記述言語：英語   出版者・発行元：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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記述言語：英語  

DOI： 10.1093/braincomms/fcaf149

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   出版者・発行元：Auris Nasus Larynx  

Objective: The “Summary of Japanese clinical practice guidelines for Bell's palsy (idiopathic facial palsy) - 2023 update edited by the Japan Society of Facial Nerve Research” aims to review the latest evidence regarding the treatment of Bell's palsy and to provide appropriate recommendations. Method: Regarding the treatment of Bell's palsy, a guideline panel identified key clinical questions using an analytic PICO framework. The panel produced recommendations following the standards for trustworthy guidelines and the GRADE approach. The panel considered the balance of benefits, harm, and preferences when making recommendations. Results: The panel identified nine key clinical questions: systemic (high/standard dose) corticosteroids, intratympanic corticosteroids, systemic antivirals, decompression surgery, acupuncture, physical therapy, botulinum toxin, and reanimation surgery. Conclusion: These guidelines strongly recommend systemic standard-dose corticosteroids for the clinical management of Bell's palsy. Other treatments are weakly recommended due to insufficient evidence. The absolute risk reduction of each treatment differed according to the disease severity. Therefore, physicians and patients should decide on treatment based on the disease severity.

DOI： 10.1016/j.anl.2024.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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その他リンク： https://link.springer.com/article/10.1186/s12877-024-05131-w/fulltext.html

記述言語：英語  

DOI： 10.1136/bmjph-2023-000186

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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その他リンク： https://www.nature.com/articles/s41598-024-62688-7

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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 2829 community-dwelling Japanese aged ≥40 years without prior AF were followed up for 10 years (2007–17). and results Day-to-day home BPV [defined as coefficient of variation (CoV) of home systolic blood pressure (SBP) for 28 days] was categorized into four groups according to the quartiles: Q1, ≤ 4.64%; Q2, 4.65–5.70%; Q3, 5.71–7.01%; Q4, ≥ 7.02%. The hazard ratios for developing AF were estimated using a Cox proportional hazards model. During the follow-up period, 134 participants developed new-onset AF. The crude incidence rates of AF increased significantly with higher CoV levels of home SBP: 2.1, 4.9, 5.2, and 8.8 per 1000 person-years in the first, second, third, and fourth quartiles, respectively (P for trend < 0.01). After adjusting for potential confounders, increased CoV levels of home SBP were associated significantly with a higher risk of AF (P for trend = 0.02). The participants in the highest quartile of CoV had a 2.20-fold (95% confidence intervals: 1.18–4.08) increased risk of developing AF compared with those in the lowest quartile. Conclusion The present findings suggest that increased day-to-day home BPV levels are associated with a higher risk of the development of AF in a general Japanese population. Lay summary• This prospective cohort study of a general Japanese population demonstrated a significant association between higher day-to-day blood pressure variability (BPV) assessed by home blood pressure monitoring and risk for the development of atrial fibrillation (AF). • In addition, the association between BPV and the development of AF tended to be stronger in participants without hypertension. • The findings of this study indicate that the evaluation of day-to-day BPV with home blood pressure monitoring may be useful to assess the future risk of AF in participants with and without hypertension, and treatment that takes into account day-to-day BPV in addition to other cardiovascular risk factors may be necessary to prevent the development of AF.

DOI： 10.1093/eurjpc/zwae035

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本臨床疫学会  

<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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.5551/jat.ER61960

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neurology  

Background and ObjectivesEpidemiologic 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.MethodsDementia-free community-dwelling Japanese aged 65 years or older underwent brain MRI scans and a comprehensive health examination. Frequency of contact with noncohabiting relatives and friends was determined by asking a single question with 4 categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV), and white matter lesion volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms.ResultsWe included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared with that in the group with the highest frequency of social contact (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesion volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency group vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q values of false discovery rate correction <0.05). The relationships seemed to be partly mediated by depressive symptoms, which accounted for 15%-29% of the observed associations.DiscussionLower 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(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。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Geriatrics  

Abstract

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&#37; 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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その他リンク： https://link.springer.com/article/10.1186/s12877-022-02939-2/fulltext.html

記述言語：英語   出版者・発行元：(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。

掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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&#37; 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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)。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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 8 695 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 questionnaires, 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 which 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本動脈硬化学会  

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

DOI： 10.5551/jat.63727

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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&#37; 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&#37; CI 0.22-0.98), and tended to be lower in individuals who commuted by walking alone (HR 0.14, 95&#37; 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&#37; 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   出版者・発行元：一般社団法人 日本動脈硬化学会  

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

DOI： 10.5551/jat.61960

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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&#37; 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&#37; CI 2.42-21.38) and advanced kidney arteriosclerosis (OR 5.28, 95&#37; 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(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)。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(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。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Neurology, Neurosurgery and Psychiatry  

<sec><title>Objective</title>To assess the association of regional grey matter atrophy with dementia risk in a general older Japanese population.

</sec><sec><title>Methods</title>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.

</sec><sec><title>Results</title>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).

</sec><sec><title>Conclusions</title>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.

</sec>

DOI： 10.1136/jnnp-2021-326611

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The identification of individuals at high risk of developing hypertension can be of great value to improve the efficiency of primary prevention strategies for hypertension. The objective of this study was to develop a risk prediction model for incident hypertension based on prospective longitudinal data from a general Japanese population. A total of 982 subjects aged 40-59 years without hypertension at baseline were followed up for 10 years (2002-12) for the incidence of hypertension. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or the use of antihypertensive agents. The risk prediction model was developed using a Cox proportional hazards model. A simple risk scoring system was also established based on the developed model. During the follow-up period (median 10 years, interquartile range 5-10 years), 302 subjects (120 men and 182 women) developed new-onset hypertension. The risk prediction model for hypertension consisted of age, sex, SBP, DBP, use of glucose-lowering agents, body mass index (BMI), parental history of hypertension, moderate-to-high alcohol intake, and the interaction between age and BMI. The developed model demonstrated good discrimination (Harrell's C statistic=0.812 [95&#37; confidence interval, 0.791-0.834]; optimism-corrected C statistic based on 200 bootstrap samples=0.804) and calibration (Greenwood-Nam-D'Agostino χ2 statistic=12.2). This risk prediction model is a useful guide for estimating an individual's absolute risk for hypertension and could facilitate the management of Japanese individuals at high risk of developing hypertension in the future.

DOI： 10.1038/s41440-021-00673-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1002/dad2.12221

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been associated with the progression of kidney impairment among patients with chronic kidney disease (CKD), but only a few studies have investigated the association between serum NT-proBNP levels and incident CKD in general populations. Methods: A total of 2486 Japanese community-dwelling residents ≥40 years of age without CKD at baseline were followed up by repeated annual health examinations for 10 years. Participants were divided into 4 groups according to serum NT-proBNP levels. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 or the presence of proteinuria. Cox proportional hazards models were used to estimate hazard ratios (HRs) for risk of CKD. Linear mixed models were used to compare changes in eGFR. Results: During the follow-up period, 800 participants developed CKD. The multivariable-adjusted HRs (95&#37; confidence intervals [CIs]) for developing CKD were 1.00 (reference), 1.32 (1.11-1.57), 1.40 (1.10-1.78), and 1.94 (1.38-2.73) for serum NT-proBNP levels of <55, 55-124, 125-299, and ≥300 pg/ml, respectively (P for trend <0.001). The decline of eGFR during the follow-up was significantly more rapid among participants with higher serum NT-proBNP levels (P for trend <0.001). Adding serum NT-proBNP to the model composed of known risk factors for CKD improved the predictive ability for developing CKD. Conclusions: Higher serum NT-proBNP levels were associated with greater risks of developing CKD and greater decline in eGFR. Serum NT-proBNP could be a useful biomarker for assessing the future risk of CKD in a general Japanese population.

DOI： 10.1016/j.ekir.2021.01.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS/INTRODUCTION: To investigate the association between midlife or late-life diabetes and the development of sarcopenia in an older Japanese population. MATERIALS AND METHODS: A total of 824 Japanese residents aged 65 to 84 years without sarcopenia were followed up from 2012 to 2017. Sarcopenia was determined following the Asian Working Group for Sarcopenia definition. The time of diabetes diagnosis was classified as midlife or late-life diabetes by the age at first diagnosis of diabetes (<65 or ≥65 years) based on annual health checkups data over the past 24 years. The duration of diabetes was categorized into 3 groups of <10, 10-15, and >15 years. The odds ratios of incident sarcopenia according to the diabetic status were estimated using a logistic regression analysis. RESULTS: During follow-up, 47 subjects developed sarcopenia. The multivariable-adjusted odds ratio for incident sarcopenia was significantly greater in subjects with diabetes at baseline than in those without it (odds ratio 2.51, 95&#37; confidence interval 1.26-5.00). Subjects with midlife diabetes had a significantly greater risk of incident sarcopenia, whereas no significant association between late-life diabetes and incident sarcopenia was observed. With a longer duration of diabetes, the risk of incident sarcopenia increased significantly (p for trend = 0.002). CONCLUSIONS: The present study suggests that midlife diabetes and a longer duration of diabetes are significant risk factors for incident sarcopenia in the older population. Preventing diabetes in midlife may reduce the risk of the development of sarcopenia in later life.

DOI： 10.1111/jdi.13550

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1253/circj.CJ-20-0794

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Folate and vitamin B-12 are essential nutrients for normal cell growth and replication, but the association of serum folate and vitamin B-12 concentrations with mortality risk remains uncertain. OBJECTIVE: This study was performed to investigate the associations of serum folate and vitamin B-12 concentrations with mortality risk and test whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism modifies these associations. METHODS: A total of 3050 Japanese community residents aged ≥40 y were prospectively followed-up for mortality between 2002 and 2012. Cox proportional hazards models and restricted cubic splines were used to estimate HRs and 95&#37; CIs of mortality. RESULTS: During a median follow-up period of 10.2 y, 336 participants died. Higher serum folate concentrations were associated with lower risks of all-cause mortality [multivariable-adjusted HR: 0.73; 95&#37; CI: 0.56, 0.96 for the second tertile (8.8-12.2 nmol/L; median 10.4 nmol/L) and HR: 0.61; 95&#37; CI: 0.46, 0.80 for the third tertile (≥12.5 nmol/L; median 15.6 nmol/L) serum folate concentrations compared with the first tertile (≤8.6 nmol/L; median 7.0 nmol/L)]. This association remained significant in all sensitivity analyses. Spline analyses showed a steady decline in all-cause mortality risk with increasing serum folate concentrations up to 20-25 nmol/L. This association persisted regardless of the MTHFR C677T genotypes. For serum vitamin B-12, the multivariable-adjusted HR of 1.32 (95&#37; CI: 0.97, 1.79) of all-cause mortality was marginally significantly greater in the first tertile compared with the second tertile. This association was attenuated and nonsignificant after the exclusion of participants with a history of cardiovascular disease or cancer, or participants aged ≥85 y at baseline, or deaths in the first 3 y of follow-up. CONCLUSIONS: Serum folate concentrations were inversely associated with the risk of all-cause mortality in Japanese adults. Serum vitamin B-12 concentrations were not consistently associated with all-cause mortality risk after accounting for reverse-causation bias.

DOI： 10.1093/jn/nxaa382

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/pcn.13204

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Biomarkers for predicting future development of atrial fibrillation (AF) have not been fully established in general populations. The aim of this study was to assess the predictive ability of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) for the development of AF. METHODS AND RESULTS: A total of 3126 community-dwelling Japanese subjects aged ≥ 40 years without a history of AF in 2002 were followed up for a median of 10.2 years. Serum NT-proBNP levels at baseline were divided into four categories (≤ 54, 55-124, 125-299, and ≥ 300 pg/mL) according to the current guidelines and prior reports. The hazard ratios for the development of AF were estimated using a Cox proportional hazards model. During the follow-up period, 153 subjects developed new-onset AF. The age- and sex-adjusted cumulative incidence of AF increased significantly with higher serum NT-proBNP levels (p < 0.001 for trend). The association remained significant after adjustment for known risk factors for AF and cardiovascular disease (hazard ratio [95&#37; confidence interval]: ≤ 54 pg/mL: 1.00 [reference]; 55-124 pg/mL: 1.72 [1.00-2.97]; 125-299 pg/mL: 3.95 [2.23-6.98]; ≥ 300 pg/mL: 8.51 [4.48-16.17]; p < 0.001 for trend). Furthermore, incorporation of serum NT-proBNP levels into the model consisting of known risk factors for AF and cardiovascular disease significantly improved the predictive ability for developing AF (Harrell's c-statistics: 0.828 to 0.844, p = 0.01; continuous net reclassification improvement: 0.41, p < 0.001; integrated discrimination improvement: 0.031, p < 0.001). CONCLUSIONS: Serum NT-proBNP levels can be a risk biomarker for predicting future development of AF in a general Japanese population.

DOI： 10.1016/j.ijcard.2020.06.018

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3390/nu12103160

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To estimate the lifetime cumulative incidence of dementia and its subtypes from a community-dwelling elderly population in Japan. METHODS: A total of 1,193 community-dwelling Japanese individuals without dementia, aged 60 years or older, were followed up prospectively for 17 years. The cumulative incidence of dementia was estimated based on a death- and dementia-free survival function and the hazard functions of dementia at each year, which were computed by using a Weibull proportional hazards model. The lifetime risk of dementia was defined as the cumulative incidence of dementia at the point in time when the survival probability of the population was estimated to be less than 0.5&#37;. RESULTS: During the follow-up, 350 participants experienced some type of dementia; among them, 191 participants developed Alzheimer disease (AD) and 117 developed vascular dementia (VaD). The lifetime risk of dementia was 55&#37; (95&#37; confidence interval, 49&#37;-60&#37;). Women had an approximately 1.5 times greater lifetime risk of dementia than men (65&#37; [57&#37;-72&#37;] vs 41&#37; [33&#37;-49&#37;]). The lifetime risks of developing AD and VaD were 42&#37; (35&#37;-50&#37;) and 16&#37; (12&#37;-21&#37;) in women vs 20&#37; (7&#37;-34&#37;) and 18&#37; (13&#37;-23&#37;) in men, respectively. CONCLUSION: Lifetime risk of all dementia for Japanese elderly was substantial at approximately 50&#37; or higher. This study suggests that the lifetime burden attributable to dementia in contemporary Japanese communities is immense.

DOI： 10.1212/WNL.0000000000009917

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The prevalence of sarcopenia defined by the Asian Working Group for Sarcopenia (AWGS) definition in Asian communities has not been fully addressed. Moreover, few studies have addressed the influence of sarcopenia on mortality. METHODS: A total of 1,371 and 1,597 residents aged 65 years or older participated in health surveys in 2012 and 2017. Sarcopenia was determined by the AWGS definition. Factors associated with the presence of sarcopenia were assessed using a logistic regression model in participants in the 2012 survey. Subjects in the 2012 survey were followed-up prospectively for a median of 4.3 years. Mortality risk for subjects with sarcopenia was examined using the Cox proportional hazards model. RESULTS: The crude prevalence of sarcopenia was 7.4&#37; and 6.6&#37; in participants at the 2012 and 2017 surveys, respectively; there was no significant difference between surveys (p = 0.44). The prevalence of sarcopenia increased significantly with age in both sexes (both p for trend < 0.001). Subjects with sarcopenia were more likely to exercise less regularly, to intake less total energy, and to exhibit a disability in activity of daily living than those without. The multivariable-adjusted hazard ratio for all-cause mortality was 2.20 (95&#37; confidence interval, 1.25-3.85) in subjects with sarcopenia, compared to those without. CONCLUSIONS: Approximately 7&#37; of older subjects had sarcopenia in a community-dwelling older Japanese population. Moreover, subjects with sarcopenia had an increased mortality risk. Our findings suggest that a public health strategy for sarcopenia is needed to extend healthy life expectancy.

DOI： 10.2188/jea.JE20190289

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To examine the association between serum total homocysteine levels (tHcy) and dementia risk. METHODS: A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia. RESULTS: During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 µmol/L), the multivariable-adjusted HRs (95% CI) of the highest quintile (≥11.5 µmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 µmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07). CONCLUSION: High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.

DOI： 10.1136/jnnp-2019-322366

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Both chronic kidney disease and brain white matter hyperintensities (WMH) are known to be risk factors of dementia and mortality.Methods and Results:In 2012, 1,214 community-dwelling Japanese subjects aged ≥65 years underwent brain magnetic resonance imaging (MRI) scans and a comprehensive health examination. This study investigated associations of the urinary albumin : creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) with the WMH volume to intracranial volume (WMHV : ICV) ratio, and the association of the combination of UACR and the WMHV : ICV ratio with cognitive decline and mortality risk. The geometric mean of the WMHV : ICV ratio was 0.223&#37; in the entire study population, and increased significantly with higher UACR levels after adjusting for potential confounding factors (0.213&#37; for normoalbuminuria, 0.248&#37; for microalbuminuria, and 0.332&#37; for macroalbuminuria; Ptrend=0.01). In contrast, there was no clear association between eGFR and the WMHV : ICV ratio. Compared with subjects with normoalbuminuria and a smaller WMHV : ICV ratio (<0.257&#37; [median]), subjects with albuminuria and a larger WMHV : ICV ratio (≥0.257&#37;) had higher probabilities of cognitive decline at baseline and all-cause death during the follow-up. CONCLUSIONS: This study suggests that subjects with albuminuria have a greater risk of WMH enlargement and that the combination of albuminuria and WMH enlargement increases the risk of cognitive decline and all-cause mortality in an elderly Japanese population.

DOI： 10.1253/circj.CJ-19-1069

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Purpose—Environmental and genetic factors contribute to the development of ischemic stroke (IS). We recently developed a genome-wide polygenic risk score (PRS) for IS using case-control datasets from 4 large-scale observational studies conducted in Japan. Our objective in the present study was to confirm the association between the PRS and the risk of IS with data from an independent prospective cohort recruited from the general Japanese population. Methods—A total of 3038 subjects aged ≥40 years were followed up for 10 years (2002–2012). The genome-wide PRS was calculated using genotype data from >350 000 single-nucleotide polymorphisms. The PRS levels were divided into quintiles. High and low genetic risk groups were defined as top 60% and bottom 40% of PRS, respectively. The hazard ratio (HR) for the development of IS was estimated using a Cox proportional hazards model. Results—During the follow-up period, 91 cases developed first-ever IS. The age- and sex-adjusted HR for IS increased with higher PRS levels (P for trend, 0.03). Subjects with the highest quintile level of PRS had a 2.44-fold (95% CI, 1.16–5.12) greater risk for IS than those with the lowest quintile level after adjusting for age and sex. A similar association was observed after adjusting for environmental risk factors (P for trend, 0.03). As compared with low genetic risk group, the age- and sex-adjusted HR in high genetic risk group was 1.63 (95% CI, 1.04–2.55), which was comparable to the HR of hypertension (HR, 1.41), diabetes mellitus (HR, 1.72), and smoking (HR, 1.54). The age- and sex-adjusted HR increased with the number of environmental risk factors in both high and low genetic risk groups without significant interaction. Conclusions—A high genome-wide PRS was a significant risk factor for IS independent of environmental risk factors in a general Japanese population. This finding suggests that PRS may be useful to identify individuals at a high risk of IS.

DOI： 10.1161/STROKEAHA.119.027520

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims/Introduction: To investigate the association of alternative glycemic measures – namely, serum glycated albumin (GA), hemoglobin A_1c (HbA_1c) and the GA : HbA_1c ratio – with global brain and hippocampal atrophy in a general elderly Japanese population. Materials and Methods: A total of 1,278 Japanese individuals aged ≥65 years in a community participated in brain magnetic resonance imaging scanning and screening examination of health status in 2012. We measured total brain volume (TBV), hippocampal volume (HV) and intracranial volume (ICV) using the data from the magnetic resonance imaging examination. The association of each glycemic measure with the ratios of TBV : ICV (an indicator of global brain atrophy) and HV : ICV (an indicator of hippocampal atrophy) was examined by analysis of covariance. Results: The mean values of the TBV : ICV and HV : ICV ratios decreased significantly with elevating serum GA levels and GA : HbA_1c ratio levels (all P for trend < 0.05), but not with higher HbA_1c levels, after adjusting for age, sex, low education, systolic blood pressure, antihypertensive medication, diabetes mellitus, serum total cholesterol, electrocardiogram abnormalities, body mass index, smoking habits, alcohol drinking habits and regular exercise. These significant associations were still observed in the sensitivity analysis after excluding individuals with mild cognitive impairment and dementia. In addition, increased serum GA levels and the GA : HbA_1c ratio levels, but not HbA_1c, were closely associated with lower mean values of the TBV : ICV and HV : ICV ratios, irrespective of the presence or absence of diabetes mellitus. Conclusions: The present study suggests that higher serum GA and higher GA : HbA_1c ratio are significantly associated with global brain and hippocampal atrophy.

DOI： 10.1111/jdi.13220

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Serum Lipopolysaccharide-Binding Protein Levels and the Incidence of Cardiovascular Disease in a General Japanese Population: The Hisayama Study.
Background Epidemiological studies have reported a link between serum LBP (lipopolysaccharide-binding protein) levels and lifestyle-related diseases. However, there have been no longitudinal studies investigating the association of serum LBP levels and the incidence of cardiovascular disease (CVD) in general populations. Methods and Results A total of 2568 community-dwelling Japanese individuals 40 years and older without prior CVD were followed for 10 years (2002-2012). Serum LBP levels were divided into quartiles (quartile 1: 2.20-9.68 μg/mL; quartile 2: 9.69-10.93 μg/mL; quartile 3: 10.94-12.40 μg/mL; quartile 4: 12.41-24.34 μg/mL). The hazard ratios (HRs) and their 95% CIs for the incidence of CVD were computed using a Cox proportional hazards model. During the follow-up period, 180 individuals developed CVD. The age- and sex-adjusted cumulative incidence of CVD increased significantly with higher serum LBP levels (P for trend=0.005). Individuals with higher serum LBP levels had a significantly greater risk of the development of CVD after adjusting for conventional cardiovascular risk factors (quartile 1: HR, 1.00 [reference]; quartile 2: HR, 1.04 [95% CI, 0.60-1.78]; quartile 3: HR, 1.52 [95% CI, 0.92-2.51]; and quartile 4: HR, 1.90 [95% CI, 1.17-3.09]; P for trend=0.01). This association remained significant after additional adjustment for homeostasis model assessment of insulin resistance (P for trend=0.01). However, when additional adjustment was made for high-sensitivity C-reactive protein, the association was attenuated to the nonsignificant level (P for trend=0.08). Conclusions The present findings suggest that higher serum LBP levels are associated with increased risk of the development of CVD in the general Japanese population. Low-grade endotoxemia may contribute to the pathogenesis of CVD through chronic systemic inflammation.

DOI： 10.1161/JAHA.119.013628

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Epidemiological evidence implies a link between heart disease and dementia. However, few prospective studies have assessed the association between serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and dementia. Methods and Results A total of 1635 community-dwelling Japanese elderly aged ≥60 years without dementia (57% women, mean age±SD 70.8±7.7 years) were followed up for 10 years. Serum NT-proBNP levels were divided into 4 categories (≤54, 55-124, 125-299, and ≥300 pg/mL). The hazard ratios were estimated using a Cox proportional hazards model. During the follow-up period, 377 subjects developed all-cause dementia, 247 Alzheimer disease, and 102 vascular dementia. The age- and sex-adjusted incidence of all-cause dementia was 31.5 per 1000 person-years and increased significantly with higher serum NT-proBNP levels, being 16.4, 32.0, 35.7, and 45.5, respectively (P for trend <0.01). Subjects with serum NT-proBNP levels of ≥300 pg/mL had a significantly higher risk of all-cause dementia (hazard ratio=2.46, 95% CI 1.63-3.71) than those with serum NT-proBNP levels of ≤54 pg/mL after adjusting for confounders. Similar risks were observed for Alzheimer disease and vascular dementia. Incorporation of the serum NT-proBNP level into a model with known risk factors for dementia significantly improved the predictive ability for incident dementia (c-statistics 0.780-0.787, P=0.02; net reclassification improvement 0.189, P=0.001; integrated discrimination improvement 0.011, P=0.003). Conclusions Higher serum NT-proBNP levels were significantly associated with an increased risk of dementia. Serum NT-proBNP could be a novel biomarker for predicting future risk of dementia in the general elderly population.

DOI： 10.1161/JAHA.118.011652

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background We investigated the prevalence of and risk factors for cerebral microbleeds (CMBs) in a cross-sectional study of a general population of Japanese elderly. Methods In 2012, brain MRI scanning at 1.5T and comprehensive health examination were conducted for 1281 residents aged 65 years or older. CMBs were defined as ovoid hypointensity lesions less than 10 mm in diameter on T2-weighted images and classified into deep/infratentorial or lobar CMBs. Age- and sex-specific and overall prevalence of CMBs were estimated, and the associations of traditional cardiovascular risk factors and APOE polymorphism with the presence of CMBs were examined using a logistic regression analysis. Results The crude prevalences of total, deep/infratentorial, and lobar CMBs were 18.7% (n = 240), 13.5% (n = 173), and 9.6% (n = 123), respectively. The prevalence of total CMBs was 23.0% in men and 15.5% in women and increased with aging in both sexes (both p for trend <0.01). Hypertension was significantly associated with the presence of both deep/infratentorial and lobar CMBs. Lower serum total cholesterol was a significant risk factor for deep/infratentorial CMBs, but not for lobar CMBs, while APOE ϵ4 carriers had a significantly higher likelihood only of lobar CMBs compared with noncarriers. Conclusions Our study suggests that approximately 1 of 5 Japanese elderly people have CMBs, and that risk factors for deep/infratentorial and lobar CMBs are different, indicating the distinct pathologic backgrounds of these lesions.

DOI： 10.1212/CPJ.0000000000000464

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cerebrospinal fluid hypovolemia (CSFH) is sometimes associated with chronic subdural hematomas (CSHs). Affected patients often develop enlargement and recurrence of the CSH, even if appropriate treatments such as epidural blood patch (EBP) and/or burr-hole surgery for the CSH are performed. This situation may lead to subclinical coagulopathy, including low coagulation factor XIII (CFXIII) activity. We retrospectively analyzed whether CFXIII activity was involved in the development of CSHs and post-treatment exacerbation of CSHs in patients with CSFH. Methods: We diagnosed CSFH by radioisotope (RI), magnetic resonance imaging (MRI) and computed tomography (CT) findings, and CSH by CT and/or MRI findings. The plasma CFXIII activity was assessed on admission. All patients with CSFH initially received conservative treatments. When these treatments were ineffective, the patients underwent EBP and/or CSH surgery according to previously reported therapeutic strategies. Results: Among 206 patients with CSFH, 19 developed CSHs. Fourteen patients with a thin hematoma underwent EBP and three with a thick hematoma underwent CSH surgery immediately after EBP on the same day. We were unable to diagnose two patients with CSFH at the time of admission, and one of these two patients underwent repeated CSH surgery before obtaining the correct diagnosis. Seven patients (36.8%) developed CSH exacerbation after the treatment. The CFXIII activity was significantly lower in patients with than without a CSH (42.1% vs. 12.8%, respectively
P = 0.003). The CFXIII activity was significantly lower in patients with than without post-treatment CSH exacerbation (P = 0.046). All five patients with low CFXIII activity who developed CSH exacerbation received intravenous injection of CFXIII and had no recurrence of CSH after the additional treatment. Conclusion: In patients with CSFH, low CFXIII activity is one of the risk factors for both the development of a CSH and the post-treatment exacerbation CSH.

DOI： 10.4103/sni.sni_82_17

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cerebrospinal fluid hypovolemia (CSFH) is sometimes associated with chronic subdural hematomas (CSHs). Affected patients often develop enlargement and recurrence of the CSH, even if appropriate treatments such as epidural blood patch (EBP) and/or burr-hole surgery for the CSH are performed. This situation may lead to subclinical coagulopathy, including low coagulation factor XIII (CFXIII) activity. We retrospectively analyzed whether CFXIII activity was involved in the development of CSHs and post-treatment exacerbation of CSHs in patients with CSFH. Methods: We diagnosed CSFH by radioisotope (RI), magnetic resonance imaging (MRI) and computed tomography (CT) findings, and CSH by CT and/or MRI findings. The plasma CFXIII activity was assessed on admission. All patients with CSFH initially received conservative treatments. When these treatments were ineffective, the patients underwent EBP and/or CSH surgery according to previously reported therapeutic strategies. Results: Among 206 patients with CSFH, 19 developed CSHs. Fourteen patients with a thin hematoma underwent EBP and three with a thick hematoma underwent CSH surgery immediately after EBP on the same day. We were unable to diagnose two patients with CSFH at the time of admission, and one of these two patients underwent repeated CSH surgery before obtaining the correct diagnosis. Seven patients (36.8%) developed CSH exacerbation after the treatment. The CFXIII activity was significantly lower in patients with than without a CSH (42.1% vs. 12.8%, respectively; P = 0.003). The CFXIII activity was significantly lower in patients with than without post-treatment CSH exacerbation (P = 0.046). All five patients with low CFXIII activity who developed CSH exacerbation received intravenous injection of CFXIII and had no recurrence of CSH after the additional treatment. Conclusion: In patients with CSFH, low CFXIII activity is one of the risk factors for both the development of a CSH and the post-treatment exacerbation CSH.

DOI： 10.4103/sni.sni_82_17

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cerebral hyperperfusion after carotid endarterectomy (CEA) is defined as an increase in ipsilateral cerebral blood flow (CBF). Practically, however, prompt and precise assessment of cerebral hyperperfusion is difficult because of limitations in the methodology of CBF measurement during the perioperative period. Arterial spin labeling (ASL) is a completely noninvasive and repeatable magnetic resonance perfusion imaging technique that uses magnetically-labelled blood water as an endogenous tracer. To clarify the usefulness of ASL in the management of cerebral hyperperfusion, we investigated signal changes by ASL with a single 1.5-s post-labeling delay on visual inspection. Methods: Thirty-two consecutive patients who underwent CEA were enrolled in this retrospective study. Results: On postoperative day 1, 22 (68.8%) and 4 (12.5%) patients exhibited increased ASL signals bilaterally (Group A) and on the operated side (Group B), respectively. Follow-up ASL showed improvement in these findings. Six (18.8%) patients showed no change (Group C). There was no apparent correlation between ASL signals on postoperative day 1 and the preoperative hemodynamic state, including the cerebrovascular reserve (P = 0.2062). Three (9.4%) patients developed cerebral hyperperfusion syndrome (two in Group A and one in Group B). Coincidence in the localization of increased ASL signals and electroencephalographic abnormalities was noted in these patients. Conclusion: Visual analysis of ASL with a single post-labeling delay overestimates CBF and cannot identify patients at risk of cerebral hyperperfusion syndrome probably because of the strong effect of the shortened arterial transit time immediately after CEA. However, ASL may be used as for screening.

DOI： 10.4103/2152-7806.196322

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cerebral venous thrombosis (CVT) has a broad spectrum of clinical presentation compared to arterial etiology. Seizure is one of the common symptoms and is more frequent than in other stroke types. Hence, transient neurological symptoms in CVT patients are usually due to epileptic seizures, while transient repetitive movement disorder is extremely rare except as a complication of epilepsy. We report a case of CVT in the superior sagittal sinus with a 1-year history of paroxysmal kinetic tremor without evident epilepsy.

DOI： 10.1159/000455022

記述言語：その他  

[Epidemiology of stroke in Japan and comparison with the world].

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cerebral hyperperfusion after carotid endarterectomy (CEA) is defined as an increase in ipsilateral cerebral blood flow (CBF). Practically, however, prompt and precise assessment of cerebral hyperperfusion is difficult because of limitations in the methodology of CBF measurement during the perioperative period. Arterial spin labeling (ASL) is a completely noninvasive and repeatable magnetic resonance perfusion imaging technique that uses magnetically-labelled blood water as an endogenous tracer. To clarify the usefulness of ASL in the management of cerebral hyperperfusion, we investigated signal changes by ASL with a single 1.5-s post-labeling delay on visual inspection. Methods: Thirty-two consecutive patients who underwent CEA were enrolled in this retrospective study. Results: On postoperative day 1, 22 (68.8%) and 4 (12.5%) patients exhibited increased ASL signals bilaterally (Group A) and on the operated side (Group B), respectively. Follow-up ASL showed improvement in these findings. Six (18.8%) patients showed no change (Group C). There was no apparent correlation between ASL signals on postoperative day 1 and the preoperative hemodynamic state, including the cerebrovascular reserve (P = 0.2062). Three (9.4%) patients developed cerebral hyperperfusion syndrome (two in Group A and one in Group B). Coincidence in the localization of increased ASL signals and electroencephalographic abnormalities was noted in these patients. Conclusion: Visual analysis of ASL with a single post-labeling delay overestimates CBF and cannot identify patients at risk of cerebral hyperperfusion syndrome probably because of the strong effect of the shortened arterial transit time immediately after CEA. However, ASL may be used as for screening.

DOI： 10.4103/2152-7806.196322

記述言語：日本語  

Infection Control Effect of Dietary Fluid with Whey Peptide in the Management of Patients with Severe Intracranial Hemorrhage During the Acute Stage

DOI： 10.15017/1563869

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: Patients with severe intracranial hemorrhage (ICH) often develop infectious complications during the acute stage. Animal experiments have demonstrated that enteral immunonutrition with a dietary fluid containing whey peptide (WP) enhances immunoactivity and prevents infection. The aim of the current study was to investigate the infection control effect of WP in the clinical management of patients with severe ICH.
METHODS: Fourteen patients with ICH were given enteral nutrition from January 2012 to December 2012. Nine patients were given WP (WP group) and the other five were given control dietary fluid (Non-WP group) for two weeks. We retrospectively analyzed the incidence of infectious complications and chronological changes in white blood cell (WBC) count, C-reactive protein (CRP), and total lymphocyte count.
RESULTS: All patients in the Non-WP Group experienced infectious complications, whereas 5 out of 9 patients in the WP Group did not experience them. There was a tendency for a decrease in WBC count and CRP value in the WP group. In contrast, WBC and CRP increased in 3 patients in the Non-WP Group. Total lymphocyte count tended to increase earlier in the WP Group; however this tendency was not noted in the Non-WP Group.
CONCLUSION: Although the number of cases was small, our study suggests that WP might have an infection control effect, capable of preventing infectious complications associated with severe ICH in the acute stage.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

"Non-convulsive'' partial status epilepticus (SE) is an important pathologic condition that should be differentiated from cerebral infarction. Herein, we reported 2 patients who had partial SE associated with old infarction in the right parietal lobe. Each patient had 2 episodes of left hemiparesis and hemisensory disturbance without convulsion. On diffusion-weighted magnetic resonance images (DW-MRI), a hyperintense lesion was noted in the cortex around the old infarction lesion, and recurrent infarction was suspected. Although electroencephalography (EEG) failed to reveal ictal discharges or interictal paroxysmal activities in 3 of 4 episodes, perfusion images with arterial spin labeling (ASL) clearly demonstrated ictal hyperperfusion in the area corresponding to the cortical hyperintense lesion on DW-MRI. After appropriate anticonvulsant treatment based on the diagnosis of partial SE, clinical symptoms were completely improved. These data stress the importance of cortical hyperintensity on DW-MRI and ictal ASL hyperperfusion, even when SE cannot be determined from EEG.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.09.026

記述言語：英語   掲載種別：研究論文（学術雑誌）  

"Non-convulsive" partial status epilepticus (SE) is an important pathologic condition that should be differentiated from cerebral infarction. Herein, we reported 2 patients who had partial SE associated with old infarction in the right parietal lobe. Each patient had 2 episodes of left hemiparesis and hemisensory disturbance without convulsion. On diffusion-weighted magnetic resonance images (DW-MRI), a hyperintense lesion was noted in the cortex around the old infarction lesion, and recurrent infarction was suspected. Although electroencephalography (EEG) failed to reveal ictal discharges or interictal paroxysmal activities in 3 of 4 episodes, perfusion images with arterial spin labeling (ASL) clearly demonstrated ictal hyperperfusion in the area corresponding to the cortical hyperintense lesion on DW-MRI. After appropriate anticonvulsant treatment based on the diagnosis of partial SE, clinical symptoms were completely improved. These data stress the importance of cortical hyperintensity on DW-MRI and ictal ASL hyperperfusion, even when SE cannot be determined from EEG.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.09.026

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanism of cerebral decompression sickness (DCS) is still unclear. We report 2 cases of breath-hold divers with cerebral DCS in whom magnetic resonance imaging (MRI) demonstrated distinctive characteristics. One case presented right hemiparesthesia, diplopia, and gait disturbance after breath-hold diving into the sea at a depth of 20 m. Brain MRI with fluid-attenuated inversion recovery (FLAIR) sequence revealed multiple hyperintense lesions in the right frontal lobe, bilateral thalamus, pons, and right cerebellar hemisphere. The second case presented visual and gait disturbance after repetitive breath-hold diving into the sea. FLAIR imaging showed hyperintense areas in the bilateral occipito-parietal lobes. In both cases, diffusion-weighted imaging and apparent diffusion coefficient mapping revealed hyperintense areas in the lesions identified by FLAIR. Moreover, follow-up MRI showed attenuation of the FLAIR signal abnormalities. These findings are suggestive of transient hyperpermeability in the microvasculature as a possible cause of cerebral DCS.

DOI： 10.1159/000357169

記述言語：日本語  

Hemodynamic brain infarction in bilateral middle cerebellar peduncles and upper pons in a patient with bilateral vertebral artery occlusion

DOI： 10.3995/jstroke.35.337

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Neurological decompression illness in a Japanese breath-held diver: a case report
We report a Japanese breath-hold diver (Ama) who presented neurological disorders after diving. He repeated diving into 25-30 meters depth in the sea for 6 hours. After diving, he felt dizziness and unsteady gait. Neurological examination showed left quadrant hemianopia, bilateral limb ataxia and ataxic gait. Head CT revealed gas bubbles in the left parietal lobe. In CT scan on 3 days after onset, gas bubbles disappeared and low density areas were observed in the bilateral parietal lobes. Brain imaging (DWI, T(2)WI and FLAIR) demonstrated high intensity in the parieto-occipital lobes. Neither pulmonary barotrauma nor intracardiac shunt was detected. He was diagnosed as having neurological decompression illness and therefore underwent hyperbaric oxygen therapy. The pathogenesis of this case was considered to be microbubbles induced by decompression. The present case suggests that repetitive rapid surfacing from the deep sea causes neurological decompression illness even in the breath-hold diver.

DOI： 10.5692/clinicalneurol.52.757

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

アンチエイジングから高齢者高血圧を考える 2.高齢者高血圧と認知機能

記述言語：日本語  

脳卒中診療の新しい展開 治療/実地医家のための脳卒中治療のポイント チーム医療の重要性とSCUの活用メリット