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DOI： 10.1111/j.1523-1755.2005.00397.x

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DOI： 10.1053/j.ajkd.2004.05.024

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DOI： 10.1152/ajprenal.00311.2002

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DOI： 10.1046/j.1365-2567.2000.00938.x

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DOI： 10.1038/s41598-025-04659-0

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Language：English   Publisher：Neuropathology  

Transthyretin (TTR) can bind to Aβ and prevent the formation of Aβ fibrils in vitro; it is thus a highly interesting molecule in the field of Alzheimer's disease (AD) research. However, the distribution of TTR and its affinity to Aβ in both healthy human brains and those of AD patients remain unclear. We therefore examined TTR in human brains using postmortem brain samples. Paraffin sections and extracted protein samples were prepared from AD and control (non-AD) brains. Immunohistochemistry was performed to detect TTR expression patterns, and immunofluorescent staining was used to reveal the relationships between the intracellular and extracellular localizations of TTR and Aβ. We also performed western blotting for TTR using brain extracts. In immunohistochemical staining of the human brain, TTR signal was detected not only in extracellular tissue but also in the cytoplasm of neurons and glia. The TTR-positive area was significantly greater in AD brains than in non-AD brains. However, expression of TTR transcripts did not differ between AD and non-AD brains in our previously obtained RNA-sequencing and microarray data. Immunofluorescent staining with multiple antibodies revealed that TTR was co-localized with Aβ in the cytoplasm of neurons. In extracellular Aβ plaques, TTR presented in the same region but was not co-localized with dense Aβ fibrils. Together, our results indicate that TTR is widely expressed in the human brain rather than being limited to the choroid plexus and that TTR is more abundant in AD brains. Our results also suggest that the affinity between TTR and Aβ changes depending on the structure of Aβ. Our data will be valuable for the future development of TTR-related AD preventative methods and medications.

DOI： 10.1111/neup.70015

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The aim of this was to develop an atrial fibrillation (AF) risk score using items usually included in Japanese governmental health check-ups.</p><p><b><i>Methods and Results:</i></b> We analyzed data from 6,476 Japanese participants registered in the Suita Study. At baseline, the participants were aged ≥30 years and were free from AF. Cox regression analysis was used to identify AF risk factors, and a 0–100 score was developed to predict AF events within 10 years. Within a median follow-up of 14.6 years, 278 participants developed AF. The risk score incorporated age [<50 years (16 points for men, 0 for women), 50–59 years (26 points for men, 14 for women), 60–69 years (41 points for men, 37 for women), ≥70 years (54 points for men, 51 for women)], current smoking with a smoking index >500 (7 points), heavy alcohol consumption (8 points), body mass index ≥25 kg/m²(6 points), hypertension (7 points), urinary proteins (4 points), glutamic-pyruvic transaminase >50 IU/dL (4 points), and cardiovascular disease history (10 points). The 10-year AF event probabilities were 7.1%, 8.4%, 10.8%, and 15.9% for scores of 47–54, 55–58, 59–69, and ≥70, respectively.</p><p><b><i>Conclusions:</i></b> The new risk score to predict AF uses items similar to those used in Japanese governmental health check-ups.</p>

DOI： 10.1253/circj.cj-24-0939

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Language：English   Publisher：Journal of Cachexia Sarcopenia and Muscle  

DOI： 10.1002/jcsm.13764

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Publisher：Journal of Affective Disorders Reports  

Background: Several clinical studies have reported an association between impaired family functioning and depressive symptoms. However, epidemiological evidence is limited. The aim of this study was to investigate the association between family functioning and the presence of depressive symptoms in a community-dwelling Japanese population. Methods: A total of 2,595 participants aged ≥40 years were included. Impaired family functioning levels were assessed by using a short version of the general functioning subscale of the McMaster Family Assessment Device (GF6+). Impaired family functioning levels were categorized as healthy (GF6+ score: ≤1.80), borderline (1.81–2.00), or unhealthy (>2.00). The presence of depressive symptoms was defined as a score of ≥10 on Patient Health Questionaire-9. A logistic regression model was used to compute the odds ratios (ORs) for the presence of depressive symptom. Results: The age-adjusted prevalence of depressive symptoms was 5.4 % for men and 7.0 % for women. In both sexes, the age-adjusted prevalence of depressive symptoms increased significantly with increasing impaired family functioning levels (both P for trend <0.001). The ORs (95 % confidence intervals) for having depressive symptoms among the borderline and unhealthy groups were 3.32 (1.51–7.29) and 4.09 (1.76–9.54) for men, and 1.04 (0.56–1.95) and 3.02 (1.76–5.18) for women, respectively, compared with the healthy group after adjustment for potential confounders. Limitation: Reverse causality is possible due to the cross-sectional design. Conclusions: Impaired family functioning was associated with an increased risk of the presence of depressive symptoms. It may be important considering the family functioning in managing depressive symptoms.

DOI： 10.1016/j.jadr.2025.100900

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Language：English   Publisher：Pain Reports  

Objectives:This study aimed to compare the prevalence of chronic pain using various definitions from previous studies and to determine the optimal definition for detecting chronic pain associated with physical and emotional dysfunction in a general Japanese population.Methods:A total of 2700 community-dwelling Japanese residents aged ≥40 years were assessed for chronic pain and its components of duration, frequency, and intensity. The activities of daily living (ADL) disability and depressive symptoms of participants were also evaluated using the modified Lankin Scale and Patient Health Questionnaire-9. The odds ratios and the population attributable fractions (PAFs) for ADL disability and depressive symptoms were estimated using a logistic regression model.Results:The prevalence of chronic pain varied greatly by definition, ranging from 13% for pain defined as pain duration ≥3 months, pain frequency ≥ twice a week, and pain intensity of ≥50 mm by a visual analogue scale (VAS) to 48% for a simple definition of pain duration ≥3 months. The PAFs for ADL disability and depressive symptoms were relatively high at 33% in participants with pain duration of ≥6 months and 30% in those with pain frequency of ≥twice a week, while the VAS ≥50 mm group had a low PAF of 12%.Conclusion:For screening people with chronic pain and ADL disability or depressive symptoms, the criteria of pain duration and pain frequency yielded essentially identical results, while the criterion of pain intensity risked overlooking individuals with chronic pain and these associated symptoms.

DOI： 10.1097/PR9.0000000000001250

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DOI： 10.1056/NEJMoa2415879

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Language：English   Publisher：Psychiatry and Clinical Neurosciences  

Aim: To investigate the association of olfactory identification ability with both the prevalence of mild cognitive impairment (MCI) and regional brain atrophy in a community-dwelling older population. Methods: A total of 1293 participants without dementia aged 65 years or older underwent a Japanese version of the 4-Item Pocket Smell Test, an assessment of cognitive function, and brain magnetic resonance imaging scanning in 2017–2018. Regional gray matter volumes (GMVs) and white matter lesions volume (WMLV) were estimated using FreeSurfer software. The association of impaired olfactory identification with the presence of MCI and regional GMVs or WMLV was estimated by logistic regression analysis and ANCOVA, respectively. We also assessed the association between impaired olfactory identification and GMVs without regions of interest, using a voxel-based morphometry (VBM) analysis. Results: Participants with impaired olfactory identification had a significantly higher likelihood of MCI than those without (odds ratio, 1.99 [95% confidence interval, 1.36–2.91]). In the FreeSurfer analysis, participants with impaired olfactory identification had significantly lower GMVs in the entorhinal cortex, inferior temporal gyrus, amygdala, thalamus, hippocampus, and cingulate gyrus, and higher WMLV than those without. The VBM analysis also showed that impaired olfactory identification was significantly associated with lower volume of the left entorhinal cortex, left amygdala, left hippocampus, bilateral thalami, and bilateral subcallosal areas. Conclusion: Our findings suggest that cognitive function and brain changes may need to be evaluated in older individuals with impaired olfactory identification, which may reflect the extent of neurodegeneration, WMLV, and subsequent cognitive impairment.

DOI： 10.1111/pcn.13813

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Language：Japanese   Publisher：株式会社医学書院  

DOI： 10.11477/mf.188160960770020119

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DOI： 10.1038/s41538-024-00364-w

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Language：English   Publisher：Brain Communications  

Longitudinal analyses of the influence of chronic pain on pain-related regional brain volumes in general populations are warranted. This prospective cohort study investigated the association between the presence of chronic pain at baseline and the subsequent changes in pain-related regional brain volumes among Japanese community-dwelling older residents. Participants aged 65 years or older who underwent brain magnetic resonance imaging (MRI) scans in both 2012 and 2017 were included. According to the presence or absence of chronic pain (defined as pain lasting for longer than 3 months) in 2012, participants were categorized into a 'chronic pain' group and 'no chronic pain' group. Region-of-interest analyses for the ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, orbitofrontal cortex, postcentral gyrus, insular cortex, thalamus, anterior cingulate cortex, posterior cingulate cortex, amygdala and hippocampus were performed using FreeSurfer software. Whole-brain analysis was conducted by voxel-based morphometry. Rates of change in regional brain volume at 5 years after baseline were estimated using analysis of covariance. Among the 766 participants included in the FreeSurfer analysis, 444 (58%) were female and 287 (37%) were categorized into the chronic pain group. The results of FreeSurfer analysis showed that the chronic pain group had significantly greater decreases in regional volume in the postcentral gyrus (-2.187% in the chronic pain group versus -1.681% in the no chronic pain group, P = 0.01), thalamus (-4.400% versus -3.897%, P = 0.006), anterior cingulate cortex (-2.507% versus -1.941%, P = 0.004) and amygdala (-4.739% versus -4.022%, P = 0.03) compared to the no chronic pain group after adjusting for age, sex, education attainment, marital status, hypertension, diabetes, serum total cholesterol level, body mass index, current smoking, current drinking, regular exercise, cerebrovascular lesions on MRI, activities in daily living disability and depressive symptoms. Among the 730 participants included in the voxel-based morphometry analysis, 433 (59%) were female and 272 (37%) were categorized into the chronic pain group. The voxel-based morphometry analysis showed that the chronic pain group had a significantly greater regional volume decrease in the right anterior insula than the no chronic pain group. Our findings suggest that the presence of chronic pain at baseline is associated with a significantly greater decrease in the volume of pain-related brain regions at 5 years after baseline in community-dwelling older Japanese.

DOI： 10.1093/braincomms/fcaf149

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Language：English   Publisher：Japan Atherosclerosis Society  

<p> <b>Aims:</b> To investigate the association between metabolic health status, defined by the combination of metabolic syndrome (MetS) and obesity, and cardiovascular disease (CVD) in a Japanese community.</p><p><b>Methods:</b> A total of 2,842 participants without prior CVD, aged 40 years or older, were followed up from 2007 until 2017. Participants were classified into 4 metabolic health statuses based on the presence of obesity (body mass index ≥ 25 kg/m²) and MetS: metabolically healthy normal weight (MHN) (obesity [-] and MetS [-]), metabolically unhealthy normal weight (MUN) (obesity [-] and MetS [+]), metabolically healthy obesity (MHO) (obesity [+] and MetS [-]), and metabolically unhealthy obesity (MUO) (obesity [+] and MetS [+]). The risk estimates were computed by using a Cox hazard regression analysis.</p><p> <b>Results:</b> During the follow-up period, 190 participants developed CVD. The MUO group had a 1.94-times greater risk of developing CVD than the MHN group after adjusting for confounders, but no excess risk was observed in the MHO group. Moreover, in 1,595 participants who had undergone a health checkup in 2002, 5 years before baseline, the risk of developing CVD was 2.18-times greater in the group that transitioned from MHO to MUO and 1.75-times higher in the stable MUO group than in the stable MHN group, but was not higher in the stable MHO group.</p><p><b>Conclusions:</b> The present findings suggest that cardiovascular risk increases when metabolic abnormalities are present simultaneously with obesity. In individuals with obesity, it may be important to maintain metabolic health and/or lose weight to prevent CVD.</p>

DOI： 10.5551/jat.65275

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Prion  

Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.

DOI： 10.1080/19336896.2024.2337981

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Language：English   Publisher：Journal of Cachexia Sarcopenia and Muscle  

Background: Dynapenic obesity is a condition characterized by high adiposity levels combined with muscle dysfunction. Although high adiposity and muscle loss/dysfunction are thought to synergistically increase the risk of cardiovascular disease (CVD), few studies have addressed the association between dynapenic and sarcopenic obesity and CVD. We aimed to investigate the association of dynapenic obesity with incident CVD events using the data from a population-based prospective longitudinal study in Japan. Methods: A total of 2490 community-dwelling Japanese aged 40–79 years (42.5% males, mean age 57.7 ± 10.6 years) without a history of CVD were followed up for a median of 24 years. Handgrip strength was classified as low, medium, or high by age- and sex-specific tertiles. Body mass index (BMI) levels were categorized as lean (<18.5 kg/m²), normal (18.5–24.9 kg/m²), or obese (≥25.0 kg/m²). Dynapenic obesity was defined as having both low handgrip strength and obesity. The outcomes were defined as the first-ever development of CVD (defined as stroke or coronary heart disease). The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the development of CVD were estimated using a Cox proportional hazards model, in which participants with high handgrip strength and normal BMI were used as a reference group. Mediation analyses used serum high-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment for insulin resistance (HOMA-IR) as mediators. Results: During the follow-up period, 482 participants developed CVD events (324 cases of stroke and 209 of coronary heart disease). The multivariable-adjusted risk of CVD increased significantly among participants with dynapenic obesity compared with the reference group (HR 1.49, 95% CI 1.03–2.17). An analysis by age groups showed a further increase in the risk of CVD among participants with dynapenic obesity aged less than 65 years (HR 1.66, 95% CI 1.04–2.65). In mediation analyses for participants aged less than 65 years, serum hs-CRP was shown to be a significant mediator explaining 13.8% of the association between dynapenic obesity and the development of CVD, while HOMA-IR explained 12.2% of this relationship. Conclusions: Dynapenic obesity was a significant risk factor for the development of CVD in a general Japanese population. This association was more pronounced among those aged <65 years. Inflammation, and possibly glucose metabolism, might partly mediate this association. Our findings suggest that preventing muscle dysfunction as well as appropriate weight control, especially in middle-age, are important for preventing the development of CVD.

DOI： 10.1002/jcsm.13564

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Language：English   Publisher：Npj Genomic Medicine  

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.

DOI： 10.1038/s41525-024-00431-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

<p> <b>Aims:</b> Hypertriglyceridemia is a risk factor for chronic kidney disease (CKD). However, whether or not it predicts the risk of CKD progression is unknown. This study evaluated the association between serum triglyceride (TG) levels and kidney disease progression in patients with non-dialysis-dependent CKD.</p><p><b>Methods:</b> The Fukuoka Kidney disease Registry (FKR) study was a multicenter, prospective longitudinal cohort study. In total, 4,100 patients with CKD were followed up for 5 years. The primary outcome was the incidence of CKD progression, defined as a ≥ 1.5-fold increase in serum creatinine level or the development of end-stage kidney disease. The patients were divided into quartiles according to baseline serum TG levels under non-fasting conditions: Q1 ＜87 mg/dL; Q2, 87–120 mg/dL; Q3, 121–170 mg/dL, and Q4 ＞170 mg/dL.</p><p><b>Results:</b> During the 5-year observation period, 1,410 patients met the criteria for CKD progression. The multivariable-adjusted Cox proportional hazards model showed a significant association between high serum TG level and the risk of CKD progression in the model without macroalbuminuria as a covariate (multivariable hazard ratio[HR] for Q4 versus Q1, 1.20; 95% CI, 1.03–1.41; <i>P</i>=0.022), but the significance disappeared after adjusting for macroalbuminuria (HR for Q4 versus Q1, 1.06; 95% CI, 0.90–1.24; <i>P</i>=0.507).</p><p><b>Conclusions:</b> The present findings suggest that individuals with high serum TG levels are more likely to develop CKD progression than those without; however, whether or not higher serum TG levels reflect elevated macroalbuminuria or lead to CKD progression via elevated macroalbuminuria is unclear.</p>

DOI： 10.5551/jat.64625

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Language：English   Publisher：(一社)日本動脈硬化学会  

Language：English   Publisher：Ophthalmology  

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.

DOI： 10.1016/j.ophtha.2024.05.026

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Language：English   Publisher：Investigative Ophthalmology and Visual Science  

PURPOSE. The purpose of this study was to investigate biologically meaningful endotypes of open-angle glaucoma (OAG) by applying unsupervised machine learning to plasma metabolites. METHODS. This retrospective longitudinal cohort study enrolled consecutive patients aged ≥20 years with OAG at Tohoku University Hospital from January 2017 to January 2020. OAG was confirmed based on comprehensive ophthalmic examinations. Among the 523 patients with OAG with available clinical metabolomic data, 173 patients were longitudinally followed up for ≥2 years, with available data from ≥5 reliable visual field (VF) tests without glaucoma surgery. We collected fasting blood samples and clinical data at enrollment and nuclear magnetic resonance spectroscopy to profile 45 plasma metabolites in a targeted approach. After computing a distance matrix of preprocessed metabolites with Pearson distance, gap statistics determined the optimal number of OAG endotypes. Its risk factors, clinical presentations, metabolomic profiles, and progression rate of sectorbased VF loss were compared across endotypes. RESULTS. Five distinct OAG endotypes were identified. The highest-risk endotype (endotype B) showed a significant faster progression of central VF loss (P = 0.007). Compared with patients with other endotypes, those with endotype B were more likely to have a high prevalence of dyslipidemia, cold extremities, oxidative stress, and low OAG genetic risk scores. Pathway analysis of metabolomic profiles implicated altered fatty acid and ketone body metabolism in this endotype, with 34 differentially enriched pathways (false discovery rate [FDR] < 0.05). CONCLUSIONS. Integrated metabolomic profiles identified five distinct etiologic endotypes of OAG, suggesting pathological mechanisms related with a high-risk group of central vision loss progression in the Japanese population.

DOI： 10.1167/iovs.65.13.44

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Language：English   Publisher：Scientific Reports  

The frequency of behavioral and psychological symptoms of dementia (BPSD) is high, and it is a challenge to elucidate its neural substrates underlying their development. In recent years, many findings have been reported on the relationship between BPSD and brain volume in dementia patients. However, the results are not fully conclusive. Furthermore, there have been few population-based studies. Therefore, the relationship between BPSD and brain volume was investigated as an exploratory study. Of the 927 older persons who participated in the fifth Nakayama study, 90 were included in this analysis, consisting of 52 patients with mild cognitive impairment and 38 patients with dementia, with head MRI and the Neuropsychiatric Inventory (NPI) data. Multiple regression analysis was used to examine the association between the total score of each BPSD score on the NPI and brain volume estimated by FreeSurfer. On multivariate adjustment, even after false discovery rate correction, insular cortical volumes decreased significantly as total scores for apathy/indifference increased (p value = 0.002, q-value = 0.01). Similarly, total brain volume decreased significantly as total scores for appetite and eating disturbance increased (p value = 0.03), and parietal, temporal, and hippocampal cortical volumes also decreased significantly as total scores for appetite and eating disturbance increased (all p and q values < 0.05). This study’s results suggest that apathy is negatively correlated with insular cortical volume, and that appetite and eating disturbance are also correlated with brain regions, including parietal, temporal, and hippocampal volume in a community-dwelling older population.

DOI： 10.1038/s41598-024-77477-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neuropathology  

The hypothalamus is the region of the brain that integrates the neuroendocrine system and whole-body metabolism. Patients with Alzheimer's disease (AD) have been reported to exhibit pathological changes in the hypothalamus, such as neurofibrillary tangles (NFTs) and amyloid plaques (APs). However, few studies have investigated whether hypothalamic AD pathology is associated with clinical factors. We investigated the association between AD-related pathological changes in the hypothalamus and clinical pictures using autopsied brain samples obtained from deceased residents of a Japanese community. A total of 85 autopsied brain samples were semi-quantitatively analyzed for AD pathology, including NFTs and APs. Our histopathological studies showed that several hypothalamic nuclei, such as the tuberomammillary nucleus (TBM) and lateral hypothalamic area (LHA), are vulnerable to AD pathologies. NFTs are observed in various neuropathological states, including normal cognitive cases, whereas APs are predominantly observed in AD. Regarding the association between hypothalamic AD pathologies and clinical factors, the degree of APs in the TBM and LHA was associated with a lower body mass index while alive, after adjusting for sex and age at death. However, we found no significant association between hypothalamic AD pathology and the prevalence of hypertension, diabetes, or dyslipidemia. Our study showed that a lower BMI, which is a poor prognostic factor of AD, might be associated with hypothalamic AP pathology and highlighted new insights regarding the disruption of the brain-whole body axis in AD.

DOI： 10.1111/neup.12974

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Obesity  

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.

DOI： 10.1038/s41366-024-01575-7

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

アルツハイマー病(AD)に関連して視床下部にみられる病理学的変化と臨床像を調査した。福岡市に隣接する久山町で2018年1月1日～2020年3月3日に死亡した住民249名のうち129名(51.8%)で剖検が行われ、そのうち解析に適した85名(男性56%、平均85.0±9.1歳)を本研究に組み入れた。認知機能が正常だったと診断されていた例は35名、AD診断例は31名存在した。脳を病理組織学的に解析したところ、結節乳頭体核(TBM)や視床下部外側野(LHA)といった視床下核のいくつかが、AD病理に冒されやすいことが明らかになった。神経原線維の変化は、認知機能正常例も含め、神経病理学的状態が様々であった剖検例にわたって観察された。それに対し、アミロイド斑はAD例で優位に観察された。視床下部のAD病理を半定量的に評価し臨床因子との関連性を検討した結果、TMBとLHAにおけるアミロイド斑の程度は生前の低BMIと関連していることが、性別・死亡年齢での調整後に示された。視床下部AD病理と、高血圧症、糖尿病、または脂質異常症の有病率との間には有意な関連性は示されなかった。以上のように、ADの予後不良因子である低BMIは、視床下部AD病理に関連していると考えられた。

Language：English   Publisher：Npj Aging  

We investigated associations of glycemic measures, and insulin resistance and secretion measures with hippocampal and subfield volumes. In this cross-sectional study, 7400 community-dwelling participants underwent brain MRI and health checkups between 2016 and 2018. Hemoglobin A<inf>1c</inf> (HbA<inf>1c</inf>), glycated albumin (GA), homeostasis model assessment for insulin resistance (HOMA-IR), and HOMA of percent β-cell function (HOMA-β) were evaluated. The associations of each measure with a smaller volume of the hippocampus and twelve hippocampal subfields were investigated. As a result, higher HbA<inf>1c</inf> or GA and lower HOMA-β levels were significantly associated with smaller volumes in multiple hippocampal subfields. Furthermore, even when we analyzed non-diabetic individuals, substantial associations remained between higher GA or lower HOMA-β levels and smaller volumes of the whole hippocampus or the fimbria. Our findings indicate that postprandial glucose fluctuations, postprandial hyperglycemia, and low insulin secretion have a specific effect on the development of smaller hippocampal volume, suggesting that primary prevention of diabetes and/or sufficient glucose control are important for the prevention of dementia.

DOI： 10.1038/s41514-024-00164-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Ophthalmology  

AIMS: To investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population. METHODS: We analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles. RESULTS: Glaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders. CONCLUSIONS: These results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.

DOI： 10.1136/bjo-2023-323987

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Language：English   Publisher：Arteriosclerosis Thrombosis and Vascular Biology  

BACKGROUND: Hyponatremia, frequently observed in patients with chronic kidney disease, is associated with increased cardiovascular morbidity and mortality. Hyponatremia or low osmolality induces oxidative stress and cell death, both of which accelerate vascular calcification (VC), a critical phenotype in patients with chronic kidney disease. Whether hyponatremia or low osmolality plays a role in the pathogenesis of VC is unknown. METHODS: Human vascular smooth muscle cells (VSMCs) and mouse aortic rings were cultured in various osmotic conditions and calcifying medium supplemented with high calcium and phosphate. The effects of low osmolality on phenotypic change and oxidative stress in the cultured VSMCs were examined. Microarray analysis was conducted to determine the main signaling pathway of osmolality-related VC. The transcellular sodium and calcium ions flux across the VSMCs were visualized by live imaging. Furthermore, the effect of osmolality on calciprotein particles (CPPs) was investigated. Associations between arterial intimal calcification and hyponatremia or low osmolality were examined by a cross-sectional study using human autopsy specimens obtained in the Hisayama Study. RESULTS: Low osmolality exacerbated calcification of the ECM (extracellular matrix) of cultured VSMCs and mouse aortic rings. Oxidative stress and osteogenic differentiation of VSMCs were identified as the underlying mechanisms responsible for low osmolality-induced VC. Microarray analysis showed that low osmolality activated the Rac1 (Ras-related C3 botulinum toxin substrate 1)-Akt (protein kinase B) pathway and reduced NCX1 (Na-Ca exchanger 1) expression. Live imaging showed synchronic calcium ion efflux and sodium ion influx via NCX1 when extracellular sodium ion concentrations were increased. An NCX1 inhibitor promoted calcifying media-induced VC by reducing calcium ion efflux. Furthermore, low osmolality accelerated the generation and maturation steps of CPPs. The cross-sectional study of human autopsy specimens showed that hyponatremia and low osmolality were associated with a greater area of arterial intimal calcification. CONCLUSIONS: Hyponatremia and low osmolality promote VC through multiple cellular processes, including the Rac1-Akt pathway activation.

DOI： 10.1161/ATVBAHA.123.320069

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Publisher：Lancet  

Background: Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension. Methods: We used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20–64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson's correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI). Findings: The correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m² (95% CI 2·31–3·28) lower for women and 1·28 kg/m² (1·02–1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone. Interpretation: BMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions. Funding: UK Medical Research Council and UK Research and Innovation (Innovate UK).

DOI： 10.1016/S0140-6736(24)01405-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

<p> <b>Aims:</b> Vascular calcification is observed in advanced atherosclerotic lesions. Vascular calcification is considered to increase the risk of intraplaque hemorrhage and subsequent plaque destabilization; however, there is limited pathohistoological evidence of the association between vascular calcification and intraplaque hemorrhage. The aim of this study was to investigate the association between vascular calcification and intraplaque hemorrhage in the coronary arteries.</p><p> <b>Methods:</b> We examined 374 coronary arteries obtained from the autopsy samples of 126 deceased individuals. The vascular calcification levels of each artery were categorized into no calcification and quintiles of calcification area size among the arteries with calcification. Macrophage infiltration and neovascularization were also evaluated. The association of the calcification area, macrophage area, or number of vessels with the presence of intraplaque hemorrhage in the coronary arteries was estimated using a logistic regression analysis.</p><p><b>Results:</b> Calcification lesions were observed in 149 coronary arteries. Arteries in the fourth quintile of calcification area size had a significantly greater likelihood of intraplaque hemorrhage than the arteries without calcification, after adjusting for confounders: odds ratio 13.13 (95% confidence interval: 2.97–58.16). After evaluating the influence of macrophage infiltration, the highest odds ratio of intraplaque hemorrhage was associated with the combination of large macrophage area and moderately sized calicification areas. The odds ratio of intraplaque hemorrhage additively increased with the combination of calcification and the number of vessels.</p><p><b>Conclusions:</b> The present findings suggest that vascular calcification is significantly associated with intraplaque hemorrhage. The association between vascular calcification and intraplaque hemorrhage may decrease above a certain size of the calcification area.</p>

DOI： 10.5551/jat.64394

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Language：English   Publisher：(一社)日本動脈硬化学会  

1988年1月～2005年11月に死亡した久山町住民のうち126名(男性49名)の剖検で得られた374の冠動脈を用いて、血管石灰化とプラーク内出血の関連性を評価した。149の冠動脈に石灰化病変が認められ、いずれも内膜にみられた。石灰化面積が第4五分位であった動脈では石灰化がなかった動脈と比較してプラーク内出血を有する確率が有意に高かった(p<0.001)。交絡因子について補正後のオッズ比(OR)は13.13(95%CI 2.97～58.16)であった。マクロファージ浸潤の影響を評価した結果、マクロファージ浸潤面積の増加に伴ってプラーク内出血の頻度が有意に増加した。マクロファージ浸潤面積が最も大きく、石灰化面積が中等度(第4五分位)の場合にプラーク内出血のORが最も大きかった。血管新生の影響を評価した結果、血管数の増加に伴ってプラーク内出血の頻度が有意に増加した。プラーク内出血のORは石灰化の存在と血管数により相加的に増加した。以上の結果から、血管石灰化はプラーク内出血と有意に関連し、その関連性は石灰化が一定の面積を超えると低下することが示唆された。

Language：English   Publisher：(一社)日本疫学会  

<Highlight>●preserved ratio impaired spirometry(PRISm)と認知症との関連は明らかにされていない。●本研究では、認知症のない65歳以上の日本人地域高齢住民1,202人を対象に、中央値5.0年間の追跡調査を行った。●PRISm群は、呼吸機能正常群と比べ認知症の発症リスクが約2倍であった。●PRISmは、認知症の発症リスクが高い集団であり、呼吸機能障害の重要なサブタイプといえる。(著者抄録)

Language：English   Publisher：Geroscience  

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.

DOI： 10.1007/s11357-024-01289-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Epidemiological Association  

<p><b>Background:</b> Studies on the association between preserved ratio impaired spirometry (PRISm) and dementia are limited. Indeed, PRISm has often been overlooked or ignored as an index of lung function impairment. Therefore, we investigated the association of PRISm with the risk for the development of dementia in an older Japanese population.</p><p><b>Methods:</b> A total of 1,202 community-dwelling, older Japanese participants aged ≥65 years without dementia were followed up for a median of 5.0 years. Participants were categorized by spirometry as follows: normal spirometry (FEV₁/FVC ≥0.70 and FEV₁ ≥80% predicted), PRISm (≥0.70 and <80%), airflow limitation (AFL) Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 (<0.70 and ≥80%), and AFL GOLD 2 to 4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using a Cox proportional hazards model.</p><p><b>Results:</b> During the follow-up period, 122 participants developed dementia. The age- and sex-adjusted incidences of dementia in the participants with normal spirometry, PRISm, AFL GOLD 1, and AFL GOLD 2 to 4 were 20.5, 37.0, 18.4, and 28.6 per 1,000 person-years, respectively. Participants with PRISm had a higher risk of dementia (HR 2.04; 95% CI, 1.19–3.49) than those with normal spirometry after adjusting for confounders. Moreover, both reduced FEV₁% predicted values and FVC% predicted values were associated with the risk of dementia.</p><p><b>Conclusion:</b> PRISm was associated with an increased risk of dementia in a general older Japanese population.</p>

DOI： 10.2188/jea.je20230207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Geriatrics  

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.

DOI： 10.1186/s12877-024-05131-w

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Language：English  

DOI： 10.1136/bmjph-2023-000186

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Psychiatry and Clinical Neurosciences  

AIM: To assess the association between plasma amyloid β (Aβ) 42/40, phosphorylated tau (p-τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population. METHODS: A total of 1346 Japanese community-dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD-X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia. RESULTS: During the follow-up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non-Alzheimer dementia (non-AD). Lower plasma Aβ42/40 levels and higher plasma p-τ181 levels were significantly associated with developing AD but not non-AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non-AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia. CONCLUSION: Our findings suggest that plasma Aβ42/40 and p-τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all-cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low-invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.

DOI： 10.1111/pcn.13661

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

血漿中Aβ42/40、リン酸化タウ(p-t181)、GFAP、ニューロフィラメント軽鎖(NfL)と認知症リスクとの関連を評価し、これらのバイオマーカーが認知症発症予測能を向上させるかどうか検討した。65歳以上の認知症でない地域在住日本人1346名を5年間前向きに追跡し、血漿バイオマーカーを測定した。Cox比例ハザードモデルを用いて、各バイオマーカーと認知症リスクとのハザード比を推定した。その結果、追跡期間中に151名が認知症を発症し、そのうち108名がアルツハイマー型認知症(AD)、3名が非アルツハイマー型認知症(non-AD)であった。低Aβ42/40および高p-t181はADリスクと有意に関連していたが、non-ADとは関連がなかった。GFAPおよびNfLはADおよびnon-ADのリスクの両方と有意に関連していた。これらのバイオマーカーを認知症リスクモデルに加えることで、発症予測精度が有意に向上した。以上の結果から、Aβ42/40およびp-t181はADの特異的マーカー、GFAPおよびNfLはall-cause dementiaの有力なバイオマーカーであり、これらの測定は臨床で認知症ハイリスク群の特定に有用であることが示唆された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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.

DOI： 10.1038/s41598-024-62688-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journals of Gerontology Series A Biological Sciences and Medical Sciences  

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.

DOI： 10.1093/gerona/glae075

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Pain United Kingdom  

BACKGROUND: Autonomic nervous system dysfunction has been reported to be associated with impaired activities of daily living (ADL) among patients with chronic pain, but the association has not been fully addressed in general populations. This study cross-sectionally investigated the association between autonomic nervous system function and the presence of subjective symptoms affecting ADL in community-dwelling residents with chronic pain. METHODS: A total of 888 residents with chronic pain, aged 40-79 years, who underwent a health examination in 2017-2018 were included. Based on heart rate variability measured by fingertip pulse wave, the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR interval differences (RMSSD), low frequency (LF) power, and high frequency (HF) power were calculated. Symptoms affecting ADL were defined as those scoring ≥1 on the modified Rankin Scale. Odds ratios (ORs) and their 95% confidence intervals (CIs) for symptoms affecting ADL were estimated using a logistic regression analysis. RESULTS: The overall prevalence of symptoms affecting ADL was 39.4%. The ORs for symptoms affecting ADL increased significantly per 1-standard-deviation decrement in log-transformed SDNN (OR 1.23 [95% CI 1.06-1.44]), RMSSD (1.25 [1.08-1.45]), LF power (1.29 [1.11-1.52]), and HF power (1.29 [1.11-1.51]) after adjusting for age, sex, education, hypertension, diabetes, serum total cholesterol level, body mass index, past medical history, current smoking, current drinking, exercise, depressive symptoms, and pain intensity. CONCLUSIONS: Decreased heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. SIGNIFICANCE: Decrease in heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. This article could help scientists understand the significance of autonomic nervous system dysfunction in the pathology of chronic pain. Approaches that target autonomic nervous system dysfunction may be an option to relieve or prevent symptoms affecting ADL for chronic pain sufferers.

DOI： 10.1002/ejp.2224

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Publisher：Power Electronic Devices and Components  

This paper presents a power-cycling degradation monitoring method of an IGBT module with a V<inf>CE(sat)</inf> sensing circuit and junction temperature prediction by a three-dimensional structure model. A chopper circuit was introduced to provide a continuous-current-conducting operation of the IGBT module. The V<inf>CE(sat)</inf> sensing circuit with a low-cost IoT platform “Leafony” was utilized to monitor the junction temperature of an IGBT chip, which transferred the measured signal as digital data, and thus obtained a higher noise immunity than an analog-based circuit. The junction temperature of IGBT chip in the power module was analyzed from the dissipated power of IGBT and the transient thermal impedance between the chips and the ambient. This analysis is effective not only to observe the degradation but also to estimate the thermal resistance. Comparing the temperature profile between experiment and prediction provides health condition of the IGBT model. Predicted thermal profiles agreed with measured ones with 10 % increase of thermal resistance, which was degraded by a power cycle tester. From these results, the proposed monitoring method is effective to detect the progress of power cycle degradation.

DOI： 10.1016/j.pedc.2024.100061

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

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.

DOI： 10.1038/s41598-024-57922-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

Several studies have found associations between poor oral health, particularly tooth loss and cognitivedecline. However, the specific brain regions affected by tooth loss and the probable causes remainunclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan.Between 2016 and 2018, 2454 residents aged ≥60 participated, covering 92.9% of the local agedemographics. This study used comprehensive approach by combining detailed dental examinations,dietary assessments, magnetic resonance imaging (MRI) analysis, and cognitive evaluations. Toothloss, even in cognitively normal individuals, is associated with parahippocampal gyrus atrophy andincreased WMH volume, both of which are characteristics of dementia. Tooth loss was associatedwith altered dietary patterns, notably a reduction in plant-based food intake and an increase in fatty,processed food intake. This study highlights a possible preventative pathway where oral health mayplay a significant role in preventing the early neuropathological shifts associated with dementia.

DOI： 10.1038/s41514-024-00146-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Preventive Cardiology  

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: A total of 2,827 community-dwelling Japanese aged ≥40 years without prior AF were followed up for 10 years (2007-2017). Day-to-day home BPV (defined as coefficients of variation [CoV] of home systolic blood pressure [SBP] for 28 days) were categorized into 4 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. RESULTS: 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, 4.7, 5.3, 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 2.18-fold (95% confidence intervals: 1.18-4.04) increased risk of developing AF compared to those in the lowest quartile. CONCLUSIONS: 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.

DOI： 10.1093/eurjpc/zwae035

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal of Diabetes Investigation  

DOI： 10.1111/jdi.14096

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Language：English   Publisher：(一社)日本疫学会  

＜Highlight＞●本研究は、血清リポ多糖結合蛋白(LBP)値とメタボリックシンドローム(MetS)発症との関連を検討した最初の前向きコホート研究である。●血清LBP値の上昇に伴いメタボリックシンドロームおよびその構成要素の発症リスクは上昇した。●媒介解析において、HOMA-IRと血清高感度CRPは血清LBPとMetS発症との関連に、部分的に介在していた。●血清LBP値とメタボリックシンドロームの発症リスクの関連はインスリン抵抗性と慢性炎症を介した機序が示唆された。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Circulation  

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

DOI： 10.1161/CIRCULATIONAHA.123.065530

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Epidemiological Association  

<p><b>Background:</b> 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.</p><p><b>Methods:</b> 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.</p><p><b>Results:</b> 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; <i>P</i> for trend <0.001). After additional adjustment for homeostasis model assessment of insulin resistance, this association was attenuated but remained significant (<i>P</i> for trend = 0.007). On the other hand, no significant association was observed after additional adjustment for serum high-sensitivity C-reactive protein (<i>P</i> for trend = 0.07).</p><p><b>Conclusion:</b> 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.</p>

DOI： 10.2188/jea.je20220232

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Geriatric Psychiatry and Neurology  

BACKGROUND: Enlarged perivascular spaces (EPVS) of the brain may be involved in dementia, such as Alzheimer's disease and cerebral small vessel disease (CSVD). Hypertension has been reported to be a risk factor for dementia and CSVD, but the association between blood pressure (BP) and perivascular spaces is still unclear. The aim of this study was to determine the association between BP and EPVS volumes and to examine the interactions of relevant factors. METHODS: A total of 9296 community-dwelling subjects aged ≥65 years participated in a brain magnetic resonance imaging and health status screening examination. Perivascular volume was measured using a software package based on deep learning that was developed in-house. The associations between BP and EPVS volumes were examined by analysis of covariance and multiple regression analysis. RESULTS: Mean EPVS volumes increased significantly with rising systolic and diastolic BP levels (P for trend = .003, P for trend<.001, respectively). In addition, mean EPVS volumes increased significantly for every 1-mmHg-increment in systolic and diastolic BPs (both P values <.001). These significant associations were still observed in the sensitivity analysis after excluding subjects with dementia. CONCLUSIONS: The present data suggest that higher systolic and diastolic BP levels are associated with greater EPVS volumes in cognitively normal older people.

DOI： 10.1177/08919887231195235

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Language：Japanese   Publisher：(一社)日本疫学会  

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Language：English   Publisher：Stroke  

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

DOI： 10.1161/STROKEAHA.123.044281

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Clinical Epidemiology  

<p><b>BACKGROUND</b></p><p>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.</p><p><b>METHODS</b></p><p>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.</p><p><b>CONCLUSIONS</b></p><p>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.</p>

DOI： 10.37737/ace.24002

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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

DOI： 10.15082/jsnt.41.4_532

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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

DOI： 10.15082/jsnt.41.4_533

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Publisher：医歯薬出版  

DOI： 10.32118/ayu287131002

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Language：English   Publisher：BMC Pulmonary Medicine  

Background: Human rhinoviruses (HRVs) infection is a common cause of exacerbations in pediatric patients with asthma. However, the effects of corticosteroids on HRV-induced exacerbations in pediatric asthma are unknown. We conducted a prospective observational study to determine the viral pathogens in school-age pediatric inpatients with asthma exacerbations. We assessed the effects of maintenance inhaled corticosteroids (ICS) on the detection rates of HRV species and treatment periods of systemic corticosteroids during exacerbations on pulmonary lung function after exacerbations. Methods: Nasopharyngeal samples and clinical information were collected from 59 patients with asthma exacerbations between April 2018 and March 2020. Pulmonary function tests were carried out 3 months after exacerbations in 18 HRV-positive patients. Changes in forced expiratory volume in 1 second (FEV<inf>1</inf>)% predicted from baseline in a stable state were compared according to the treatment periods of systemic corticosteroids. Results: Fifty-four samples collected from hospitalized patients were analyzed, and viral pathogens were identified in 45 patients (83.3%) using multiplex PCR assay. HRV-A, −B, and -C were detected in 16 (29.6%), one (1.9%), and 16 (29.6%) patients, respectively. The detection rates of HRV-C were lower in the ICS-treated group compared with those in the ICS-untreated group (p = 0.01), whereas maintenance ICS treatment did not affect the detection rate for viral pathogens in total and HRV-A. Changes in FEV<inf>1</inf>% predicted in patients treated with systemic corticosteroids for 6–8 days (n = 10; median, 4.90%) were higher than those in patients treated for 3–5 days (n = 8; median, − 10.25%) (p = 0.0085). Conclusions: Maintenance ICS reduced the detection rates of HRV (mainly HRV-C) in school-age inpatients with asthma exacerbations, and the treatment periods of systemic corticosteroids during exacerbations affected lung function after HRV-induced exacerbations. The protective effects of corticosteroids on virus-induced asthma exacerbations may be dependent upon the types of viral pathogen.

DOI： 10.1186/s12890-023-02798-6

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DOI： 10.5551/jat.ER61960

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

PURPOSE: To examine the association between choroidal thickness and myopic maculopathy in a general Japanese population. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 2841 residents of a Japanese community aged ≥ 40 years, who consented to participate and had available data of choroidal thickness and fundus photographs, were enrolled in this study. METHODS: The choroidal thickness was measured by swept-source OCT. Participants were divided into quartiles of choroidal thickness. Myopic maculopathy was defined according to the classification system of the Meta-analysis of Pathologic Myopia Study Group. Main outcome measures were odds ratios (ORs) of choroidal thickness for prevalent myopic maculopathy. The ORs and 95% confidence intervals (CIs) were estimated using a logistic regression model. MAIN OUTCOME MEASURES: Prevalent myopic maculopathy. RESULTS: Eighty-one participants had myopic maculopathy (45 diffuse chorioretinal atrophy, 31 patchy chorioretinal atrophy, and 5 macular atrophy). Individuals in the lowest quartile of choroidal thickness had a significantly greater OR for the presence of myopic maculopathy than those in the highest quartile of choroidal thickness (OR: 4.78 [95% CI: 1.78-16.72]) after adjusting for confounders, including axial length. The sensitivity analysis among the 1176 myopic individuals with axial length of ≥ 24.0 mm also showed that thinner choroidal thickness was significantly associated with prevalent myopic maculopathy. CONCLUSIONS: The present study demonstrated the significant inverse association between choroidal thickness and the likelihood of myopic maculopathy, suggesting that the measurement of choroidal thickness in addition to axial length would be useful for assessing the risk of myopic maculopathy and elucidating its pathogenesis. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found after the references.

DOI： 10.1016/j.xops.2023.100350

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Publisher：Scientific Reports  

We analyzed the seasonal variations in the number of renal biopsies and clinical characteristics of primary glomerular disease in Japan using the Japan Renal Biopsy Registry (J-RBR). We retrospectively collected clinical and pathological data of patients with primary glomerular disease who were registered in the J-RBR between 2007 and 2018. Immunoglobulin A nephropathy (IgAN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and postinfectious acute glomerulonephritis (PIAGN) constituted the four major glomerular disorders included in this study (total, 13,989; IgAN, 9121; MCNS, 2298; MN, 2447; and PIAGN, 123). The number of patients with IgAN or MCNS was higher during summer. However, no overt seasonal variations were observed in patients with MN or PIAGN. Subgroup analyses suggested that in the patients with IgAN, more renal biopsies of severe cases were performed during winter, probably owing to age and blood pressure. Furthermore, more renal biopsies of severe cases were performed during spring and winter in patients with MCNS even after adjusting for the abovementioned host factors. This study suggests that seasonal factors influence the decision to perform renal biopsy as well as the pathogenesis of primary glomerular disease. Thus, our findings may provide important insights regarding the pathophysiology of primary glomerular disease.

DOI： 10.1038/s41598-023-32182-7

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Language：English   Publisher：BMC Endocrine Disorders  

Following publication of the original article [1], the authors reported an error in the number of participants in Fig. 2. The original Fig. 2 was: The updated Fig. 2 should read: The original article [1] has been updated.

DOI： 10.1186/s12902-023-01513-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Background

Studies have shown that decreased gait speed is associated with impaired cognitive function. However, whether this association is equivalent across ages or genders in the older population remains unclear. Thus, we examined the association between mild cognitive impairment (MCI) and gait speed emphasising the influence of age and gender.

Methods

Overall, 8233 Japanese participants aged ≥65 years were enrolled in this cross‐sectional study between 2016 and 2018. After stratification by gender and age group, the participants' gait speeds were divided into quintiles, and the difference in MCI prevalence at each gait speed quintile was calculated. Logistic regression analyses were performed to assess the odds of MCI for each quintile and to assess the influence of age and gender.

Results

Males had a consistently higher prevalence of MCI than females. The odds of MCI were increased as gait speed decreased. Logistic regression analyses revealed that in the multivariable‐adjusted model 2, the odds ratios (95% confidence interval; CI) for MCI were 2.02 (1.47–2.76) for females and 1.75 (1.29–2.38) for males in the slowest gait speed quintiles compared to the fastest quintile. In the stratified analyses, only males showed an age‐dependent increase in the associations between gait speed and MCI, while females exhibited comparable associations across age groups.

Conclusions

Reduced gait speed was associated with increased odds of MCI, and this association may vary according to gender and age. Therefore, gait speed could serve as a valuable screening tool for MCI, with gender‐ and age‐dependent clinical implications.

DOI： 10.1111/psyg.13013

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Publisher：Nature Medicine  

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance.

DOI： 10.1038/s41591-023-02610-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Clinical Nutrition  

BACKGROUND: The presence of atrial fibrillation (AF) is associated with an over 2-fold increased risk of stroke, heart failure, and cardiovascular mortality. Long chain n-6 PUFAs have been suggested to have a variety of beneficial biologic effects that may reduce AF development; however, prior studies evaluating this relationship are limited. OBJECTIVES: We prospectively evaluated the association between circulating levels of linoleic acid (LA) and arachidonic acid (AA) with incident AF. METHODS: We used participant-level data from a global consortium of 11 prospective cohort studies with measurements of LA and AA in adults (aged ≥18 y). Participating studies conducted de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcomes, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 41,335 participants, 6173 incident cases of AF were ascertained, with median follow-up time of 14 y. In multivariable analysis, per interquintile range (difference between the 10th and 90th percentiles for each fatty acid), circulating n-6 levels were not associated with incident AF. For LA, the hazard ratio per interquintile range was 0.96 (95% confidence interval [CI]: 0.89, 1.04), and for AA, 1.02 (95% CI: 0.94, 1.10), with little evidence of heterogeneity between cohorts. Associations were similarly nonsignificant across subgroups of age, race, and biomarker fraction. CONCLUSIONS: Biomarkers of n-6 fatty acids including LA and AA are not associated with incident AF. These findings suggest that overall effects of n-6 PUFAs on influencing AF development are neutral.

DOI： 10.1016/j.ajcnut.2023.09.008

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

日本人高齢者における軽度認知障害(MCI)と歩行速度の関連について検討した。2016～2018年にJPSC-ADに参加した65歳以上の日本人8233人(男性3540人、女性4693人、平均72.8±6.0歳)を対象とした。性別及び年齢グループにより層別化した後、参加者の歩行速度を5グループに分けた。その結果、歩行速度の低下はMCIのオッズ上昇と関連し、性別及び年齢により変化していた。また、歩行速度はMCIのスクリーニングツールとして有用であることが示された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Endocrine Disorders  

OBJECTIVE: To investigate associations between parenting styles during childhood and diabetes in adulthood in a Japanese community. METHODS: In 2011, 710 community-dwelling Japanese residents aged ≥ 40 years were assessed for the presence of diabetes and for their perceptions of the parenting style of their parents, as measured using the "care" and "overprotection" scales of the Parental Bonding Instrument. Care and overprotection scores for each parent were dichotomized by age-specific median values. Diabetes mellitus was defined as a fasting plasma glucose level of ≥ 7.0 mmol/L, a 2-h post-loaded glucose level of ≥ 11.1 mmol/L, HbA1c ≥ 6.5%, and/or the current use of insulin or oral glucose-lowering agents. The odds ratios (ORs) for prevalent diabetes were calculated using a logistic regression model. RESULTS: The prevalence of diabetes was 14.9%. Subjects with a high paternal overprotection score had a significantly greater likelihood of prevalent diabetes than those with a low paternal overprotection score after adjusting for confounders (OR 1.71, 95% confidence interval [CI] 1.06-2.77), while there was no significant association between paternal care and diabetes. Additionally, the multivariable-adjusted ORs for the presence of diabetes were significantly higher in subjects with a low maternal care score (OR 1.61, 95%CI 1.00-2.60) or in subjects with a high maternal overprotection score (OR 1.73, 95%CI 1.08-2.80). Moreover, the subjects with a low care score and high overprotection score for both their father and mother had a significantly higher multivariable-adjusted OR of diabetes than those with a high care score and low overprotection score for both parents (OR 2,12, 95%CI 1.14-3.95). CONCLUSIONS: This study suggests that inadequate care and excessive overprotection during childhood may contribute to the development of diabetes in adulthood.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：New England Journal of Medicine  

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

DOI： 10.1056/NEJMoa2206916

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DOI： 10.1016/S2213-8587(23)00223-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurology  

BACKGROUND AND OBJECTIVES: Epidemiological 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 underwent brain MRI scans and a comprehensive health examination. Frequency of contact with non-cohabiting relatives and friends was determined by asking a single question with four categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV) and white matter lesions 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 to that in the group with the highest frequency (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesions volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency 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 value of FDR correction <0.05). The relationships appeared to be partly mediated by depressive symptoms, which accounted for 15% to 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.

DOI： 10.1212/WNL.0000000000207602

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DOI： 10.1523/ENEURO.0209-23.2023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the American College of Cardiology  

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

DOI： 10.1016/j.jacc.2023.05.024

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Language：English   Publisher：Japan Atherosclerosis Society  

<p>The Hisayama Study is an ongoing epidemiological study of stroke, coronary artery disease (CAD), and other noncommunicable diseases in a general Japanese population established in 1961. According to the longitudinal data from the Hisayama Study, average levels of systolic blood pressure among hypertensive individuals have decreased with time since 1961. In contrast, the prevalence of metabolic risk factors such as obesity, hypercholesterolemia, and glucose intolerance has increased with time. The incidence rates of ischemic stroke in this population have declined significantly as a result of improvement in hypertension management, but the proportion of atherothrombotic brain infarction (ATBI) and embolic stroke among the total ischemic stroke cases have increased probably due to the increased prevalence of metabolic risk factors and the increased number of patients with atrial fibrillation (AF) with super-aging population. Therefore, a strategy to reduce the risks of ATBI and embolic stroke by comprehensive management of their risk factors is necessary.</p><p>In this review, we first show the secular trends in the incidence of stroke and the prevalence of its risk factors using the data from the Hisayama Study. Then, the studies for the association of traditional risk factors with stroke development in the Hisayama Study are introduced. Finally, we developed risk prediction models to estimate the absolute risk of atherosclerotic cardiovascular disease (ASCVD; including ATBI and CAD) and AF, that may be used for the stratification of future risk of ATBI and AF-related stroke in clinical practice or health examination.</p>

DOI： 10.5551/jat.rv22004

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal of Dental Research  

Ectopic enrichment of oral microbes in the gut is a notable alteration in gut microbial balance. These microbes are likely delivered from the oral cavity with saliva and food; however, evidence of oral–gut microbial transmission is insufficient and needs further investigation. In this observational study, we examined 144 pairs of saliva and stool samples collected from community-dwelling adults to verify the oral–gut microbial link and identify the relevant influencing factors on the increased abundance of oral microbes within the gut. The bacterial composition of each sample was determined using PacBio single-molecule long-read sequencing of the full-length 16S ribosomal RNA gene and amplicon sequence variant (ASV) analysis. Although the bacterial compositions of salivary and gut microbiota were distinctly different, at least 1 ASV was shared between salivary and gut microbiota in 72.9% of subjects. Shared ASVs accounted for 0.0% to 63.1% (median 0.14%) of the gut microbiota in each subject and frequently included abundant Streptococcus salivarius and Streptococcus parasanguinis. Their total relative abundance in the gut was significantly higher in older subjects or those with dental plaque accumulation. The gut microbiota with ≥5% of shared ASVs displayed a higher abundance of Streptococcus, Lactobacillus, and Klebsiella and a lower abundance of Faecalibacterium, Blautia, Megamonas, and Parabacteroides. Our study presents evidence for the translocation of oral bacteria to the gut in community-dwelling adults and suggests that aging and dental plaque accumulation contribute to an increased abundance of oral microbes in the gut, which might be relevant to the compositional shift in the gut commensals.

DOI： 10.1177/00220345231160747

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Endocrinology and Metabolism  

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.

DOI： 10.1210/clinem/dgad011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

<p> <b>Aim:</b> 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.</p><p> <b>Methods:</b> 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.</p><p><b>Results:</b> 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.</p><p><b>Conclusion:</b> In a Japanese community, the serum EPA/AA ratio decreased over 10 years at the population level, especially in middle-aged participants.</p>

DOI： 10.5551/jat.63727

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Psychiatry and Clinical Neurosciences  

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.

DOI： 10.1111/pcn.13533

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

高齢者集団における白質病変容積(WMLV)及び脳萎縮と認知症リスクの関係について検討した。福岡県久山町の認知症がない65歳以上の住民のうち、脳MRIを実施した1158人(男性512人、女性646人、平均73.6±6.2歳)を対象とした。WMLVをLesion Segmentation Toolboxを用いてセグメント化し、全脳容積(TBV)と局所灰白質容積をvoxel-based morphometryを用いて推定した。頭蓋内脳容積(ICV)に対するWMLVの比(WMLV/ICV)を計算し、WMLV/ICVと認知症リスクの関連をCox比例ハザードモデルにより推定した。ICVに対するTBVの比(TBV/ICV)で定義された全脳萎縮と、著者等の過去の報告で定義された認知症関連の脳局所萎縮を算出した。5年間の経過観察期間中に113人が認知症を発症した。認知症リスクはWMLV/ICVとともに有意に増加した。WMLV/ICVが大きくTBV/ICVが小さい住民と、WMLV/ICVが大きく認知症関連の脳局所萎縮の数が多い住民では認知症リスクが相加的に増加することが観察された。

Language：English   Publisher：(一社)日本動脈硬化学会  

日本の集団ベース研究である久山町研究のデータを用いて、集団レベルでの血清エイコサペンタエン酸(EPA)/アラキドン酸(AA)比、血清EPA濃度、血清AA濃度の10年間の変化を評価した。2002～2003年と2012～2013年に久山町研究に参加した40歳以上でEPA薬を服用していない地域住民(2002～2003年は3194名、2012～2013年は3220名)のデータを解析した。血清EPA/AA比は10年間で低下し、2002年と2012年の幾何平均値はそれぞれ0.40、0.32であった。血清EPA濃度は軽度に上昇し、2002年と2012年の幾何平均値はそれぞれ59.0μg/mL、65.1μg/mLであった。血清AA濃度は大きく上昇し、2002年と2012年の幾何平均値はそれぞれ147.6μg/mL、199.9μg/mLであった。年齢群別の解析では、血清EPA/AA比は80歳以上を除いて有意に低下し、若年群ほど低下が大きかった。血清EPA濃度は50～59歳で有意に低下し、70歳以上で有意に上昇した。血清AA濃度はすべての年齢群で有意に上昇した。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: Poor family functioning has been reported to be associated with the severity of chronic pain in outpatients, but the association has not been fully addressed in general populations. The present study aimed to examine the association between family dysfunction levels and the presence of chronic pain in a community-dwelling Japanese population. METHODS: A total of 2598 participants aged ≥40 years were classified as having healthy, borderline or unhealthy family functioning. Chronic pain was defined as subjective pain for three months or longer, and further classified by pain intensity, the number of chronic pain sites, pain duration and the extent of pain spread. A logistic regression model was used to compute the odds ratios (ORs) for chronic pain outcomes. RESULTS: The prevalence of chronic pain was 49%. The age- and sex-adjusted prevalence of total and severe chronic pain were increased significantly with increasing family dysfunction levels (all p for trend <0.01). After adjusting for sociodemographic, physical, social and family structure factors, the ORs (95% confidence intervals [CI]) for having chronic pain among borderline and unhealthy groups were 1.20 (1.01-1.44) and 1.43 (1.15-1.79), respectively, as compared with a healthy family function group. The association was stronger among people who were employed and those who were living with their children. In addition, the ORs for severe chronic pain increased significantly with increasing levels of family dysfunction. CONCLUSIONS: The family dysfunction level was positively associated with the presence as well as the severity of chronic pain in a community-dwelling population. SIGNIFICANCE: A biopsychosocial burden due to family relationships could worsen the clinical presentation of pain. Social support or family therapy for dysfunctional families would be a potential initiative for the prevention or management of chronic pain.

DOI： 10.1002/ejp.2076

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Publisher：Nature  

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being^1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m^–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.

DOI： 10.1038/s41586-023-05772-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Archives of Gerontology and Geriatrics  

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.

DOI： 10.1016/j.archger.2022.104883

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Kidney Medicine  

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.

DOI： 10.1016/j.xkme.2022.100593

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Publisher：Plos One  

Stay-at-home strategies taken during the COVID-19 pandemic changed our lifestyle drastically. Although marital status and household size are important social determinants of health that affect lifestyle, their impacts on lifestyle during the pandemic are still unclear. We aimed to evaluate the association between marital status, household size, and lifestyle changes during the first pandemic in Japan. Questionnaire surveys on lifestyle changes from before to during the first COVID-19 pandemic were conducted on October 2020 in Japan. Classified into age groups, multivariable logistic regression analysis was performed to examine the combined association of marital status and household size on lifestyle, adjusted for potential confounders including socioeconomic factors. In our prospective cohort study, 1928 participants were included. Among older participants, the singles living alone were likely to perceive more unhealthy lifestyle changes (45.8%), compared with the married (33.2%), and significantly associated with at least one unhealthy change [adjusted odds ratio (OR): 1.81, 95% confidence interval (CI): 1, 18-2.78], mainly due to decreased physical activity and increased alcohol consumption. Meanwhile, the younger participants showed no significant association between marital status, household size, and unhealthy changes, while those living alone had 2.87 times higher odds of weight gain (≥ 3 kg) than the married (adjusted OR: 2.87, 95% CI: 0.96-8.54) during the pandemic. Our findings suggest that older singles living alone are potentially vulnerable subgroups to drastic social changes which warrant special attention to prevent adverse health outcomes and additional burden on health systems in the following future.

DOI： 10.1371/journal.pone.0283430

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Diabetes  

BACKGROUND: This study investigated the sex differences in the risk of end-stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. METHODS: This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. RESULTS: During a median follow-up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02-1.75; p = .034) and death (HR 1.64; 95% CI 1.24-2.16; p = .001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo- and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. CONCLUSIONS: In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Purpose: To examine the secular trends in the prevalence, incidence, and progression rates of diabetic retinopathy (DR) in a Japanese community. Methods: Community-dwelling Japanese residents aged ≥ 40 years with diabetes participated in comprehensive systemic and ophthalmological surveys, including an examination for DR, in 1998 (n = 220), 2007 (n = 511), 2012 (n = 515), and 2017 (n = 560). DR was assessed using colour fundus photographs after pupil dilation according to the modified Airlie House classification system. To compare the frequencies of newly developed or progressed DR between the studied decades, two eye cohorts were established (the 2000s cohort included 145 participants examined in 1998 and 2007; the 2010s cohort included 255 participants examined in 2007, 2012, and 2017). Trends in the prevalence, incidence, and progression rate of DR were tested by logistic regression analysis with a generalised estimating equation. Results: The age-adjusted prevalence of DR among individuals with diabetes decreased significantly with time from 1998 to 2017 (27.4% in 1998, 22.8% in 2007, 12.8% in 2012, and 6.4% in 2017; p for trend < 0.001). During this period, the prevalence of DR was decreasing in every haemoglobin A<inf>1c</inf> category, but it remained constant in the high systolic blood pressure category. In addition, the rates of new-onset of DR were significantly lower in the 2010s compared to the 2000s (p < 0.001). Conclusion: Our findings suggest that the prevalence and incidence of DR among diabetic people significantly decreased with time over the past two decades in a general Japanese population.

DOI： 10.1007/s00417-022-05839-8

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

<p>代謝性疾患の有病率の増加に伴い，冠動脈疾患に加えアテローム血栓性脳梗塞の予防の重要性が増している．そのため，これらの動脈硬化性疾患発症の絶対リスク評価に基づいた予防対策は有意義であるといえる．福岡県久山町で継続されている循環器疾患の前向きコホート研究（久山町研究）では，高い予測能を有する動脈硬化性疾患発症のリスク予測モデルを開発した．本稿では，このリスク予測モデルの作成の経緯と活用法を紹介する．</p>

DOI： 10.2169/naika.112.165

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Human lifespan is reported to be heritable. Although previous genome-wide association studies (GWASs) have identified several loci, a limited number of studies have assessed the genetic associations with the real survival information on the participants. We conducted a GWAS to identify loci associated with survival time in the Japanese individuals participated in the BioBank Japan Project by carrying out sex-stratified GWASs involving 78,029 males and 59,664 females. Of them, 31,324 (22.7%) died during the mean follow-up period of 7.44 years. We found a novel locus associated with survival (BET1L; P = 5.89 × 10⁻⁹). By integrating with eQTL data, we detected a significant overlap with eQTL of BET1L in skeletal muscle. A gene-set enrichment analysis showed that genes related to the BCAR1 protein–protein interaction subnetwork influence survival time (P = 1.54 × 10⁻⁷). These findings offer the candidate genes and biological mechanisms associated with human lifespan.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ  

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN: Pooled analysis. DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2 and <75% of baseline rate. RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I2=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I2=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I2=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m2), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

DOI： 10.1136/bmj-2022-072909

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publisher：Clinical and Experimental Nephrology  

Background: In 2012, we established a CKD network in collaboration with the public health service, primary care physicians, and nephrologists in the Kasuya area. The aim of this study was to clarify if our CKD network was effective in preventing CKD progression. Methods: 1591 subjects, who had CKD in health checks in 2012 were included in this study. The slope of estimated glomerular filtration rate (eGFR) was compared before and after 2012. Parameters at the first health check visit before 2012, visit in 2012, and the last visit after 2012, were compared. Paired t test, analysis of variance for repeated measurements, and the Friedman test were used for the analysis. Results: Mean age was 65 years. There were 781 men and 810 women. Mean eGFR was 59 ml/min/1.73 m². The mean slope of eGFR before 2012 was −1.833 ml/min/1.73 m²/year and significantly reduced to − 0.297 after 2012. Low-density lipoprotein cholesterol showed a significant serial lowering. Uric acid was significantly elevated in 2012 compared to the first visit and had decreased by the last. The dipstick urinary protein significantly increased in 2012 compared to the first visit and decreased by the last. The number of current smokers showed a significant reduction over time. On the other hand, systolic blood pressure (SBP) and HbA1c significantly elevated at the last visit. Conclusion: The Kasuya CKD network may be effective in preventing CKD progression.

DOI： 10.1007/s10157-022-02267-0

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Language：English   Publisher：(一社)日本腎臓学会  

粕屋地区CKD対策連携システムは、福岡県の粕屋地区で公的保健サービス、一次診療医、腎臓科医が連携し慢性腎臓病(CKD)の進行予防を目指すネットワークとして2012年に設立された。本研究では、上記システムの効果を明らかにした。2012年に健康診断を受けたCKD罹患の被検者1591名(女性810名、平均65±7歳)を組み入れた。推算糸球体濾過量(eGFR)の平均値は59mL/分/1.73m2であった。2012年以前で最初の健康診断受診時と、2012年以後の最直近の受診時の結果も加えてeGFRの変化速度を計算した。その結果、2012年以前の時期では-1.83mL/分/1.73m2/年であったが、2012年以後では-0.30mL/分/1.73m2/年と、その低下速度は緩やかになっていた。低比重リポ蛋白(LDL)コレステロール値は経時的にみて有意に低下していた。尿酸値、および尿試験紙による尿蛋白は初回受診時に比べ2012年には有意に増高し、最直近の受診時までには低減していた。現喫煙者数は全期間を通じて有意に減少していた。収縮期血圧とHbA1c値は最直近の受診時において有意な上昇が示されていた。粕屋地区CKD対策連携システムはCKD進行予防に効果があると考えられた。

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Language：Japanese   Publisher：Japanese Society of Biological Psychiatry  

DOI： 10.11249/jsbpjjpp.34.1_38

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Language：Japanese   Publisher：Japanese Society of Neurological Therapeutics  

DOI： 10.15082/jsnt.40.6_s167

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Atherosclerosis Society  

<p> <b>Aim:</b> 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.</p><p><b>Methods:</b> 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.</p><p><b>Results:</b> 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.</p><p><b>Conclusions:</b> 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.</p>

DOI： 10.5551/jat.63344

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Language：English   Publisher：(一社)日本動脈硬化学会  

一般日本人集団の前向き追跡データを用いて、再発性脳卒中の5年リスクにみられる傾向を半世紀にわたり検討した。福岡県久山町の住民を対象に、1961年から続けられている久山町研究のデータを利用した。1961年(154名)、1974年(144名)、1988年(172名)、2002年(146名)を起点とする四つのコホートを設定し、脳卒中発症患者を起点から10年間追跡したデータを用いて再発性脳卒中リスクを調査した。全種類の脳卒中および虚血性脳卒中を発症した後の再発性脳卒中リスクは、一番目(1961年)のコホートから三番目のコホートにかけて有意に低下していたが、三番目から四番目のコホートでは明瞭な変化は示されなかった。出血性脳卒中後の同リスクは主として一番目から二番目のコホートにかけて低下しており、二番目から四番目まででは明らかな低下はみられなかった。こうした傾向は年齢・性別で調整しても実質的に不変であった。

Language：English   Publisher：Circulation  

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

DOI： 10.1161/CIRCULATIONAHA.122.060700

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Language：English   Publisher：Nature  

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry^1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis³, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach⁴, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry⁵. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

DOI： 10.1038/s41586-022-05165-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Publisher：Clinical and Experimental Nephrology  

Background: Hypertension is an important prognostic predictor in patients with chronic kidney disease (CKD), and the recommended target blood pressure has been continuously revised. This study aimed to reveal the current antihypertensive practices in Japanese patients with CKD. Methods: In the Fukuoka Kidney disease Registry, we extracted 3664 non-dialysis-dependent patients with CKD. Apparent treatment-resistant hypertension (aTRH) was defined as a failure of blood-pressure control treated with three antihypertensive medication classes or a treatment with ≥ 4 classes regardless of blood pressure. The blood-pressure control complied with the target blood pressure recommended by the KDIGO 2012 guideline. Results: The median age of the patients was 67 years, body mass index (BMI) was 23 kg/m², and estimated glomerular filtration rate (eGFR) was 40 mL/min/1.73 m². The number of patients with unachieved blood-pressure control was 1933, of whom 26% received ≥ 3 classes of antihypertensive medications. The first choice of medication was renin–angiotensin system inhibitors, followed by calcium-channel blockers. The rate of thiazide use was low in all CKD stages (3–11%). The prevalence of aTRH was 16%, which was significantly associated with BMI (odds ratio [95% confidence interval] per 1-standard deviation change, 1.38 [1.25–1.53]), decreased eGFR (1.87 [1.57–2.23]), as well as age, diabetes mellitus, and chronic heart disease. Conclusions: Renal dysfunction and obesity are important risk factors of aTRH. Even under nephrologist care, most patients were treated with insufficient antihypertensive medications. It is important to prescribe sufficient classes of antihypertensive medications, including diuretics, and to improve patients’ lifestyle habits.

DOI： 10.1007/s10157-022-02250-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pain  

ABSTRACT: Chronic low back pain (CLBP) is the leading cause of years lived with disability. Recently, it has been reported that CLBP is associated with alterations in the central nervous system. The present study aimed to investigate the association between CLBP and regional brain atrophy in an older Japanese population. A total of 1106 community-dwelling participants aged ≥65 years underwent brain magnetic resonance imaging scans and a health examination in 2017 to 2018. We used the FreeSurfer software for the analysis of brain magnetic resonance imaging. Chronic pain was defined as subjective pain for ≥3 months. Participants were divided into 3 groups according to the presence or absence of chronic pain and the body part that mainly suffered from pain: a "no chronic pain (NCP)" group (n = 541), "CLBP" group (n = 189), and "chronic pain in body parts other than the lower back (OCP)" group (n = 376). The brain volumes of the ventrolateral and dorsolateral prefrontal cortex, the posterior cingulate gyrus, and the amygdala were significantly lower in the CLBP group than in the NCP group after adjustment for sociodemographic, physical, and lifestyle factors and depressive symptoms. In addition, the left superior frontal gyrus was identified as a significant cluster by the Query, Design, Estimate, Contrast interface. There were no significant differences in the brain volumes of pain-related regions between the NCP and the OCP groups. The present study suggests that CLBP is associated with lower brain volumes of pain-related regions in a general older population of Japanese.

DOI： 10.1097/j.pain.0000000000002612

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Language：English   Publisher：Journal of Neuropathology and Experimental Neurology  

The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of <2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.

DOI： 10.1093/jnen/nlac078

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1401209919

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the American Heart Association  

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.

DOI： 10.1161/JAHA.122.027173

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Diabetes Investigation  

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.

DOI： 10.1111/jdi.13844

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

通勤手段の違いが糖尿病発症リスクに及ぼす影響について検討した。対象は福岡県久山町の住民検診を受診した40～79歳の住民1208名で、通勤手段に徒歩か自転車を含む活動的通勤者が189名、自動車や公共交通機関のみの非活動的通勤者が653名、非通勤者が366名であった。追跡期間中央値14年で191名が糖尿病を発症した。Cox比例ハザードモデルによる解析の結果、活動的通勤者は非活動的通勤者に比べて糖尿病発症リスクが有意に低かった(調整HR 0.54、95%CI 0.31～0.92、p=0.02)。通勤形態別にみた糖尿病発症のHR(95%CI)は、非活動的通勤者を基準として、自転車のみが0.46(0.22～0.98、p=0.04)、徒歩のみが0.14(0.02～1.02、p=0.053)であった。徒歩と非活動的通勤手段の併用は、糖尿病発症リスクの低下と関連しなかった(HR 1.69、95%CI 0.77～3.71)。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journals of Gerontology Series A Biological Sciences and Medical Sciences  

Altruistic social activity, such as giving support to others, has shown protective benefits on dementia risk and cognitive decline. However, the pathological mechanism is unclear. In the present study, we investigated the association between altruistic social activity and brain regional gray matter. Furthermore, to explore the psychological interplay in altruistic social activity, we tested mediating effect of depressive symptoms on brain regional gray matter. We performed a cross-sectional Voxel-Based Morphology (VBM) analysis including 8695 old adults (72.9±6.1 years) from Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) Cohort. We measured altruistic social activities by self-report questionnaire, depressive symptoms by Geriatric Depression Scale (GDS)-short version. We employed the whole-brain VBM method to detect relevant structural properties related to altruistic social activity. We then performed multiple regression models to detect the mediating effect of depressive symptoms on particular brain regional gray matter volume while adjusting possible physical and social lifestyle covariables. We found that altruistic social activity is associated with larger gray matter volume in posterior insula, middle cingulate gyrus, hippocampus, thalamus, superior temporal gyrus, anterior orbital gyrus, and middle occipital gyrus. Depressive symptoms mediated over 10% on altruistic social activity and hippocampus volume, over 20% on altruistic social activity and cingulate gyrus volume. Our results indicated that altruistic social activity might preserve brain regional gray matter where are sensitive to aging and cognitive decline. Meanwhile, this association may be explained by indirect effect on depressive symptoms, suggesting that altruistic social activity may mitigate the neuropathology of dementia.

DOI： 10.1093/gerona/glac093

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Respiratory and Critical Care Medicine  

RATIONALE: Several Western studies have reported that participants with preserved ratio impaired spirometry (PRISm) have higher risks of airflow limitation (AFL) and death. However, evidence in East Asian populations is limited. OBJECTIVES: To investigate the relation between PRISm and the risks of death and incident AFL in a Japanese population. METHODS: A total of 3,032 community-dwelling Japanese participants aged ≥40 years were followed up for a median of 5.3 years by annual spirometry examinations. Participants were classified into lung function categories at baseline as follows: normal spirometry (forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ≥0.70 and FEV1 ≥80% predicted), PRISm (≥0.70 and <80%), AFL Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 (<0.70 and ≥80%), and AFL GOLD 2-4 (<0.70 and <80%). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed using a Cox proportional hazard model. MEASUREMENTS AND MAIN RESULTS: During the follow-up period, 131 participants died, 22 of whom died from cardiovascular disease, and 218 participants developed AFL. When examining the prognosis of each baseline pulmonary function category, participants with PRISm had higher risks of all-cause death (HR 2.20 [95%CI: 1.35 to 3.59]) and cardiovascular death (HR 4.07 [1.07 to 15.42]) than those with normal spirometry after adjusting for confounders. Moreover, the multivariable-adjusted risk of incident AFL was greater in participants with PRISm than in those with normal spirometry (HR 2.48 [1.83 to 3.36]). CONCLUSIONS: PRISm was associated with higher risks of all-cause and cardiovascular death and a greater risk of the development of AFL in a Japanese community. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI： 10.1164/rccm.202110-2302OC

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Human Brain Mapping  

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.

DOI： 10.1002/hbm.25899

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Psychogeriatrics  

BACKGROUND: The number of dementia patients is increasing worldwide, especially in Japan, which has the world's highest ageing population. The increase in the number of older people with dementia is a medical and socioeconomic problem that needs to be prevented, but the actual situation is still not fully understood. METHODS: Four cross-sectional studies on dementia were conducted in 1997, 2004, 2012, and 2016 for complete enumeration of all residents aged 65 years and older. We examined the secular trends in the prevalence of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and other/unclassified dementia. RESULTS: The age-standardised prevalence of all-cause dementia significantly increased (4.5% in 1997, 5.7% in 2004, 5.3% in 2012, 9.5% in 2016; P for trend <0.05). Similar trends were observed for AD (1.7%, 3.0%, 2.5% and 4.9%, respectively; P for trend <0.05) and other/unclassified dementia (0.8%, 1.0%, 1.0% and 2.2%, respectively; P for trend <0.05), whereas no significant change in VaD was seen (2.1%, 1.8%, 1.8%, 2.4%, respectively; P for trend = 0.77). The crude prevalence of all-cause dementia and AD increased from 1997 to 2016 among participants aged 75-79 years and ≥85 years (all P for trend <0.05). Similar trends were observed for other/unclassified dementia among participants aged ≥80 years (all P for trend <0.05), but not in VaD. CONCLUSIONS: The prevalence of dementia has increased beyond the ageing of the population, suggesting that factors in addition to ageing are involved in the increase in the number of older people with dementia. To control the increase in the number of older people with dementia, elucidation of secular trends in the incidence, mortality, and prognosis of dementia as well as the factors that promote and protect against dementia, and development of preventive strategies are necessary.

DOI： 10.1111/psyg.12865

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

日本人高齢者における認知症有病率の経時変化について検討した。愛媛県中山町の65歳以上の全住民を対象とした横断調査を1997年、2004年、2012年、2016年に実施した。認知症と診断された高齢者をアルツハイマー病(AD)、脳血管性認知症、その他/分類不能に分けた。その結果、全原因認知症の年齢標準化有病率は有意に上昇していた(1997年4.5%、2004年5.7%、2012年5.3%、2016年9.5%、P for trend<0.05)。AD、その他/分類不能でも有意な上昇が認められたが、脳血管性認知症では有意な変化は認められなかった。全原因認知症およびADの粗有病率は、1997～2016年に75～79歳および85歳以上で有意に上昇していた。80歳以上におけるその他/分類不能認知症でも有意な上昇が認められたが、脳血管性認知症では、いずれの年齢層においても有意な経年変化は認められなかった。以上から、認知症高齢者の増加の背景には高齢化以外の要因が関与していることが示唆された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Physical frailty has been associated with adverse outcomes such as dementia. However, the underlying structural brain abnormalities of physical frailty are unclear. We investigated the relationship between physical frailty and structural brain abnormalities in 670 cognitively unimpaired individuals (mean age 70.1 years). Total brain volume (TBV), hippocampal volume (HV), total white matter hypointensities volume (WMHV), and estimated total intracranial volume (eTIV) on the 3D T1-weighted images were automatically computed using FreeSurfer software. Participants were divided into two states of physical frailty (robust vs. prefrail) based on the revised Japanese version of the Cardiovascular Health Study criteria. The multivariable-adjusted mean values of the TBV-to-eTIV ratio was significantly decreased, whereas that of the WMHV-to-eTIV ratio was significantly increased in the prefrail group compared with the robust group. Slowness, one of the components of physical frailty, was significantly associated with reduced TBV-to-eTIV and HV-to-eTIV ratios, and slowness and weakness were significantly associated with an increased WMHV-to-eTIV ratio. Our results suggest that the prefrail state is significantly associated with global brain atrophy and white matter hypointensities. Furthermore, slowness was significantly associated with hippocampal atrophy.

DOI： 10.1038/s41598-022-16190-7

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publisher：ESMO Open  

The authors regret that despite our best care and attention, we have discovered one error in text and corresponding errors in Table 3 and Supplementary Table S2. 1) One error, placed in the “Toxicity” paragraph in Results section has now been corrected as follows:“Radiation pneumonitis, the most clinically important toxicity, occurred in 14 (82%; grade 1) and 2 (12%; grade 2) patients; …”. 2) In Table 3, number and proportion of those with any grade radiation pneumonitis in CRT phase have also been corrected as “16 (94)”.3) Supplementary Table S2 has also been corrected, according to the former correction of number of patients who had pneumonitis events from 14 to 16.The authors would like to apologize for any inconvenience caused.

DOI： 10.1016/j.esmoop.2022.100532

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

We examined the association of serum s-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH) (methionine metabolites), and their ratio on the risk of dementia and death in a community-dwelling population of older Japanese individuals. 1371 residents of Hisayama, Japan, aged 65 years or older and without dementia, were followed for a median of 10.2 years (2007-2017). We divided serum SAM, SAH, and SAM/SAH ratio into quartiles. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of serum SAM, SAH, and SAM/SAH ratio levels on the risk of a composite outcome of all-cause dementia or death, and each outcome. During the follow-up, 635 participants developed all-cause dementia and/or died, of which 379 participants developed dementia and 394 deaths occurred. The multivariable-adjusted HRs of the composite outcome decreased significantly with increasing serum SAM levels (P for trend = 0.01), while they increased significantly with higher serum SAH levels (P for trend = 0.03). Higher serum SAM/SAH ratio levels were significantly associated with a lower risk of the composite outcome (P for trend = 0.002), as well as with lower risk of each outcome. Our findings suggest that the balance of methionine metabolites may closely associate with the risk of dementia and death.

DOI： 10.1038/s41598-022-16242-y

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Diabetes Care  

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.

DOI： 10.2337/dc21-1911

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ophthalmology Science  

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.

DOI： 10.1016/j.xops.2022.100157

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1111/jth.15698

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jth.15698

Publisher：東京医学社  

DOI： 10.24479/kd.0000000167

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publisher：Journal of Periodontology  

Background: This study aimed to examine whether modifiable risk factors can predict tooth loss over 10 years and estimate population attributable risk (PAR) for a combination of modifiable factors. Methods: This longitudinal study included 1466 participants who underwent dental examinations in 2007 and 2017 and were aged 40 to 79 years at baseline. Periodontal conditions were assessed using the 2018 periodontal classification. Incident tooth loss was defined as ≥4 teeth lost over a 10-year period. We calculated the partial PAR (pPAR%) for tooth loss to estimate the combined effect of modifiable risk factors. Results: Incidence of tooth loss was 17.5%. Directed acyclic graphs were used to identify risk factors for tooth loss. A logistic regression model showed that baseline periodontitis, dental caries experience, no regular dental visit, periodontal treatment, smoking, and obesity were associated with tooth loss after adjusting for covariates; pPAR% was 55.5% (95% confidence interval: 31.1% to 73.0%) in periodontitis Stage III to IV and 87.6% (50.4% to 97.4%) in the combination of all factors, respectively. The sex-stratified analysis showed that smoking and no regular dental visit in men and obesity in women were identified as potential risk factors for tooth loss. Conclusions: Modifiable factors accounted for most cases of incident tooth loss. Risk factors for tooth loss might differ by sex, suggesting that the appropriate approach for preventing tooth loss base on sex.

DOI： 10.1002/JPER.21-0191

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the American Geriatrics Society  

BACKGROUND: Little is known about the influence of serum level of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is a soluble type of an innate immune receptor expressed on the microglia, on the association of the daily sleep duration with the risk of dementia. METHODS: A total of 1230 Japanese community-residents aged 60 and older without dementia were followed prospectively for 10 years (2002-2012). Serum sTREM2 levels were divided into two groups using the median value (334.8 pg/ml). Self-reported daily sleep duration was grouped into three categories of <5.0, 5.0-7.9, and ≥8.0 h. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) of daily sleep duration on the risk of dementia according to serum sTREM2 levels. RESULTS: During the follow-up, 262 subjects developed dementia. In subjects with low serum sTREM2 levels, subjects with ≥8.0 h of daily sleep had a significantly greater risk of dementia (multivariable-adjusted HR 2.05 [95% CI 1.32-3.19]) than those with 5.0-7.9 h of daily sleep, but those with <5.0 h did not. In contrast, the risk of dementia increased significantly in subjects with both <5.0 (1.95 [1.03-3.68]) and ≥8.0 h of daily sleep (1.48 [1.06-2.07]) in the subjects with high serum sTREM2 levels. CONCLUSIONS: The influence of daily sleep duration on risk of dementia differed according to serum sTREM2 levels in the older Japanese population. Short daily sleep may be associated with greater risk of dementia only in subjects with a high serum sTREM2 level.

DOI： 10.1111/jgs.17634

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Periodontology  

AIM: To evaluate the longitudinal association between yogurt product intake and oral health in a population-based study. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

DOI： 10.1111/jcpe.13593

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Geriatrics  

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 < 0.05), but not VaD, after adjusting for confounders. Subjects allocated the highest quartile of vegetable intake had 27 and 31% lower risk of dementia and AD, respectively, than those with the lowest quartile. The risk of dementia decreased significantly with higher intakes of vitamin A, riboflavin, vitamin C, magnesium, calcium, and potassium (all P-trend < 0.05). Subjects with higher total dietary fiber intake tended to be at decreased risk for total dementia (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.

DOI： 10.1186/s12877-022-02939-2

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Language：English   Publisher：Japan Atherosclerosis Society  

<p><b>Aim:</b>To develop and validate a new risk prediction model for predicting the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in Japanese adults. </p><p><b>Methods:</b> 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. </p><p><b>Results:</b> 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: <i>P</i>=0.29 for the multivariable model, 0.52 for the simplified score). </p><p><b>Conclusion:</b> 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. </p>

DOI： 10.5551/jat.61960

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurology Neurosurgery and Psychiatry  

OBJECTIVE: To assess the association of regional grey matter atrophy with dementia risk in a general older Japanese population. METHODS: We followed 1158 dementia-free Japanese residents aged ≥65 years for 5.0 years. Regional grey matter volume (GMV) at baseline was estimated by applying voxel-based morphometry methods. The GMV-to-total brain volume ratio (GMV/TBV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. We assessed whether the predictive ability of a model based on known dementia risk factors could be improved by adding the total number of regions with grey matter atrophy among dementia-related brain regions, where the cut-off value for grey matter atrophy in each region was determined by receiver operating characteristic curves. RESULTS: During the follow-up, 113 participants developed all-cause dementia, including 83 with Alzheimer's disease (AD). Lower GMV/TBV of the medial temporal lobe, insula, hippocampus and amygdala were significantly/marginally associated with higher risk of all-cause dementia and AD (all p for trend ≤0.08). The risks of all-cause dementia and AD increased significantly with increasing total number of brain regions exhibiting grey matter atrophy (both p for trend <0.01). Adding the total number of regions with grey matter atrophy into a model consisting of known risk factors significantly improved the predictive ability for AD (Harrell's c-statistics: 0.765-0.802; p=0.02). CONCLUSIONS: Our findings suggest that the total number of regions with grey matter atrophy among the medial temporal lobe, insula, hippocampus and amygdala is a significant predictor for developing dementia, especially AD, in the general older population.

DOI： 10.1136/jnnp-2021-326611

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Language：English   Publisher：(一社)日本動脈硬化学会  

心血管疾患の既往がない成人被験者2454名(男性1026名、女性1428名、平均58.2±11.1歳)を対象に、Cox比例ハザードモデルを用いてアテローム動脈硬化性心血管疾患(ASCVD)発症のリスク予測モデルを開発し、妥当性を検証した。対象は久山町研究に参加した40歳から84歳までの一般住民で、ASCVDは冠状動脈性心疾患またはアテローム血栓性脳梗塞と定義した。平均追跡期間は24年で、ASCVDは270名で初発した。発生率は1000人あたり5.8人年であった。リスク予測モデルの予測因子として年齢、性別、収縮期血圧、糖尿病、血中HDLコレステロール、LDLコレステロール、蛋白尿、喫煙習慣、定期的な運動を選択した。上記の変数を組み込んで10年後のASCVD発症予測モデルを構築し、簡便なリスクスコアを作成した。C統計量により妥当性を評価したところ、ASCVD発症リスク予測モデル(0.786)と簡便なリスクスコア(0.789)のいずれも優れた識別能を呈した。またGreenwood-Nam-D' Agostino検定で良好なキャリブレーションが確認された(それぞれP=0.29とP=0.52)。

Language：English   Publisher：Kidney International Reports  

DOI： 10.1016/j.ekir.2022.01.1044

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Language：English   Publisher：Japan Atherosclerosis Society  

<p><b>Aim:</b> We investigated the influence of weight change on concurrent changes in predicted cardiovascular disease (CVD) risk and individual CVD risk factors over time. </p><p><b>Methods:</b> 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. </p><p><b>Results:</b> 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. </p><p><b>Conclusions:</b> 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. </p>

DOI： 10.5551/jat.59394

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Nephrology  

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 <0.01). Individuals in the Q5 group had a significantly greater likelihood of advanced glomerular sclerosis (OR 7.19, 95% CI 2.42-21.38) and advanced kidney arteriosclerosis (OR 5.28, 95% CI 1.77-15.80) than individuals in the Q1 group after adjusting for potential covariates. There was no evidence of significant associations of SUA levels with either the arteriolar hyalinosis index or the presence of advanced arteriolar hyalinosis. 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.

DOI： 10.1159/000521426

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Language：English   Publisher：(一社)日本動脈硬化学会  

体重変化が、モデルから予測される心血管疾患(CVD)の包括的リスクと個々の心血管リスクの変化に及ぼす影響について検討した。久山町研究の縦断データを用いて、2002年と2007年の健康診断に参加した40～74歳の地域住民2140名を対象に解析を行った。BMI 25kg/m2以上を肥満とし、2002年と2007年のBMIにより、「安定肥満」(両年とも肥満)、「肥満から非肥満」、「非肥満から肥満」、「安定非肥満」(両年とも肥満)に分類した。CVDの推定累積リスクおよびCVDリスク因子の2002年から2007年にかけての変化を群間比較した。2140名を解析対象とした。CVDの推定リスクは、2007年にかけて全ての群で増加した。CVDの推定リスクの増加は、「肥満から非肥満」群で最も小さく、「非肥満から肥満」群で最も大きかった。「肥満から非肥満」群は「安定肥満」群よりもウエスト周囲長、血圧、空腹時血糖値、血清HDLコレステロール値、血清トリグリセリド値、肝酵素の望ましい変化量が大きかった。全変数について、「非肥満から肥満」群と「安定非肥満」群では逆の傾向が認められた。以上から、肥満者での減量および非肥満者での過剰な体重増加の回避と、CVD包括的リスクおよび個々のCVDリスク要因に望ましい関連が認められた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neuropathology and Experimental Neurology  

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

DOI： 10.1093/jnen/nlab126

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Language：Japanese   Publisher：The Health Care Science Institute  

DOI： 10.4091/iken.31-495

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Publisher：Research Square Platform LLC  

Abstract

Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.

DOI： 10.21203/rs.3.rs-1175817/v1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Brain Pathology  

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. β amyloid (Aβ) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aβ phase score (A2-3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V-VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.

DOI： 10.1111/bpa.13014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ Global Health  

INTRODUCTION: The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the variations in national prevalence within Asia. We aimed to consolidate available data and quantify estimates of the CKD burden in this region. METHODS: We systematically searched MEDLINE, Embase and Google Scholar for observational studies and contacted national experts to estimate CKD prevalence in countries of Asia (Eastern, Southern and South Eastern Asia). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or the presence of proteinuria. For countries without reported data, we estimated CKD prevalence using agglomerative average-linkage hierarchical clustering, based on country-level risk factors and random effects meta-analysis within clusters. Published CKD prevalence data were obtained for 16 countries (of the 26 countries in the region) and estimates were made for 10 countries. RESULTS: There was substantial variation in overall and advanced (eGFR <30 mL/min/1.73 m2) CKD prevalence (range: 7.0%-34.3% and 0.1%-17.0%, respectively). Up to an estimated 434.3 million (95% CI 350.2 to 519.7) adults have CKD in Asia, including up to 65.6 million (95% CI 42.2 to 94.9) who have advanced CKD. The greatest number of adults living with CKD were in China (up to 159.8 million, 95% CI 146.6 to 174.1) and India (up to 140.2 million, 95% CI 110.7 to 169.7), collectively having 69.1% of the total number of adults with CKD in the region. CONCLUSION: The large number of people with CKD, and the substantial number with advanced CKD, show the need for urgent collaborative action in Asia to prevent and manage CKD and its complications.

DOI： 10.1136/bmjgh-2021-007525

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Translational Vision Science and Technology  

PURPOSE: To estimate the prevalence of glaucoma and its risk factors in a Japanese community. METHODS: This study included 3405 Japanese community dwellers who were ≥40 years of age and enrolled in the Hisayama Study. This population-based, cross-sectional study was conducted from 2017 to 2018. A glaucoma screening test was performed using stereo fundus images and swept-source optical coherence tomography. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. RESULTS: The prevalence of glaucoma was 7.6% (95% confidence interval [CI], 6.7-8.6) overall. The prevalence of primary open-angle glaucoma (POAG) was 5.8% (95% CI, 5.0-6.6); that of primary angle-closure glaucoma (PACG) was 0.7% (95% CI, 0.5-1.1); and that of exfoliation glaucoma was 1.1% (95% CI, 0.7-1.4). In addition to aging, lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.15; 95% CI, 1.02-1.33), higher intraocular pressure (OR = 1.06; 95% CI, 1.01-1.12), longer axial length (OR = 1.44; 95% CI, 1.31-1.59), and thinner central corneal thickness (CCT) (OR = 1.09; 95% CI, 1.04-1.15) were significant risk factors for POAG. Diabetes (OR = 2.81; 95% CI, 1.19-6.62) was a significant risk factor for PACG, and diabetes (OR = 2.15; 95% CI, 1.03-4.47) and thinner CCT (OR = 1.14; 95% CI, 1.02-1.28) were significant risk factors for exfoliation glaucoma. CONCLUSIONS: The prevalence of glaucoma was approximately 8%, probably due to the increase in the Japanese aging population. Not only ocular factors but also lower eGFR for POAG and diabetes for PACG and exfoliation glaucoma were risk factors in a general Japanese population. TRANSLATIONAL RELEVANCE: Systemic factors such as eGFR and diabetes must also be considered when implementing preventive measures against glaucoma.

DOI： 10.1167/tvst.11.11.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Alzheimer S Disease  

BACKGROUND: Glucose dysmetabolism is an important risk factor for dementia. OBJECTIVE: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. METHODS: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer's disease (AD) and vascular dementia (VaD) were investigated. RESULTS: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08-1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %-6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19-2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00-1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. CONCLUSION: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

DOI： 10.3233/JAD-215153

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CiNii Research

Language：Japanese   Publisher：Japan Society of Health Evaluation and Promotion  

DOI： 10.7143/jhep.49.92

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Physical Fitness and Sports Medicine  

DOI： 10.7600/jspfsm.71.44

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