Twenty-year prospective cohort study of the association between a Japanese dietary pattern and incident dementia: the NILS-LSA project.

PURPOSE: Evidence has suggested that adherence to a Japanese diet may be beneficial for health. However, its association with incident dementia remains unclear. The aim was to explore this association in older Japanese community-dwellers, taking apoprotein E genotype into consideration. METHODS: A 20-year follow-up cohort study involving 1504 dementia-free older Japanese community-dwellers (aged 65-82 years) living in Aichi Prefecture, Japan, was conducted. Based on a previous study, a 9-component-weighted Japanese Diet Index (wJDI9) score (range - 1 to 12) was calculated using 3-day dietary record data and used as an indicator of adherence to a Japanese diet. Incident dementia was confirmed by the Long-term Care Insurance System certificate, and dementia events occurring within the first 5 years of follow-up were excluded. A multivariate-adjusted Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia, and Laplace regression was used to estimate percentile differences (PDs) and 95% CIs (expressed in months) in age at incident dementia (i.e., dementia-free duration differences), according to tertiles (T1-T3) of wJDI9 scores. RESULTS: The median (IQR) follow-up duration was 11.4 (7.8-15.1) years. During the follow-up period, 225 (15.0%) cases of incident dementia were identified. Because the smallest prevalence of incident dementia was 10.7% for the T3 group of wJDI9 scores, to avoid inaccurately estimating the dementia-free duration of participants in the T3 group, the 11th PDs in age at incident dementia between the T1 and T3 groups of wJDI9 scores were estimated. A higher wJDI9 score was associated with a lower risk of incident dementia and a longer dementia-free duration difference. The multivariate-adjusted HR (95% CI) and 11th PDs (95% CI) in age at incident dementia for participants in the T1 vs. T3 group were 1.00 (reference) vs. 0.58 (0.40, 0.86), and 0 (reference) vs. 36.7 (9.9, 63.4) months, respectively. Each 1-point increase of the wJDI9 score was associated with a 5% lower risk of incident dementia (P value = 0.033) and 3.9 (0.3, 7.6) additional months of dementia-free duration (P value = 0.035). No differences were seen in sex or smoking status (current smoker vs. non-current smoker) at baseline. CONCLUSION: These findings suggest that adherence to a Japanese diet defined by wJDI9 is associated with a lower risk of incident dementia in older Japanese community-dwellers, suggesting the benefit of the Japanese diet for dementia prevention.

Basic lifestyle habits and volume change in total gray matter among community dwelling middle-aged and older Japanese adults.

The brain controls human behavior, and the gray matter is the main resource of neuronal cells. We examined the longitudinal relationship between six basic lifestyle habits (diet, exercise, sleep, alcohol consumption, smoking, and social activity including employment) and total gray matter volume in community-dwelling adults in Japan. This two-year follow-up study with data derived from the National Institute for Longevity Sciences, Longitudinal Study of Aging, Aichi, Japan, included adults aged 40-87 years (n = 1665, men: 51%). Lifestyle habits were assessed at baseline (2008-2010) using self-reported questionnaires and three-day dietary records. Total gray matter volume at baseline and after two years was estimated using T1-weighted brain magnetic resonance imaging and FreeSurfer software. The association between each lifestyle factor, the total number of healthy lifestyle habits, and gray matter volume change was determined via a multiple linear regression analysis adjusting for baseline age, total gray matter volume, and other confounders. The mean ± standard deviation decrease in total gray matter volume during the two-year follow-up period was 0.94 ± 1.86% in men and 0.61 ± 2.27% in women. In the multiple regression analysis, volume loss in total gray matter positively correlated with male smoking, while it was negatively correlated with male social activity and employment, female dietary diversity, and the total number of healthy lifestyle habits (standardized beta coefficient; -0.061 in men [p = 0.07], -0.113 in women [p < 0.05]). Therefore, engaging in social activities, non-smoking, a diverse diet, or adopting one healthy lifestyle habit may help prevent gray matter volume loss.

Interaction between cognitive leisure activity and long-chain polyunsaturated fatty acid intake on global cognitive decline in a Japanese longitudinal cohort study: National Institute for Longevity Sciences-Longitudinal Study of Aging.

BACKGROUND: There is a growing interest in the significance of adopting a variety of lifestyle habits for maintaining cognitive function among older adults. A lifestyle that is easy to modify, simple, and less burdensome for older people is ideal. We investigated the longitudinal association between global cognitive decline and cognitive leisure activities (CLAs) combined with long-chain polyunsaturated fatty acids (LCPUFAs) intake. METHODS: The National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) enrolled community-dwelling middle-aged and older men and women who were randomly selected from Obu-City and Higashiura Town, Aichi, Japan. Baseline data (2006-2008), including CLAs and dietary intake, were obtained from 517 participants (aged 60-84 years) with normal cognition. Global cognitive decline, defined as the Mini-Mental State Examination (MMSE) score ≤ 27, was assessed at baseline and four years later. Interaction between CLAs and LCPUFAs on cognitive decline was investigated using a multiple logistic analysis with adjustment for confounders. CLA engagement and LCPUFA intake were divided into high and low groups according to the frequency at which each participant engaged in the activity and the median intake level according to sex, respectively. RESULTS: A significant interaction was detected for the combination of CLA engagement and LCPUFA intake. Logistic regression coefficients revealed significant interactions when participants engaged in more than five CLA varieties. One of the CLAs, art appreciation, produced a significant main effect against cognitive decline and a significant interaction in combination with LCPUFA intake. The major LCPUFAs-docosahexaenoic acid and arachidonic acid-also exhibited a significant interaction. The combination of high LCPUFA intake and high art appreciation frequency yielded a lower adjusted odds ratio for cognitive decline than the combination of low LCPUFA and low art appreciation [0.25 (95 % confidence intervals, 0.11-0.56)]. CONCLUSIONS: Preserving cognitive function might be associated with a combination of varied and high-frequency engagement in CLAs combined with high LCPUFA intake.

A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice.

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic ß-amyloid protein 42 (Aß42) to Aß40. Because of its neurotoxicity, Aß42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aß40 has neuroprotective effects against Aß42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aß42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aß42-to-Aß40-converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/- mice and found that a decrease in ACE levels promoted Aß42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Green tea and coffee intake and risk of cognitive decline in older adults: the National Institute for Longevity Sciences, Longitudinal Study of Aging.

OBJECTIVE: To examine the association between green tea and coffee intake and cognitive decline in older adults. DESIGN: A prospective cohort study. The average intake of green tea and coffee in the previous year was assessed through a dietitian interview using a dietary questionnaire. A Mini-Mental State Examination (MMSE) was conducted up to six times biennially. Cognitive decline was screened using the MMSE; its incidence was defined as the first time a score of <27 points was obtained in a biennial test from the baseline. Hazard ratios for incidence of cognitive decline were estimated according to the intake of the two beverages using multivariable Cox proportional hazard regression, controlling for sociodemographic and lifestyle factors. SETTING: The National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA) in Japan. PARTICIPANTS: Men (n 620) and women (n 685), aged 60-85 years, from the NILS-LSA. RESULTS: During a mean of 5·3 (sd 2·9) years of follow-up, 432 incident cases of cognitive decline were observed. Compared with participants who consumed green tea

Protein intake per day and at each daily meal and skeletal muscle mass declines among older community dwellers in Japan.

OBJECTIVE: To examine associations between protein intake per day and at different meals and skeletal muscle mass declines. DESIGN: Two-year prospective cohort study among older community dwellers. SETTING: National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan. PARTICIPANTS: Older men (n 292) and women (n 363) aged 60-87 years who participated in the baseline (2006-2008) and follow-up studies (2008-2010) of NILS-LSA and did not exhibit low skeletal muscle mass at baseline. Muscle mass was assessed using dual-energy X-ray absorptiometry at baseline and follow-up. Low muscle mass was defined as skeletal muscle mass index <7·0 kg/m2 for men and <5·4 kg/m2 for women at follow-up. Daily protein intake and protein intake at each meal were calculated from 3 d dietary records at baseline and sex-stratified tertiles were determined. RESULTS: Mean (sd) protein intake at breakfast, lunch and dinner was 22·7 (7·8), 26·7 (9·3) and 37·4 (10·5) g for men and 19·3 (6·3), 23·2 (7·3) and 28·5 (7·0) g for women, respectively. After adjusting for age, baseline skeletal muscle mass and other confounders in logistic modelling, greater total protein intake was associated with lower prevalence of skeletal muscle mass decline among men at follow-up (P = 0·024). Particularly, the OR (95 % CI) for high lunchtime protein intake was low (0·11 (0·02, 0·61); P = 0·01). No significant association between total protein intake and prevalence of skeletal muscle mass decline was found among women. CONCLUSIONS: High total protein intake, particularly at lunchtime, is associated with retention of skeletal muscle mass in men.

Hemoglobin A1c and 10-year information processing speed in Japanese community dwellers.

BACKGROUND: Hyperglycemia is believed to be a risk factor for cognitive decline, but the longitudinal relationship between hyperglycemia and cognitive decline in the Japanese population is unclear. The present study aimed to clarify the association between blood glucose levels and information processing ability in middle-aged and older adults. METHODS: The subjects were 866 men and 815 women aged 40-79 years not taking medication for diabetes who participated in the first study wave (1997-2000) and then participated at least once in the subsequent six study waves (2000-2012) of the National Institute for Longevity Sciences-Longitudinal Study of Aging, Japan. Hemoglobin A1c (HbA1c) levels were categorized into four groups (< 5.6, 5.6 to < 6.0, 6.0 to < 6.5, ≥ 6.5%), and a mixed-effects model was used to evaluate the effects of the HbA1c level (four groups) on repeated measures of information processing speed. The models also included baseline age, body mass index, ethanol intake, smoking status, educational level, family income, and history of stroke, hypertension, heart disease, and dyslipidemia as covariates. RESULTS: Mean (standard deviation) HbA1c and follow-up time in participants were 5.2 (0.5) % and 10.0 (3.6) years, respectively. A linear mixed model showed that the main effect of the four HbA1c groups on information processing ability was not significant in either men or women, but the interaction of HbA1c and time with information processing speed in the higher HbA1c level groups (≥ 6.5% group in men, 6.0 to < 6.5% and ≥ 6.5% groups in women) was significant compared to the lower HbA1c level (< 5.6%) group (P < 0.05). When the slope of information processing speed by HbA1c level at baseline was examined, the slope of information processing speed in the higher HbA1c level (≥ 6.5%) group was higher than in the lower HbA1c level (< 5.6%) group, both in men (- 0.31/year) and in women (- 0.30/year), as well as in women with an HbA1c level of 6.0 to < 6.5% (- 0.40/year). CONCLUSIONS: Higher baseline HbA1c was associated with greater subsequent decline in information processing ability in Japanese community dwellers, even with the pre-clinical HbA1c level (6.0 to < 6.5%) in women. The results suggest that good glycemic control or prevention of hyperglycemia may contribute to maintaining information processing ability.

What is the best adjustment of appendicular lean mass for predicting mortality or disability among Japanese community dwellers?

BACKGROUND: Age-related declines in skeletal muscle mass and strength, representing "sarcopenia," are a growing concern in aging societies. However, the prevalence of low muscle mass based on the height2-adjustment has been shown to be extremely low, and a more appropriate definition of low muscle mass is needed, particularly for Asian women. The aim of this study was to explore the most appropriate adjustment of appendicular lean mass (ALM) for predicting mortality or disability risk using ALM or any of 5 adjustments of ALM among community-dwelling Japanese. METHODS: Subjects comprised 1026 men and 952 women between 40 and 79 years old at baseline (1997-2000) who participated in the National Institute for Longevity Sciences - Longitudinal Study of Aging, Japan. ALM (kg) and 5 adjusted indices of ALM (ALM/leg length, ALM/height, ALM/height2, ALM/weight, and ALM/body mass index [BMI]) were assessed at baseline. Disability was defined by long-term care insurance certification based on responses to a survey mailed in 2013, and death records were obtained as vital statistics until December 2014. Crude and adjusted Cox proportional hazard models were used to estimate hazard ratios for mortality or disability by sex-stratified quintiles of each ALM index (ALM and adjusted ALM) or sarcopenia-related indices. The area under the curve (AUC) was calculated with the multivariate-adjusted logistic regression model. Additionally, mixed-effects analyses were used to clarify the age-related ALM indices decline over 12 years (n = 1838). RESULTS: Crude Cox proportional hazard models and multivariate-adjusted logistic model (AUC) indicated that higher ALM and ALM/BMI in women, and higher ALM, ALM/leg length, ALM/height, and ALM/BMI in men were associated with lower risks for mortality or disability than ALM/height2. The mixed effect model indicated all ALM indices in men, and ALM, ALM/leg length, and ALM/height in women could better predict age-related lean muscle mass decline. CONCLUSIONS: Unadjusted ALM in women, and ALM/leg length, ALM/height, ALM/BMI, and ALM in men may be more appropriate for predicting future mortality or disability than ALM/height2. Considering the age-related muscle mass decline, unadjusted ALM would be the first variable to assess, regardless of sex, in this Japanese cohort study.

[Aging-related frailty and sarcopenia. Epidemiology of Frailty and Sarcopenia.]

Frailty and sarcopenia present significant risks for adverse outcomes such as disability, falls, and mortality in Japanese older adults. Among community-dwelling Japanese older adults, the prevalence of frailty, which was characterized using three or more limitations(shrinking, exhaustion, low activity, slowness, and weakness), was 5.2% and 12.0% in men and women, respectively. The prevalence of sarcopenia based on a diagnosis of low appendicular muscle mass, low grip strength, and low gait speed was 9.6% in men and 7.7% in women. Further, the prevalence of frailty with comorbidity of sarcopenia was 21.6% and 52.2% in men and women, respectively, and the prevalence of sarcopenia with comorbidity of frailty was 28.6% and 34.4% in men and women, respectively. The estimated number of prevalent cases of frailty, pre-frailty, and sarcopenia in Japanese older adults was approximately 3,090,000, 17,950,000, and 2,710,000, respectively.

Cross-sectional association between serum concentrations of n-3 long-chain PUFA and depressive symptoms: results in Japanese community dwellers.

The effect of n-3 long-chain PUFA (n-3 LCPUFA) on depression in healthy subjects is unclear, and most of the previous studies have focused on populations eating Western diets with lower fish intake. The present study investigated the association between blood levels of n-3 LCPUFA and depressive symptoms in Japanese community dwellers with higher n-3 LCPUFA blood levels. A cross-sectional study was conducted from 2006 to 2008, including 1050 men and 1073 women aged 40 years or older from the National Institute for Longevity Sciences--the Longitudinal Study of Aging. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms. Multiple logistic regression analysis was performed to estimate the OR and 95% CI for a CES-D score ≥ 16. Serum concentrations of n-3 PUFA, but not n-6 PUFA, were inversely associated with depressive symptoms. Compared with the lowest quintile, the adjusted OR for serum EPA at the fourth and fifth quintiles were 0·55 (95% CI 0·35, 0·85) and 0·64 (95% CI 0·42, 0·98), respectively, and at the fifth quintile for DHA it was 0·58 (95% CI 0·37, 0·92), for the presence of depressive symptoms (P for trend=0·013 and 0·011, respectively). Serum levels of EPA and DHA were inversely associated with depressive symptoms in Japanese community dwellers with higher blood levels of n-3 LCPUFA, suggesting that n-3 LCPUFA intakes corresponding to higher levels in a Japanese population may have implications for a lower prevalence of depression.

The Associations Between Smoking Habits and Serum Triglyceride or Hemoglobin A1c Levels Differ According to Visceral Fat Accumulation.

BACKGROUND: Whether smokers and former smokers have worse lipid profiles or glucose levels than non-smokers remains unclear. METHODS: The subjects were 1152 Japanese males aged 42 to 81 years. The subjects were divided according to their smoking habits (nonsmokers, former smokers, and current smokers) and their visceral fat area (VFA) (<100 cm(2) and ≥100 cm(2)). RESULTS: The serum triglyceride (TG) levels of 835 males were assessed. In the VFA ≥100 cm(2) group, a significantly greater proportion of current smokers (47.3%) exhibited TG levels of ≥150 mg/dL compared with former smokers (36.4%) and non-smokers (18.8%). The difference in TG level distribution between former smokers and non-smokers was also significant. However, among the subjects with VFA of <100 cm(2), the TG levels of the three smoking habit groups did not differ. The serum hemoglobin A1c (HbA1c) levels of 877 males were also assessed. In the VFA <100 cm(2) group, significantly higher proportions of current smokers (17.9%) and former smokers (14.9%) demonstrated HbA1c levels of ≥5.6% compared with non-smokers (6.3%). In contrast, in the VFA ≥100 cm(2) group, significantly fewer former smokers displayed HbA1c levels of ≥5.6% compared with non-smokers and current smokers. Furthermore, the interaction between smoking habits and VFA was associated with the subjects' TG and HbA1c concentrations, and the associations of TG and HbA1c concentrations and smoking habits varied according to VFA. CONCLUSIONS: Both smoking habits and VFA exhibited associations with TG and HbA1c concentrations. The associations between smoking habits and these parameters differed according to VFA.

Effects of knee extensor muscle strength on the incidence of osteopenia and osteoporosis after 6 years.

The association of knee extensor muscle strength with bone mineral density (BMD) has been reported in cross-sectional epidemiological studies, but it remains unclear whether or not this is the case with longitudinal change. Thus, we investigated whether or not the knee extension strength can predict the incidence of osteopenia or osteoporosis after 6 years, then compared the difference between sexes. Subjects were 1255 community-dwelling Japanese men and menopaused women, aged 40-81 years. BMD of lumbar spine and femoral neck was assessed by dual-energy X-ray absorptiometry twice at 6-year intervals. Subjects were divided into three groups, normal, osteopenia, and osteoporosis, depending on their young adult mean BMD % value. In the cross-sectional analysis the correlations between the knee extension strength and BMD of the two regions were examined, using Pearson's correlation coefficient. Longitudinal analyses were then conducted to determine the odds ratio, controlled for age and BMI, given that those who were normal in the initial stage developed osteopenia or osteoporosis after 6 years, for every 1 SD decrease in knee extension strength, as well as those who first had normal or osteopenia and then developed osteoporosis. Cross-sectional analysis showed a statistically significant relation between knee extensor muscle strength and BMD at both the lumbar spine (p = 0.02) and the femoral neck (p < 0.0001) only in men. The longitudinal analysis showed the significant effect of muscle strength on the loss of femoral neck BMD from normal to osteopenia or osteoporosis both in men (OR 1.84, 95 % CI 1.36-2.48, p < 0.0001) and in women (OR 1.29, 95 % CI 1.002-1.65, p < 0.05), as well as on the loss of spinal BMD from normal or osteopenia to osteoporosis only in men (OR 2.97, 95 % CI 1.07-8.23, p < 0.05). The results suggest the importance of knee extension strength to maintain the bone health of the proximal femur and spine in aging particularly in men.

The association between hearing impairment and polymorphisms of genes encoding inflammatory mediators in Japanese aged population.

BACKGROUND: Aging process is accompanied by a chronic sub-clinical systemic inflammation. This study aimed to assess the association between hearing impairment and polymorphisms of genes encoding cytokines deeply-committed to the inflammatory response and immune homeostasis in an elderly Japanese population. Data were collected in the Longitudinal Study of Aging surveyed biennially between 1997 and 2010. The participants without any missing information at baseline were 1,957 individuals, and the gross accumulated number of 8,675 subjects (40-89 years of age) was analyzed. Two hearing impairment criteria were taken as the better ear pure-tone average (PTABE) greater than 25 dB and greater than 40 dB. We analyzed cumulative data using generalized estimating equations to investigate the effect of 9 polymorphisms, namely, tumor necrosis factor (TNF) α, rs1800630; TNF receptor super family (TNFRSF) 1B, rs1061624; interleukin (IL)-1A, rs1800587; IL-1B, rs16944; IL-4R, rs1801275; IL-6, rs1800796; IL-10, rs1800872; IL-1 receptor-associated kinase 1 (IRAK1), rs1059702; C reactive protein (CRP), rs1130864. RESULTS: The odds ratios for the hearing impairment (PTABE >25 dB) risk under additive genetic model were significant in TNF-α rs1800630 and TNFRSF1B rs1061624, which were respectively 1.172 (confidence interval [CI]: 1.005-1.367), 1.211 (CI: 1.053-1.392) in model after adjustment for possible confounders. Using the criterion of PTABE >40 dB as disabling hearing impairment, the association remains significant in TNFRSF1B rs1061624, but not in TNF-α rs1800630. No other polymorphisms showed a significant association. CONCLUSIONS: The present population-based cohort study demonstrated that TNF-α rs1800630 and TNFRSF1B rs1061624 contributed to the incremental risk of hearing impairment in the elderly. TNF-α and TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response, and also cause programmed cell death and cell proliferation. The present observation implied the signalling cascades of TNF were involved in ear aging.

[Transdisciplinary Approach for Sarcopenia. Sarcopenia : definition and the criteria for Asian elderly people].

Sarcopenia is a syndrome characterized by loss of skeletal muscle mass and function (strength and physical performance) with a risk of adverse outcomes. Asian criteria have been decided recently by the Asia Working Group for Sarcopenia (AWGS) . AWGS defined sarcopenia as low skeletal muscle mass plus low muscle strength and/or low physical performance based on the previous reports. AWGS recommend cutoff values for muscle mass (7.0 kg/m(2) for men and 5.4 kg/m(2) for women by using dual X-ray absorptiometry, and 7.0 kg/m(2) for men and 5.7 kg/m(2) for women by using bioelectrical impedance analysis) , handgrip strength (<26 kg for men and <18 kg for women) , and usual gait speed (<0.8 m/s) . The prevalence of sarcopenia in Japanese elderly men and women diagnosed using Asian criteria was 9.6% and 7.7%, respectively. The estimated number of prevalent cases of sarcopenia in Japanese elderly men and women was approximately 1.3 million and 1.4 million, respectively.

Differential Longitudinal Associations Between Domains of Cognitive Function and Physical Function: A 20-Year Follow-Up Study.

OBJECTIVES: Cognitive and physical functions are both associated with disability and death. Recent studies have addressed the relationship between cognitive declines and physical declines; however, whether various facets of cognition are diversely associated with specific physical functions is yet to be ascertained. The present work examines the longitudinal associations between fluid and crystallized cognitive functions (Gf and Gc) and physical functions. METHODS: The sample consisted of 863 community-dwelling older adults (baseline age 60-79 years) from the National Institute for Longevity Sciences-Longitudinal Study of Aging. The participants were tested on a set of Gf and Gc tests and physical tests (grip strength and gait speed). We ran a series of Multivariate Latent Growth Curve models. Specifically, we tested the relationship between cognitive and physical functions in terms of baseline performance (intercept) and rate of change (slope). RESULTS: The slope-slope correlations between Gf and physical function were large (grip strength r = 0.64 and gait speed r = 0.68, ps < .001). By contrast, the slope correlations between Gc and physical functions were weak (rs ≤ 0.31) and barely or marginally significant (ps ≤ .06). DISCUSSION: The results show that distinct domains of cognitive functions have different associations with physical functions. Namely, the aging-associated declines in the tested physical functions are robustly correlated with the declines in Gf, but are only weakly correlated with the declines in Gc. Therefore, Gc measures may be poor proxies for the patient's frailty and should be considered with caution in clinical assessment.

Association between polymorphisms in genes encoding methylenetetrahydrofolate reductase and the risk of Ménière's disease.

Folate metabolism is essential for cellular functioning. Despite extensive research on the roles of folate-metabolism-related gene polymorphisms in the pathophysiology of many diseases, such as cardiovascular disease, cancers, and sudden sensorineural hearing loss, little is known about their association with Ménière's disease (MD). The aim of this study was to investigate the effect of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) on the risk of MD in a Japanese population. We examined the C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the MTHFR gene and compared them between 1946 adults (986 men and 960 women) participating in the National Institute for Longevity Sciences Longitudinal Study of Aging and 86 cases of MD. A multiple logistic regression was performed to obtain odds ratios (ORs) for the risk of MD regarding the MTHFR polymorphisms before (model 1) and after (model 2) adjustment for age and sex factors. The OR of MTHFR C677T for the risk of MD was 0.669 (95% confidence interval [CI], 0.479-0.934) in model 1 and 0.680 (95% CI, 0.484-0.954) in model 2. In contrast, the OR of MTHFR A1298C for the risk of MD was 1.503 (95% CI, 1.064-2.123) in model 1 and 1.505 (95% CI, 1.045-2.167) in model 2. Our results imply that the MTHFR C677T and A1298C polymorphisms are associated with the risk of MD.

[The perspective of reference value -normal and abnormal in medicine].

A normal value is a laboratory parameter to discriminate between "normal" and "abnormal" in clinical decision-making. Because individual differences in the elderly are large, it can be difficult to determine a normal value as a group, thus reference values are basically used to assess laboratory parameters. However, the reference value only shows the range of average values in the healthy population, and does not determine or predict present and future health status. In geriatric practice, reference values of laboratory parameters in life-style related disease to predict independent life is indispensable. Although there are many risk factors of cognitive impairment related to independent life, the contribution rate of each factor is small and it is often difficult to determine a cut-off point by conventional methods. A new methodology is required to determine the optimal range of clinical parameter of life-style-related disease using longitudinal data.

[Construction of a scale of attitude toward death in the middle-aged and elderly and its validity and reliability].

AIM: The purpose of this study was to construct a scale that measures multidimensional attitudes regarding death in the middle-aged and elderly, using scale items for adolescents, and to examine its reliability and validity. METHODS: Twenty-nine items which were selected from the scale of Attitudes toward Death (Tange, 1999) were administered to subjects, consisting of 2,223 community-living Japanese men and women aged 40-79 years. Both exploratory factor analysis and confirmatory factor analysis were performed to examine the factor structures. The reliability and validity of the scale were examined. RESULTS: Exploratory factor analysis was performed to examine the factor structures of death attitudes, using the data from half of the subjects, indicated 5 factors. Confirmatory factor analysis, using the data from the remaining half, supported the goodness of fit of that model. Using this structure, the attitude toward death scale for the middle-aged and elderly (ATDS-A; five subscales) was constructed; "fear of death", "belief in existence of afterlife", "intention to live out own life", "meaning of death for life", "approval of death with dignity". For these subscales, the alpha coefficients ranged from 0.59-0.87. The validity of the subscales was suggested through the relation with the ego integration score. CONCLUSIONS: This study suggested that the ATDS-A was reliable and valid, and was useful for the measurement of death attitudes in the middle-aged and elderly.

Basal ganglia lesions may be a risk factor for characteristic features of a glaucomatous optic disc: population-based cohort study in Japan.

BACKGROUND: We conducted a study to investigate the relationship between optic nerve vertical cup-to-disc ratio (VCDR), body and ocular parameters, and brain lesions in middle-aged and above Japanese subjects, because although various risk factors for glaucoma have been previously characterised, it is theorised that there are unidentified neurological components. METHODS: In this population-based, age/gender-stratified, cross-sectional study that involved 2239 Japanese subjects (1127 men and 1112 women) aged 40 years and older (mean age: 59.3±11.7 years) living in the central geographical region of Japan who participated in the National Institute of Longevity Sciences-Longitudinal Study of Aging between 2002 and 2004, 4327 eyes and 2239 obtained MRIs of the head were evaluated. Multivariate mixed model and trend analyses were also performed. RESULTS: No significant relationship between VCDR and brain lesions, other than basal ganglia lesions, was found. VCDR significantly increased with the high grade of basal ganglia infarct lesions (p=0.0193) and high intraocular pressure (p<0.0001) after adjustment for influential factors using a multivariate mixed model. A significant positive linear trend was observed between the predicted VCDR and the degrees of the basal ganglia lesions (p value trend=0.0096). CONCLUSION: Our findings suggest that in subjects with higher grades of basal ganglia lesions, strict attention should be paid to elevated VCDR; however, further studies are needed to support/confirm our results.

Effects of APOEɛ4 genotype on age-associated change in cognitive functions among Japanese middle-aged and older adults: A 20-year follow-up study.

BACKGROUND AND AIMS: Carriers of the apolipoprotein E ε4 allele (APOEɛ4) have an increased risk of developing dementia (e.g., Alzheimer's disease). However, it is less clear whether the APOEɛ4 might also be involved in cognitive aging among the non-clinical population of older adults. While some studies have suggested that the APOEɛ4 is related to accelerated cognitive decline in the normal aging process, others have failed to provide compelling evidence of such an impact. Notably, these discrepancies may depend on methodological shortcomings, including short time spans, few assessments, and small sample sizes. The present study overcomes the above limitations and aims to clarify the impact of the APOEɛ4 genotype on long-term longitudinal changes in cognitive functions in middle-aged and older adults in Japan. METHODS AND RESULTS: The data were retrieved from the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) survey (N = 1832; 40 to 79 years of age at baseline). The participants were tested over nine waves covering a period of approximately 20 years. Latent Growth Curve (LGC) modeling was employed to test the impact of the interaction between APOEɛ4 status and age on several cognitive functions. Four tests of the WAIS-R were administered: Information, Similarities, Picture completion, and Digit Symbol Substitution Test (DSST). The results showed that the APOEɛ4 carriers experienced a more pronounced decline in the DSST (p = 0.001) and Similarities (p = 0.022) tests. A similar tendency was found in the Information test (p = 0.034). By contrast, no effect was found in the Picture completion test (p = 0.563). CONCLUSIONS: APOEɛ4 carriers seem to exhibit a steeper cognitive decline, which becomes apparent in old age. This effect is more robust in fluid cognitive skills (DSST) than crystallized cognitive skills (Information and Similarities). Overall, the APOEɛ4 genotype may be a significant risk factor in normal (i.e., non-clinical) cognitive aging.