Jun Hata

Insulin resistance is associated with the pathology of Alzheimer disease The Hisayama Study

Objective: We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD. Methods: This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimers Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses. Results: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE ε4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR. Conclusion: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE ε4.

Glucose tolerance status and risk of dementia in the community The Hisayama Study

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.

A nonsynonymous SNP in PRKCH (protein kinase C η) increases the risk of cerebral infarction

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 × 10−7, crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCη was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

High-Sensitivity C-Reactive Protein and Coronary Heart Disease in a General Population of Japanese The Hisayama Study

Objective—The purpose of this study was to investigate the effects of high-sensitivity C-reactive protein (hs-CRP) on the risks of coronary heart disease (CHD) in a general population of Japanese. Methods and Results—The Hisayama study is a population-based prospective cohort study. A total of 2589 participants aged 40 years or older were followed up for 14 years. Outcomes are incident CHD (myocardial infarction, coronary revascularization, and sudden cardiac death). The median hs-CRP level was 0.43 mg/L at baseline. During the follow-up period, 129 coronary events were observed. Age- and sex-adjusted annual incidence rates of CHD rose progressively with higher hs-CRP levels: 1.6, 3.3, 4.5, and 7.4 per 1000 person-years for quartile groups defined by hs-CRP levels of <0.21, 0.21 to 0.43, 0.44 to 1.02, and >1.02 mg/L, respectively (P<0.0001 for trend). The risk of CHD in the highest quartile group was 2.98-fold (95% CI, 1.53 to 5.82) higher than that in the lowest group even after controlling for other cardiovascular risk factors. Conclusions—hs-CRP levels were clearly associated with future CHD events in a general population of Japanese. In Japanese populations, the hs-CRP cut-off point for high-risk of future development of CHD is likely to be >1.0 mg/L, which is much lower than that for Western populations.

LDL Cholesterol and the Development of Stroke Subtypes and Coronary Heart Disease in a General Japanese Population The Hisayama Study

Background and Purpose— Although the relation between serum LDL cholesterol level and coronary heart disease (CHD) is well established, its relation with stroke subtypes is less clear. Methods— A total of 2351 inhabitants age ≥40 years in a Japanese community were followed up for 19 years. Results— During follow-up, 271 subjects developed stroke and 144 developed CHD. Whereas the age- and sex-adjusted incidences of CHD significantly increased with increasing LDL cholesterol levels (P for trend <0.001), the associations between LDL cholesterol level and the incidences of ischemic or hemorrhagic stroke were not significant. The age- and sex-adjusted incidences of atherothrombotic infarctions (ATIs) and lacunar infarctions (LIs) significantly increased with increasing LDL cholesterol level (P for trend=0.03 for ATIs and=0.02 for LIs), but no such association was observed for cardioembolic infarction. After multivariate adjustment, the positive associations of LDL cholesterol level with the risks of ATI and CHD remained significant (P for trend=0.02 for ATIs and=0.03 for CHD), whereas the association with LIs was not significant. The risk of ATI significantly increased in the fourth quartile of LDL cholesterol compared with the first quartile (multivariate-adjusted hazard ratio=2.84; 95% CI, 1.17 to 6.93). The multivariate-adjusted risks for developing nonembolic infarction (ATIs and LIs) and CHD were significantly elevated in the groups with elevated LDL cholesterol values with and without the metabolic syndrome. Conclusions— Our findings suggest that an elevated LDL cholesterol level is a significant risk factor for developing ATI as well as CHD, and these associations are independent of the metabolic syndrome.

Midlife and Late-Life Blood Pressure and Dementia in Japanese Elderly: The Hisayama Study

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

Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus The ADVANCE Trial

Background— Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. Methods and Results— The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99–2.39) for macrovascular events and 1.84 (1.19–2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73–7.66) and 2.18 (1.04–4.58), respectively. Conclusion— Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00145925.

Secular Trends in the Incidence of and Risk Factors for Ischemic Stroke and Its Subtypes in Japanese Population

Background— The study of long-term trends in the incidence of and risk factors for ischemic stroke subtypes could offer insights into primary and secondary prevention. Methods and Results— We established 3 cohorts of residents ≥40 years of age in 1961, 1974, and 1988 in the Japanese community of Hisayama. Morphological examinations by autopsy or brain imaging were performed on most of the ischemic stroke cases developed in these cohorts. When 13-year follow-up data were compared, the age-adjusted incidence of ischemic stroke and lacunar infarction declined significantly from the first to the third cohort for both sexes, whereas the incidences of atherothrombotic and cardioembolic infarction did not change during this period. Hypertension was a powerful risk factor for the development of ischemic stroke, and improvement of hypertension control would have largely influenced this declining trend: The age- and sex-adjusted hazard ratio of hypertension decreased from 3.25 (95% CI 2.17 to 4.86) in the first cohort to 1.83 (1.29 to 2.58) in the third cohort. A rapid increase in the prevalence of metabolic disorders may have offset the impact of improvements in hypertension control and resulted in a slowdown of the decline in the incidence of ischemic stroke in the cohorts in the present study; however, hypertension still makes a large contribution to the development of ischemic stroke. Conclusions— These findings suggest that in the Japanese population, the incidence of ischemic stroke has declined significantly over the past 40 years, probably owing to better management of hypertension. There is a need for greater primary prevention efforts in the treatment of hypertension and metabolic disorders.

Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese Half-Century Data From the Hisayama Study (1961–2009)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors. # Clinical Perspective {#article-title-30}Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

Proteinuria and clinical outcomes after ischemic stroke

Objectives: The impact of chronic kidney disease (CKD) on clinical outcomes after acute ischemic stroke is still not fully understood. The aim of the present study was to elucidate how CKD and its components, proteinuria and low estimated glomerular filtration rate (eGFR), affect the clinical outcomes after ischemic stroke. Methods: The study subjects consisted of 3,778 patients with first-ever ischemic stroke within 24 hours of onset from the Fukuoka Stroke Registry. CKD was defined as proteinuria or low eGFR (<60 mL/min/m2) or both. The study outcomes were neurologic deterioration (≥2-point increase in the NIH Stroke Scale during hospitalization), in-hospital mortality, and poor functional outcome (modified Rankin Scale score at discharge of 2 to 6). The effects of CKD, proteinuria, and eGFR on these outcomes were evaluated using a multiple logistic regression analysis. Results: CKD was diagnosed in 1,320 patients (34.9%). In the multivariate analyses after adjusting for confounding factors, patients with CKD had significantly higher risks of neurologic deterioration, in-hospital mortality, and poor functional outcome (p <0.001 for all). Among the CKD components, a higher urinary protein level was associated with an elevated risk of each outcome (p for trend < 0.001 for all), but no clear relationship between the eGFR level and each outcome was found. Conclusions: CKD is an important predictor of poor clinical outcomes after acute ischemic stroke. Proteinuria independently contributes to the increased risks of neurologic deterioration, mortality, and poor functional outcome, but the eGFR may not be relevant to these outcomes.