Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals.

PURPOSE: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. DESIGN: Cross-sectional analysis. PARTICIPANTS: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). METHODS: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. MAIN OUTCOME MEASURE: Proportion of patients with POAG after stratification according to the GRS. RESULTS: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10-4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10-6). CONCLUSIONS: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of sarcopenia with regional brain atrophy and white matter lesions in a general older population: the Hisayama Study.

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

Skin carotenoid scores and metabolic syndrome in a general Japanese population: the Hisayama study.

BACKGROUND: Higher vegetable intake is being promoted as an initiative to prevent lifestyle-related diseases. Carotenoids are yellow or red pigment components and are widely present in vegetables. Since ingested carotenoids accumulate in the skin, skin carotenoid levels are a quantitative indicator of vegetable intake. Recently, noninvasive optical sensors for assessing skin carotenoid levels were developed. We here examined the association between skin carotenoid scores measured using optical sensors and the presence of metabolic syndrome. METHODS: A total of 1618 individuals (604 men and 1014 women) aged ≥ 40 years (mean age 63.1 years) participated in the study. Skin carotenoid scores were determined using a noninvasive optical sensor based on multiple spatially resolved reflectance spectroscopy. Metabolic syndrome was defined based on the Joint Scientific Statement criteria developed by six international scientific societies. Multivariable-adjusted logistic regression models were used. RESULTS: The prevalence of metabolic syndrome was 31.3% (n = 506). A remarkably strong association was found between higher skin carotenoid scores and lower prevalence of metabolic syndrome after adjusting for confounders. The multivariable-adjusted odds ratio for the presence of metabolic syndrome in individuals with the highest quartile of skin carotenoid scores was 0.39 (95% confidence interval, 0.28-0.55) compared to those with the lowest quartile. CONCLUSIONS: Our findings suggest that higher skin carotenoid scores measured by non-invasive optimal sensors are significantly associated with a lower likelihood of having metabolic syndrome in the general Japanese population.

Association between masticatory function, frailty, and functional disability: an observational study.

BACKGROUND: Increase in functional disability in aging societies is an international medical and public health issue. Masticatory function may be a potential risk factor for functional disability, but the role of frailty in the association has not been clarified. METHODS: Forty thousand five hundred sixty-two community-dwelling older adults aged 65 years and over who were insured by public health insurance as of April 2018 were followed up for a median of 3.0 years. Masticatory function was categorized as good, moderate, or poor based on a self-reported questionnaire. The development of functional disability was defined as a new certification of the need for long-term care. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). RESULTS: During the follow-up period, 1,397 individuals experienced functional disability. After adjusting for age, sex, comorbidities, medical history, and lifestyle behaviors, the HR for incident functional disability was significantly higher in the moderate and poor groups compared to the good group (moderate, HR 1.21 [95% CI, 1.07-1.37]; poor, HR 1.64 [95% CI, 1.03-2.62]). However, after additional adjustment for frailty-related factors-namely, underweight, regular exercise, and gait speed-the association was attenuated in both the moderate group (HR 1.06 [95% CI, 0.94-1.21]) and the poor group (HR 1.51 [95% CI, 0.94-2.41]). CONCLUSIONS: Masticatory dysfunction was significantly associated with incident functional disability in a community-dwelling older Japanese population. Our findings suggest that masticatory dysfunction may be a surrogate of frailty rather than a direct cause of functional disability.

Association between retinopathy and risk of dementia in a general Japanese population: the Hisayama Study.

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

Database profile of the Fukuoka-City Information Platform for Community-based Integrated Care.

BACKGROUND: The Fukuoka-City Information Platform for Community-based Integrated Care is an advanced big data platform that aggregates information on the health and medical services of Fukuoka citizens. Fukuoka City is engaged in a joint project with Kyushu University to promote policy making through a large-scale real-world data analysis. This paper describes the framework for this cooperative effort and the features of the analytical platform. METHODS: Fukuoka City is the fifth most populous ordinance-designated city in Japan, with an estimated population of approximately 1.6 million. Under an agreement with Fukuoka City, Kyushu University was granted access to a portion of the city's anonymized healthcare database as secondary-use information. The database contains information on resident registration, health insurance claims, specific health checkups and health checkups for the older adults, specific health guidance, long-term care insurance data, and cancer screenings collected after fiscal year 2012. Each of these constituent datasets can be interlinked using anonymized hashed key variables, allowing individuals to be followed across databases and over time. CONCLUSIONS: The platform allows longitudinal investigation of the complex association between various aspects of healthcare, such as medical procedures, examinations, interviews, medical costs, long-term care certifications, and care costs. The platform can provide valuable public-health information because it is relatively large for a single database, and because it allows analysis of data across multiple domains and tracing of individuals over time.

Serum high-sensitivity C-reactive protein and dementia in a community-dwelling Japanese older population (JPSC-AD).

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

Association Between Serum NT-proBNP and Gray Matter Atrophy Patterns in an Older Japanese Population: The Hisayama Study.

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

Day-to-day home blood pressure variability and risk of atrial fibrillation in a general Japanese population: the Hisayama Study.

AIMS: Several prospective studies have reported that higher visit-to-visit blood pressure variability (BPV) is associated with atrial fibrillation (AF). However, no studies have investigated the association between day-to-day BPV assessed by home blood pressure measurement and the development of AF. METHODS AND RESULTS: A total of 2829 community-dwelling Japanese aged ≥40 years without prior AF were followed up for 10 years (2007-17). Day-to-day home BPV [defined as coefficient of variation (CoV) of home systolic blood pressure (SBP) for 28 days] was categorized into four groups according to the quartiles: Q1, ≤ 4.64%; Q2, 4.65-5.70%; Q3, 5.71-7.01%; Q4, ≥ 7.02%. The hazard ratios for developing AF were estimated using a Cox proportional hazards model. During the follow-up period, 134 participants developed new-onset AF. The crude incidence rates of AF increased significantly with higher CoV levels of home SBP: 2.1, 4.9, 5.2, and 8.8 per 1000 person-years in the first, second, third, and fourth quartiles, respectively (P for trend < 0.01). After adjusting for potential confounders, increased CoV levels of home SBP were associated significantly with a higher risk of AF (P for trend = 0.02). The participants in the highest quartile of CoV had a 2.20-fold (95% confidence intervals: 1.18-4.08) increased risk of developing AF compared with those in the lowest quartile. CONCLUSION: The present findings suggest that increased day-to-day home BPV levels are associated with a higher risk of the development of AF in a general Japanese population.

This prospective cohort study of a general Japanese population demonstrated a significant association between higher day-to-day blood pressure variability (BPV) assessed by home blood pressure monitoring and risk for the development of atrial fibrillation (AF). In addition, the association between BPV and the development of AF tended to be stronger in participants without hypertension. The findings of this study indicate that the evaluation of day-to-day BPV with home blood pressure monitoring may be useful to assess the future risk of AF in participants with and without hypertension, and treatment that takes into account day-to-day BPV in addition to other cardiovascular risk factors may be necessary to prevent the development of AF.

Association Between Frequency of Social Contact and Brain Atrophy in Community-Dwelling Older People Without Dementia: The JPSC-AD Study.

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

CKD, Brain Atrophy, and White Matter Lesion Volume: The Japan Prospective Studies Collaboration for Aging and Dementia.

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

Association of white matter lesions and brain atrophy with the development of dementia in a community: the Hisayama Study.

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

Changes in the Eicosapentaenoic Acid to Arachidonic Acid Ratio in Serum over 10 Years in a Japanese Community: The Hisayama Study.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: In a Japanese community, the serum EPA/AA ratio decreased over 10 years at the population level, especially in middle-aged participants.

Association of gait speed with regional brain volumes and risk of dementia in older Japanese: The Hisayama study.

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

Association of Inner Retinal Thickness with Prevalent Dementia and Brain Atrophy in a General Older Population: The Hisayama Study.

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

Day-to-Day Blood Pressure Variability and Risk of Incident Chronic Kidney Disease in a General Japanese Population.

Background Several longitudinal studies have reported that higher visit-to-visit blood pressure variability is associated with greater risk for developing chronic kidney disease. However, no population-based studies have investigated the association between day-to-day home blood pressure variability and incident chronic kidney disease. Methods and Results A total of 2342 Japanese community-dwelling residents aged ≥40 years without chronic kidney disease at baseline were followed up by annual health examinations for 10 years. Home blood pressure was measured 3 times every morning for 28 days. Day-to-day coefficients of variation of home systolic blood pressure levels were categorized into quintiles. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or the presence of proteinuria. The hazard ratios for developing chronic kidney disease were estimated with a Cox proportional hazards model. During the follow-up period, 772 participants developed chronic kidney disease. Increased coefficients of variation of home systolic blood pressure were associated significantly with higher risk of chronic kidney disease after adjusting for confounders (P for trend <0.001): Individuals in the highest quintile of coefficients of variation had a 1.50-fold (95% CI, 1.17-1.94) greater risk of developing chronic kidney disease than those in the lowest quintile. The combination of higher coefficients of variation and higher mean value of home systolic blood pressure was associated with the multivariable-adjusted risk of developing chronic kidney disease. Conclusions These findings suggest that increased day-to-day blood pressure variability is a significant risk factor for developing chronic kidney disease in a general Japanese population.

Active commuting, commuting modes and the risk of diabetes: 14-year follow-up data from the Hisayama study.

AIMS/INTRODUCTION: We aimed to investigate the association of active commuting (cycling or walking to work), as well as the association of the individual commuting modes, with the risk of diabetes in a prospective cohort of community-dwelling adults in Japan. MATERIAL AND METHODS: A total of 1,270 residents aged 40-79 years were followed up for a median of 14 years. Active commuting was defined as either cycling or walking to work. A Cox proportional hazards model was used to examine the association of active commuting with the risk of diabetes. Associations for different forms of active commuting (cycling, walking and mixed modes of cycling or walking with non-active components) were also examined. RESULTS: During the follow-up period, 191 participants developed diabetes. Active commuting was associated with a lower risk of diabetes than non-active commuting after adjustment for potential confounders (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.31-0.92). With regard to the commuting modes, the risk of diabetes was significantly lower in individuals who commuted by cycling alone (HR 0.46, 95% CI 0.22-0.98), and tended to be lower in individuals who commuted by walking alone (HR 0.14, 95% CI 0.02-1.02) compared with that in individuals with non-active commuting. Meanwhile, no significant associations were observed for the mixed mode of walking and non-active commuting (HR 1.69, 95% CI 0.77-3.71). CONCLUSIONS: Active commuting, particularly that consisting exclusively of cycling or walking, was associated with a reduced risk of diabetes. Our findings support a public health policy that promotes the choice of active commuting for the prevention of diabetes.

Association Between Diabetes and Gray Matter Atrophy Patterns in a General Older Japanese Population: The Hisayama Study.

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

Higher-resolution quantification of white matter hypointensities by large-scale transfer learning from 2D images on the JPSC-AD cohort.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.