of tooth loss, which was defined as two or more teeth lost over 5 years. The intake of yogurt products, defined as yogurt and lactic acid beverages, was estimated using a semi-quantitative food frequency questionnaire. The composition of the salivary microbiota was evaluated.The Poisson regression model showed that a higher intake of yogurt products was negatively associated with the incidence of tooth loss (p for trend = .020), adjusted for potential confounding factors. Mediation analysis confirmed that periodontal condition partly mediated the effect of yogurt product intake on tooth loss, while dental caries experience did not. Additionally, we confirmed the association of a high intake of yogurt products with a low percentage of the salivary microbiota pattern, which was associated with poor oral health.These findings suggest that the intake of yogurt products is associated with a lower risk of tooth loss resulting from periodontal disease, probably via modulation of the oral microbiome composition.

Context Serum Mac-2 binding protein glycosylation isomer (M2BPGi) concentrations are known to be an indicator of chronic liver injury and fibrosis. Objective This study aimed to investigate the association between serum M2BPGi concentrations and the development of type 2 diabetes in a Japanese community. Methods A total of 2143 community-dwelling Japanese individuals aged 40-79 years without diabetes at baseline were followed up for 7 years. Serum M2BPGi concentrations were divided into quintiles: Q1, ≤0.37 cutoff index (COI); Q2, 0.38-0.49 COI; Q3, 0.50-0.62 COI; Q4, 0.62-0.80 COI; and Q5, ≥0.81 COI. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs for the development of type 2 diabetes. Results During the follow-up period, 219 individuals developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes significantly increased with elevating serum M2BPGi levels (P for trend < .01). This association remained significant after adjustment for potential confounders (P for trend = .04). This significant association attenuated to a nonsignificant level after additionally adjusting for serum high-sensitivity C-reactive protein or homeostasis model assessment of insulin resistance. Conclusion The present study demonstrated that higher serum M2BPGi concentrations were significantly associated with higher risk of diabetes in a Japanese community. Moreover, inflammation and insulin resistance were suggested to contribute to the excess risk of diabetes in individuals with higher serum M2BPGi levels. These findings shed light on the importance of inflammation and insulin resistance when considering the pathogenesis of diabetes.

natriuretic peptide is associated with myocardial fibrosis in animal models and among patients with heart disease. However, it remains unclear whether serum N-terminal pro-B-type peptide (NT-proBNP) levels are associated with histopathologically proven myocardial fibrosis among individuals without apparent heart disease. This study aimed to evaluate the association between serum NT-proBNP levels and the histopathologically estimated myocardial fibrotic area in autopsied samples from a community.we selected 63 cases without apparent heart disease with available data of serum NT-proBNP concentrations within six years before death (average age: 82 years; male: 52%) from autopsied cases in a community, and evaluated the percentage areas of myocardial fibrosis in four cardiac segments from each case (i.e. 252 cardiac segments in total). The association between serum NT-proBNP levels and the percentage area of myocardial fibrosis was estimated using a linear mixed model for repeated measures.serum NT-proBNP levels were positively correlated with myocardial fibrotic area [Pearson's correlation coefficient: r = 0.49 (95% confidence interval: 0.28-0.66), p 0.001]. Serum NT-proBNP levels were significantly associated with the percentage areas of myocardial fibrosis after adjusting for potential confounding factors. There was no evidence of heterogeneity in the association between the subgroups with and without reduced estimated glomerular filtration rate (60 mL/min/1.73 mthe present study demonstrated that elevated serum NT-proBNP levels were associated with the histopathologically measured myocardial fibrotic area in autopsied cases from a community. These findings may help clarify the association between elevated serum NT-proBNP levels and myocardial fibrosis and their influence on prognosis.

Circulating omega-3 and omega-6 polyunsaturated fatty acids may to contribute to cardiovascular health at the population level. Over a decade, we investigated changes in the serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio, and in serum concentrations of the individual fatty acids, in a Japanese community.Community surveys took place in 2002-2003 and 2012-2013 in a rural area of Japan. The community surveys included 3,194 and 3,220 community dwellers aged ≥ 40 years who did not take EPA medication in 2002-2003 and 2012-2013, respectively. Fatty acid fractionations in serum were measured using a gas chromatography method. Changes in the serum EPA/AA ratio over time were examined using linear mixed models.Overall, the average serum EPA/AA ratio decreased over the 10 years. A decreasing trend in the serum EPA/AA ratio occurred in all age groups except participants aged ≥ 80 years, with larger decreases in the younger age groups. A similar decline in serum EPA/AA ratio occurred in participants with and those without lipid-lowering therapy. Serum EPA concentrations were slightly increased in the whole population but remained stable or even decreased in participants aged 40-69. In contrast, the average serum AA concentrations increased in all age groups.In a Japanese community, the serum EPA/AA ratio decreased over 10 years at the population level, especially in middle-aged participants.

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia in the elderly, and causes complications such as cardioembolic stroke. Serum high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, has been reported to be a risk factor for developing AF in Western countries. However, few community-based studies have examined this issue in general Asian populations.Methods and Results:A total of 2,510 community-dwelling Japanese participants aged ≥40 years without a history of AF were divided into 4 groups according to the sex-specific quartiles of serum hs-CRP concentrations (Q1, lowest and Q4, highest) and followed up for 24 years. The hazard ratios and their 95% confidence intervals for the development of AF were estimated using a Cox proportional hazards model. During the follow up, 234 subjects developed AF. The risk of AF increased significantly with elevating serum hs-CRP levels after adjustment for potential confounding factors (hazard ratio [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.26 [0.83-1.92]; Q3, 1.77 [1.18-2.66]; and Q4, 1.89 [1.24-2.86]; P for trend

Introduction Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels have been associated with the progression of kidney impairment among patients with chronic kidney disease (CKD), but only a few studies have investigated the association between serum NT-proBNP levels and incident CKD in general populations. Methods A total of 2486 Japanese community-dwelling residents ≥40 years of age without CKD at baseline were followed up by repeated annual health examinations for 10 years. Participants were divided into 4 groups according to serum NT-proBNP levels. CKD was defined as an estimated glomerular filtration rate (eGFR), Graphical abstract

Aim The present study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in subjects at high cardiovascular risk. Methods A total of 3,080 participants without prior cardiovascular disease (CVD), aged ≥ 40 years, were followed up for a median of 8.3 years, which were divided into two groups, those with serum sdLDL cholesterol levels of ＜35 mg/dL or ≥ 35 mg/dL. Then, subjects were stratified by the status of diabetes, CVD-related comorbidities (defined as the presence of diabetes, chronic kidney disease, or peripheral artery disease), and the CVD risk assessment according to the Japan Atherosclerosis Society Guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using a Cox proportional hazards model. Results During the follow-up, 79 subjects developed CHD. The risk for incident CHD was higher in subjects with serum sdLDL cholesterol of ≥ 35 mg/dL than those with sdLDL cholesterol of ＜35 mg/dL (HR 2.09, 95%CI 1.26-3.45) after adjusting for traditional risk factors. In the subgroup analyses, the multivariable-adjusted HR for incident CHD increased significantly in those with serum sdLDL cholesterol of ≥ 35 mg/dL among subjects with diabetes (HR 2.76, 95%CI 1.09-7.01), subjects with CVD-related comorbidities (HR 2.60, 95%CI 1.21-5.58), and high-risk category defined as the presence of CVD-related comorbidities or a Suita score of ≥ 56 points (HR 1.93, 95%CI 1.02-3.65). Conclusions Elevated serum sdLDL cholesterol was associated with the development of CHD even in subjects at high cardiovascular risk.

The purpose of the present study was to investigate the effects of serum triglyceride levels on the risk of new-onset hypertension in Japanese.Five thousand nine hundred and thirty-three Japanese workers without hypertension at baseline, who participated in medical check-ups from 2006 to 2018, were followed retrospectively. The participants were divided into quartiles of casual serum triglyceride levels and were followed from the first to last visit of the study period. The outcome was development of hypertension. Risk estimates were computed using Cox's proportional hazards model.During the follow-up period (average: 6.7 years), 946 individuals developed hypertension. The crude incidence rates of hypertension (per 1000 person-years) increased with rising serum triglyceride levels: 10.1 for quartile 1 (0.76 mmol/l), 19.6 for quartile 2 (0.76-1.17 mmol/l), 26.0 for quartile 3 (1.18-1.84 mmol/l), and 36.5 for quartile 4 (1.84 mmol/l) (P 0.0001 for trend). These associations remained significant even after adjustment for other risk factors: the multivariable-adjusted hazard ratio was 1.29 (1.01-1.66) for the second quartile, 1.27 (0.99-1.63) for the third quartile, and 1.39 (1.09-1.77) for the highest quartile compared with the lowest. There were comparable effects of serum triglyceride levels for incidence of hypertension between subgroups defined by sex, obesity, and diabetes (all P 0.1 for interaction), whereas stronger associations were observed for participants under 40 years of age than for those aged 40 or above (P = 0.002 for interaction).Serum triglyceride levels were significantly associated with development of hypertension in a Japanese worksite population.

We aimed to investigate the association of serum glycated albumin (GA) levels with the risk of cardiovascular disease (CVD) and its subtypes, including coronary heart disease (CHD) and stroke, in a general Japanese population.A total of 2965 Japanese community-dwellers aged ≥40 years were followed prospectively for a median of 10.2 years (2002-2012). Serum GA was measured by the enzymatic method and divided into quartiles. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of serum GA levels on CVD risk.During the follow-up, 213 subjects developed CVD; 95 had CHD, and 133 had stroke. The cumulative incidence of CVD, CHD, and stroke increased significantly with increasing serum GA levels (all p for trend0.02). Compared with the lowest serum GA quartile (13.6%), the multivariable-adjusted HRs (95% CI) of the highest quartile (≥15.7%) were 2.33 (1.46-3.68) for CVD, 2.23 (1.11-4.50) for CHD, and 2.47 (1.38-4.40) for stroke. In addition, a subgroup analysis showed that CVD risk increased significantly with increasing levels of serum GA in both subjects with and without diabetes mellitus. The increasing trend of CVD risk for higher serum GA levels was also observed in subjects with low hemoglobin AOur findings suggest that higher serum GA levels are significantly associated with the development of CVD and its subtypes, even among subjects without diabetes or those with normal hemoglobin A

Aims/Introduction The investigation of the influence of dietary fiber intake on the incidence of type 2 diabetes in a general Japanese population. Materials and Methods A total of 1,892 individuals aged 40–79 years without diabetes at baseline were prospectively followed up for 14 years. The glucose tolerance status of participants was defined by a 75‐g oral glucose tolerance test with the 1998 World Health Organization criteria. Dietary fiber intake was estimated by a semiquantitative food frequency questionnaire and divided to quintile levels separately by sex. A Cox proportional hazards model was applied for computing the hazard ratios and their 95% confidence intervals for the incidence of diabetes. Results During the follow‐up period, 280 participants had developed diabetes. The age‐adjusted cumulative diabetes incidence decreased significantly with higher total dietary fiber intake (P‐for trend = 0.01). Participants in the highest quintile of total dietary fiber intake had a 0.53‐fold (95% confidence interval 0.31–0.90) lower risk of developing diabetes than those in the lowest quintile after for the adjustment with potential confounding factors. Total dietary fiber intake showed a moderate positive correlation to the intake of soybean and soybean products, green vegetables, and other vegetables. Similar associations with diabetes and food sources were observed for both of the soluble and insoluble dietary fiber intake. Conclusions The present study showed that higher dietary fiber intake was associated with a lower risk of type 2 diabetes in a general Japanese population. The intake of high dietary fiber foods might be useful for diabetes prevention., The present study found that higher dietary fiber intake was associated with a lower risk of type 2 diabetes in a general Japanese population. The intake of foods rich in dietary fiber might be beneficial for diabetes prevention.

Despite the clinical usefulness of self-measured home blood pressure (BP), reports on the characteristics of home BP have not been sufficient and have varied due to the measurement conditions in each study. We constructed a database on self-measured home BP, which included five Japanese general populations as subdivided aggregate data that were clustered and meta-analyzed according to sex, age category, and antihypertensive drug treatment at baseline (treated and untreated). The self-measured home BPs were collected after a few minutes of rest in a sitting position: (1) the morning home BP was measured within 1 h of waking, after urination, before breakfast, and before taking antihypertensive medication (if any); and (2) the evening home BP was measured just before going to bed. The pulse rate was simultaneously measured. Eligible data from 2000 onward were obtained. The morning BP was significantly higher in treated participants than in untreated people of the same age category, and the BP difference was more marked in women. Among untreated residents, home systolic/diastolic BPs measured in the morning were higher than those measured in the evening; the differences were 5.7/5.0 mmHg in women (ranges across the cohorts, 5.3-6.8/4.7-5.4 mmHg) and 7.3/7.7 mmHg in men (ranges, 6.4-8.5/7.0-8.7 mmHg). In contrast, the home pulse rate in women and men was 2.4 (range, 1.5-3.7) and 5.6 (range, 4.6-6.6) beats per minute, respectively, higher in the evening than in the morning. We demonstrated the current status of home BP and home pulse rate in relation to sex, age, and antihypertensive treatment status in the Japanese general population. The approach by which fine-clustered aggregate statistics were collected and integrated could address practical issues raised in epidemiological research settings.

Background Although many studies have been conducted on the relationship between masticatory performance and nutrient ingestion in the elderly, few large-scale studies have been carried out using relatively young individuals. Objectives The objective of this study was to clarify the association between the masticatory performance evaluated by the gummy-jelly test, not by visual examination, and nutrient ingestion state based on the brief self-administered diet history questionnaire (BDHQ). Methods This was a cross-sectional survey of 540 male workers. Somatometry, blood pressure measurement, blood test and medical interview were performed as a periodic health check-up. In the dental check-up, an oral examination, gummy-jelly test (glucosensor) and survey of ingested food and nutrients using BDHQ were performed. The participants were classified into two groups with low and normal values of masticatory performance. Participants with a score on the gummy-jelly test below 150 mg/dL or 150 mg/dL or higher were included in the low and normal groups, respectively. Results Two hundred and forty-eight participants (45.8%) had low masticatory performance, and 292 (53.2%) had normal masticatory performance. The intakes of some minerals and vitamins, such as calcium, vitamin D, vitamin B2 , small fish with bones and non-oily fish, were significantly lower in the low masticatory group than in the normal group. In contrast, the intake of sugar for coffee and tea and that of chicken were significantly higher in the low masticatory group than in the normal group. Conclusion This study suggested that low masticatory performance can affect nutrient intake, which may cause non-communicable diseases.

ObjectiveTo examine the association between serum total homocysteine levels (tHcy) and dementia risk.MethodsA 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.ResultsDuring 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).ConclusionHigh 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.

Studies on the association between serum uric acid levels and the risk of cardiovascular disease have yielded inconsistent results. We investigated the association of serum uric acid levels with cardiovascular disease mortality in a Japanese community. A total of 2633 community-dwelling Japanese people aged ≥40 years without a history of cardiovascular disease were followed up for 19 years. Serum uric acid levels were categorized into quintiles (Q1, lowest; Q5, highest). The hazard ratios for mortality from cardiovascular disease, stroke, and coronary heart disease were computed using a Cox proportional hazards model. During the follow-up, 235 subjects died from cardiovascular disease (including 84 from stroke and 53 from coronary heart disease). Risks for cardiovascular disease mortality were higher in both the Q1 and Q5 groups than in the Q3 group after adjustment for confounding factors (Q1, hazard ratio 1.50 [95% confidence interval 0.94-2.39]; Q2, 1.06 [0.66-1.72]; Q3, 1.00 [reference]; Q4, 1.44 [0.93-2.23]; and Q5, 1.89 [1.23-2.91]). A similar U-shaped association was observed for stroke mortality (Q1, 3.26 [1.29-8.25]; Q2, 2.21 [0.85-5.73]; Q3, 1.00 [reference]; Q4, 2.65 [1.07-6.58]; and Q5, 3.77 [1.54-9.24]), while coronary heart disease mortality was increased only in the Q5 group (Q1, 1.27 [0.46-3.50]; Q2, 0.85 [0.29-2.48]; Q3, 1.00 [reference]; Q4, 1.57 [0.63-3.92]; and Q5, 2.53 [1.03-6.18]). Elevated serum uric acid was suggested to be a significant risk factor for stroke or coronary heart disease mortality in a Japanese community. Conversely, the excess risk of stroke mortality in individuals with lower serum uric acid levels may indicate a possible cerebroprotective role of uric acid.

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

The association between chronic lipopolysaccharide exposure and the development of metabolic syndrome (MetS) is unclear. In this study we examined the association between serum lipopolysaccharide-binding protein (LBP) levels, an indicator of lipopolysaccharide exposure, and the development of MetS in a general Japanese population.1,869 community-dwelling Japanese individuals aged ≥40 years without MetS at baseline examination in 2002-2003 were followed up by repeated examination in 2007-2008. MetS was defined according to the Japanese criteria. Serum LBP levels were classified into quartiles (quartiles 1-4: 2.20-9.56, 9.57-10.78, 10.79-12.18, and 12.19-24.34 μg/mL, respectively). Odds ratios (ORs) for developing MetS were calculated using a logistic regression model.At the follow-up survey, 159 participants had developed MetS. Higher serum LBP levels were associated with greater risk of developing MetS after multivariable adjustment for age, sex, smoking, drinking, and exercise habits (OR [95% confidence interval] for quartiles 1-4: 1.00 [reference], 2.92 [1.59-5.37], 3.48 [1.91-6.35], and 3.86 [2.12-7.03], respectively; P for trend0.001). After additional adjustment for homeostasis model assessment of insulin resistance, this association was attenuated but remained significant (P for trend=0.007). On the other hand, no significant association was observed after additional adjustment for serum high-sensitivity C-reactive protein (P for trend=0.07).In the general Japanese population, our findings suggest that higher serum LBP levels are associated with elevated risk of developing MetS. Low-grade endotoxemia could play a role in the development of MetS through systemic chronic inflammation and insulin resistance.

Introduction: Information regarding the influence of serum uric acid (SUA) levels on pathological changes in the kidney is limited. In this study, we examined the association between SUA levels and pathological findings of nephrosclerosis in population-based autopsy samples. Methods: A total of 923 deceased individuals in a Japanese community underwent autopsy examinations between 1974 and 1994. Of these, 547 individuals with available kidney tissues and health examination data within a median of 3 years before death were eligible for the present study. SUA levels were categorized into quintiles (Q1, 107–237; Q2, 238–279; Q3, 280–326; Q4, 327–380; Q5, 381–755 μmol/L). Advanced degrees of glomerular sclerosis, kidney arteriolar hyalinosis, and kidney arteriosclerosis were defined as the 90th percentile or more of a glomerular sclerosis index and an arteriolar hyalinosis index, and the 10th percentile or less of a wall-lumen ratio, respectively. A logistic regression model was used to evaluate odds ratios (ORs) and their 95% confidence intervals (CIs) of SUA levels on each kidney lesion. Results: Higher SUA levels were significantly associated with higher values of the age- and sex-adjusted glomerular sclerosis index and lower values of the wall-lumen ratio (both p for trend Conclusions: Elevated SUA levels were significantly associated with advanced glomerular sclerosis and advanced kidney arteriosclerosis, but not with advanced arteriolar hyalinosis in community-based autopsy samples of Japanese.

Background Several prospective Western studies have reported an inverse association of vegetable and fruit intake with dementia risk. However, there is limited epidemiologic evidence in Asians. This study investigated the association of intakes of vegetables, fruits, and their nutrients on the risk of incident dementia and its subtypes in a Japanese community. Methods A total of 1071 participants (452 men and 619 women) aged ≥60 years without dementia at baseline were prospectively followed up for 24 years. Intakes of vegetables, fruits, and nutrients were evaluated using a 70-item semiquantitative food frequency questionnaire at baseline and were categorized into quartiles separately by gender. The outcome measure was the development of dementia and its subtypes—namely, Alzheimer’s disease (AD) and vascular dementia (VaD). The risk estimates of incident dementia were computed using a Cox proportional hazards model. Results During the long-term follow-up period, 464 subjects developed dementia, of whom 286 had AD and 144 had VaD. Higher vegetable intake was associated gradually with lower risk of developing dementia and AD (both P-trend P-trend P-trend = 0.07). Meanwhile, there were no significant associations between fruit intake and the risk of dementia and its subtypes. Conclusion Higher intakes of vegetables and their constituent nutrients were associated with a lower risk of dementia in Japanese older adults. A diet rich in vegetables may be beneficial in reducing the dementia risk in Asians.

Introduction We aimed to develop a risk prediction model for incident dementia using predictors that are available in primary‐care settings. Methods A total of 795 subjects aged 65 years or over were prospectively followed‐up from 1988 to 2012. A Cox proportional‐hazards regression was used to develop a multivariable prediction model. The developed model was translated into a simplified scoring system based on the beta‐coefficient. The discrimination of the model was assessed by Harrell's C statistic, and the calibration was assessed by a calibration plot. Results During the follow‐up period, 364 subjects developed dementia. In the multivariable model, age, female sex, low education, leanness, hypertension, diabetes, history of stroke, current smoking, and sedentariness were selected as predictors. The developed model and simplified score showed good discrimination and calibration. Discussion The developed risk prediction model is feasible and practically useful in primary‐care settings to identify individuals at high risk for future dementia.

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 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.

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.

OBJECTIVE This study investigated the association between serum ethylamine levels as an indicator of l-theanine consumption and the development of type 2 diabetes in a Japanese community. RESEARCH DESIGN AND METHODS A total of 2,253 community-dwelling Japanese individuals aged 40–79 years without diabetes were monitored for 7 years. Serum ethylamine levels were divided into quartiles: ≤0.86, 0.87–2.10, 2.11–5.28, and ≥5.29 ng/mL. Kinetic analysis of serum ethylamine concentrations was performed after ingestion of l-theanine–rich green tea products containing 8 mg of l-theanine by 12 healthy volunteers. RESULTS During follow-up, 282 subjects developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes decreased significantly with elevating levels of serum ethylamine (P for trend = 0.04). This association remained unchanged after adjusting for potential confounding factors. The multivariable-adjusted hazard ratio (HR) for type 2 diabetes was significantly lower in the fourth quartile of serum ethylamine than in the first quartile (HR 0.69, 95% CI 0.49–0.98). This trend of decrease in diabetic risk across serum ethylamine levels was more prominent in middle-aged subjects and in subjects with prediabetes, obesity, or insulin resistance. Kinetic analysis estimated that the minimum concentration at the steady state was >5.90 ng/mL in the case of twice-daily ingestion with an interval of 12 h. CONCLUSIONS Higher serum ethylamine was significantly associated with lower risk of the development of type 2 diabetes in a general Japanese population. The measurement of serum ethylamine concentration would be a useful biomarker for the objective estimation of l-theanine consumption.

Background and aims Predicting cardiovascular events is of practical benefit for disease prevention. The aim of this study was to develop and evaluate an updated risk prediction model for cardiovascular diseases and its subtypes. Methods A total of 2462 community residents aged 40–84 years were followed up for 24 years. A Cox proportional hazards regression model was used to develop risk prediction models for cardiovascular diseases, and separately for stroke and coronary heart diseases. The risk assessment ability of the developed model was evaluated, and a bootstrapping method was used for internal validation. The predicted risk was translated into a simplified scoring system. A decision curve analysis was used to evaluate clinical usefulness. Results The multivariable model for cardiovascular diseases included age, sex, systolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking habits, and regular exercise as predictors. The models for stroke and coronary heart diseases incorporated both shared and unique variables. The developed models showed good discrimination with little evidence of overfitting (optimism-corrected Harrell's C statistics 0.726–0.777) and calibrations (Hosmer-Lemeshow test, p = 0.44–0.90). The decision curve analysis revealed that the predicted risk-based decision-making would have higher net benefit than either a CVD intervention strategy for all individuals or no individuals. Conclusions The developed risk prediction models showed a good performance and satisfactory internal validity, which may help understand individual risk and setting personalized goals, and promote risk stratification in public health strategies for CVD prevention.

Background Epidemiological evidence has shown that serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, a diagnostic biomarker for heart failure, are positively associated with cardiovascular risk. Since NT-proBNP in serum is excreted in urine, it is hypothesized that urinary NT-proBNP concentrations are correlated with serum concentrations and linked with cardiovascular risk in the general population. Methods A total of 3060 community-dwelling residents aged ≥ 40 years without history of cardiovascular disease (CVD) were followed up for a median of 8.3 years (2007–2015). Serum and urinary concentrations of NT-proBNP at baseline were compared. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the association between NT-proBNP concentrations and the risk of developing CVD were computed using the Cox proportional hazards model. Results The median values (interquartile ranges) of serum and urinary NT-proBNP concentrations at baseline were 56 (32–104) pg/mL and 20 (18–25) pg/mL, respectively. There was a strong quadratic correlation between the serum and urinary concentrations of NT-proBNP (coefficient of determination [R2] = 0.72): urinary concentrations of 20, 27, and 43 pg/mL were equivalent to serum concentrations of 55, 125, and 300 pg/mL, respectively. During the follow-up period, 170 subjects developed CVD. The age- and sex-adjusted risk of CVD increased significantly with higher urinary NT-proBNP levels (P for trend < 0.001). This association remained significant after adjustment for traditional cardiovascular risk factors (P for trend = 0.009). The multivariable-adjusted risk of developing CVD almost doubled in subjects with urinary NT-proBNP of ≥ 43 pg/mL as compared to those with urinary NT-proBNP of ≤ 19 pg/mL (HR 2.07, 95% CI 1.20–3.56). Conclusions The present study demonstrated that urinary NT-proBNP concentrations were well-correlated with serum concentrations and were positively associated with cardiovascular risk. Given that urine sampling is noninvasive and does not require specially trained personnel, urinary NT-proBNP concentrations have the potential to be an easy and useful biomarker for detecting people at higher cardiovascular risk.

Background The risk prediction of incident atrial fibrillation (AF) is useful to prevent AF and its complications. The aim of this study is to develop a new risk prediction model for incident AF using the prospective longitudinal data from a general Japanese population.Methods and Results:A total of 2,442 community-dwelling AF-free residents aged ≥40 years were followed up from 1988 to 2012 (46,422 person-years). The development of AF was confirmed by a standard 12-lead electrocardiogram at repeated health examinations and by medical records at clinics or hospitals. The risk prediction model for incident AF was developed using a Cox proportional hazards model. During the follow up, 230 AF events were confirmed. Age, sex, systolic blood pressure, waist circumference, estimated glomerular filtration rate, abnormal cardiac murmur, high R-wave amplitude, and arrhythmia other than AF were selected for inclusion in the model. This model showed good discrimination (Harrell's c statistics: 0.785) and calibration (Greenwood-Nam-D'Agostino test: P=0.87) for AF risk at 10 years. Conclusions The new risk prediction model showed good performance on the individual risk assessment of the future onset of AF in a general Japanese population. As this model included commonly used clinical parameters, it may be useful for determining the requirements for the careful evaluation of AF, such as frequent electrocardiogram examinations in clinical settings, and subsequent reductions in the risk of AF-related complications.

Aim We investigated the influence of weight change on concurrent changes in predicted cardiovascular disease (CVD) risk and individual CVD risk factors over time. Methods A total of 2,140 community-dwellers aged 40-74 years participated in both 2002 and 2007 health examinations. Obesity was defined as body mass index ≥ 25 kg/m2. Weight trajectories were classified as: "stable obese" (obese at both examinations), "obese to nonobese" (obese in 2002 but nonobese in 2007), "nonobese to obese" (nonobese in 2002 but obese in 2007), or "stable nonobese" (nonobese at both examinations). We compared changes in the model-predicted risk for CVD and individual CVD risk factors across weight-change categories. Results The predicted risk for CVD increased during 5 years in all groups; the increment in the predicted risk for CVD was smallest in the obese to nonobese participants and steepest in the nonobese to obese subjects. Compared with the stable obese participants, the obese to nonobese participants had greater favorable changes in waist circumferences, blood pressure, fasting plasma glucose, serum high-density lipoprotein cholesterol, serum triglycerides, and liver enzymes. For all these parameters, opposite trends were observed when comparing the nonobese to obese participants with the stable nonobese group. Conclusions We demonstrated the favorable association of losing weight in obese people and avoiding excessive weight gain in nonobese people with global risk of future CVD and individual CVD risk factors in a real-world setting. The findings could improve behavioral lifestyle interventions that provide information on the health consequences of weight change at health checkups.

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

Few studies have examined the association between the accumulation of unhealthy eating habits and the likelihood of obesity or central obesity in a general Japanese population. We examined this association in a sample of 1906 community-dwelling Japanese subjects (age: 40&ndash, 74 years) who participated in a health check-up in 2014. A face-to-face questionnaire interview was conducted to collect information about three unhealthy eating habits, i.e., snacking, eating quickly, and eating late-evening meals. Obesity was defined as body mass index &ge, 25 kg/m2 and central obesity was defined as waist circumference &ge, 90 cm in men and &ge, 80 cm in women. The odds ratios (OR) were estimated by using a logistic regression analysis. Subjects with any one of the three eating habits had a significantly higher likelihood of obesity than those without that habit after adjusting for confounding factors. The multivariable-adjusted OR for obesity increased linearly with an increase in the number of accumulated unhealthy eating habits (p for trend &lt, 0.001). Similar associations were observed for central obesity. Our findings suggest that modifying each unhealthy eating habit and avoiding an accumulation of multiple unhealthy eating habits might be important to reduce the likelihood of obesity.

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