Search

BackgroundCynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD.MethodsIn community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA.ResultsEighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10–6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10–4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes.ConclusionsHigh CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.

BACKGROUND Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

Objectives A feature of late-life depression is alterations of the stress hormone system. The CYP21A2 gene encodes for the steroid 21-hydroxylase enzyme which is required for the biosynthesis of mineralocorticoids and glucocorticoids, two main components of the stress response in humans. Variants in the CYP21A2 gene could influence risk of late-life depression, but this has not been examined. This study investigated possible associations between five variants in the CYP21A2 gene and late-life depression in 1007 older community-dwelling men and women. Results In multivariate logistic regression model, significant associations were found between three single-nucleotide polymorphisms (rs389883, rs437179, and rs630379) and depression in women specifically (OR ranging from 1.51 to 1.68, p-values 0.025 to 0.0045), and the two latter remained significant after correction for multiple testing. Variants of the CYP21A2 gene appear as susceptibility factors for late-life depression in a sex-specific manner, independently of somatic and neuropsychiatric comorbidity.

International audience; Diurnal salivary cortisol was measured in 334 older adults without dementia, at four times on two separate days, under quiet and stressful conditions. In multivariate Cox proportional hazard models, higher global diurnal cortisol secretion was associated with incident dementia (HR = 1.09 [1.02–1.15] per one-unit increase in cortisol measure, p = 0.007) and Alzheimer’s disease (HR = 1.12 [1.04–1.21], p = 0.003) over a mean (SD) of 8.1 (4.0) years, independent of potential confounders and stressful conditions. Individuals with incident dementia had a slower rate of cortisol elimination under non-stressful conditions, reflected by higher cortisol levels in the evening, and an abnormal response to stress (blunted evening stress response).

Objectives: The objectives of this study were to examine whether weight loss, weight status (based on body mass index [BMI] categories), and abdominal obesity (based on waist circumference [WC]) were associated with a 17-year mortality risk in community-dwelling older adults. Methods: Participants were 2,017 community-dwelling adults aged 65 years or above in the longitudinal Enquête de Santé Psychologique-Risques, Incidence et Traitement study. Self-reported weight loss was collected at baseline during face-to-face interviews. Bodyweight (kg), height (m), and WC (cm) were independently measured at the baseline. BMI was categorized as follows: underweight (BMI 2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). Abdominal obesity was defined by a WC of ≥102 cm in men and ≥88 cm in women. Adjusted Cox proportional hazards models were used to examine associations of weight loss, weight status, and abdominal obesity with all-cause mortality. Results: Over 17 years of follow-up (median 15.5 years), 812 participants died. Abdominal obesity compared to nonabdominal obesity was associated with a 49% increased mortality risk (95% confidence interval (CI): 1.22–1.83). However, being overweight (but not obese) was associated with a 20% decreased risk (95% CI: 0.66–0.97) compared to a normal BMI. Gender did not affect these associations. In the whole cohort, self-reported weight loss at baseline was not associated with an increased mortality risk after adjusting for health and lifestyle factors. However, in men, a baseline self-reported recent weight loss of >3 kg was associated with a 52% increase in mortality risk (95% CI: 1.05–2.18) in a fully adjusted model. Conclusion: In community-dwelling adults aged ≥65 years, abdominal obesity was strongly associated with increased mortality risk. Being overweight appeared, however, to be protective against mortality. Modest self-reported weight loss was not associated with all-cause mortality in community-dwelling older adults after adjusting for health and lifestyle factors. However, men reporting recent weight loss of more than 3 kg may be at increased risk. The findings of this study support the use of WC, rather than BMI, as a predictor of mortality risk in older adults.

BackgroundDepression is a well-known risk factor for recurrent cardiac events (RCEs) but findings are less consistent for anxiety, not previously reported on using a time-dependent approach. We aimed to study the prognostic effect of anxiety and depression symptom levels on RCEs.MethodsData (N = 595) were drawn from the UPBEAT-UK heart disease patient cohort with 6-monthly follow-ups over 3 years. Hospital Anxiety and Depression Scale symptoms were grouped into: agitation (three items), anxiety (four items), and depression (seven items) subscales. We performed two types of multivariate analyses using Cox proportional hazard models with delayed entry: with baseline variables (long-term analysis), and with variables measured 12-to-18 months prior to the event (short-term time-dependent analysis), as RCE risk factors.ResultsIn the baseline analysis, both anxiety and depression, but not agitation, were separate RCE risk factors, with a moderating effect when considered jointly. In the short-term time-dependent analysis, elevated scores on the anxiety subscale were associated with increased RCE risk even when adjusted for depression [hazard ratio (95% confidence interval) 1.22 (1.05–1.41), p = 0.009]. Depression was no longer a significant predictor when adjusted for anxiety [1.05 (0.87–1.27), p = 0.61]. For anxiety, individual items associated with RCEs differed between the two approaches: item 5 ‘worrying thoughts’ was the most significant long-term risk factor [1.52 (1.21–1.91), p = 0.0004] whereas item 13 ‘feelings of panic’ was the most significant time-dependent short-term risk factor [1.52 (1.18–1.95), p = 0.001].ConclusionsAnxiety is an important short-term preventable and potentially causal risk factor for RCEs, to be targeted in secondary cardiac disease prevention programmes.

International audience; Background: Subjective cognitive decline (SCD) is recognized as a risk stage for Alzheimer's disease (AD) and other dementias, but its prevalence is not well known. We aimed to use uniform criteria to better estimate SCD prevalence across international cohorts. Methods: We combined individual participant data for 16 cohorts from 15 countries (members of the COSMIC consortium) and used qualitative and quantitative (Item Response Theory/IRT) harmonization techniques to estimate SCD prevalence. Results: The sample comprised 39,387 cognitively unimpaired individuals above age 60. The prevalence of SCD across studies was around one quarter with both qualitative harmonization/QH (23.8%, 95%CI = 23.3-24.4%) and IRT (25.6%, 95%CI = 25.1-26.1%); however, prevalence estimates varied largely between studies (QH 6.1%, 95%CI = 5.1-7.0%, to 52.7%, 95%CI = 47.4-58.0%; IRT: 7.8%, 95%CI = 6.8-8.9%, to 52.7%, 95%CI = 47.4-58.0%). Across studies, SCD prevalence was higher in men than women, in lower levels of education, in Asian and Black African people compared to White people, in lower- and middle-income countries compared to high-income countries, and in studies conducted in later decades. Conclusions: SCD is frequent in old age. Having a quarter of older individuals with SCD warrants further investigation of its significance, as a risk stage for AD and other dementias, and of ways to help individuals with SCD who seek medical advice. Moreover, a standardized instrument to measure SCD is needed to overcome the measurement variability currently dominant in the field.

Background Dementia shows sex difference in its epidemiology. Childbirth, a distinctive experience of women, is associated with the risk for various diseases. However, its association with the risk of dementia in women has rarely been studied. Methods We harmonized and pooled baseline data from 11 population-based cohorts from 11 countries over 3 continents, including 14,792 women aged 60 years or older. We investigated the association between parity and the risk of dementia using logistic regression models that adjusted for age, educational level, hypertension, diabetes mellitus, and cohort, with additional analyses by region and dementia subtype. Results Across all cohorts, grand multiparous (5 or more childbirths) women had a 47% greater risk of dementia than primiparous (1 childbirth) women (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.10–1.94), while nulliparous (no childbirth) women and women with 2 to 4 childbirths showed a comparable dementia risk to primiparous women. However, there were differences associated with region and dementia subtype. Compared to women with 1 to 4 childbirths, grand multiparous women showed a higher risk of dementia in Europe (OR = 2.99, 95% CI = 1.38–6.47) and Latin America (OR = 1.49, 95% CI = 1.04–2.12), while nulliparous women showed a higher dementia risk in Asia (OR = 2.15, 95% CI = 1.33–3.47). Grand multiparity was associated with 6.9-fold higher risk of vascular dementia in Europe (OR = 6.86, 95% CI = 1.81–26.08), whereas nulliparity was associated with a higher risk of Alzheimer disease (OR = 1.91, 95% CI 1.07–3.39) and non-Alzheimer non-vascular dementia (OR = 3.47, 95% CI = 1.44–8.35) in Asia. Conclusion Parity is associated with women’s risk of dementia, though this is not uniform across regions and dementia subtypes.

International audience; Stress may be a risk factor for dementia, however it is unknown whether post-traumatic stress disorder (PTSD) symptoms are associated with incident dementia in community-dwelling older individuals. The aim was to determine whether lifetime major trauma with and without re-experiencing of PTSD symptoms is associated with later-life cognition and dementia risk. Participants were 1,700 community-dwelling older adults (65+) in the longitudinal ESPRIT study followed over 14 years. Lifetime major traumatic exposure and PTSD were assessed using Watson's PTSD Inventory. Cognitive tests assessed global cognition, visual memory, verbal fluency, psychomotor speed and executive function. Incident dementia was diagnosed according to DSM-IV criteria. Lifetime major trauma (versus no trauma) was associated with significantly increased executive function and increased global function in men, however women with lifetime trauma and re-experiencing symptoms had a significantly increased risk of low global cognition. Over 14 years, lifetime trauma without re-experiencing symptoms was associated with a significantly decreased risk of incident dementia, particularly for women. Lifetime major trauma without re-experiencing symptoms (but not with) may be protective for later life cognitive function. However, the mechanisms and moderating factors underlying these association requires further investigation.

Background Cumulative exposure to high glucocorticoid levels is detrimental for the brain and may have particular implications in later life. A feature of late-life depression is increased cortisol secretion. Variants in the CYP11B1 gene, which codes for the enzyme responsible for cortisol synthesis, could influence risk of late-life depression, but this hypothesis has not been examined. We investigated the associations between variants in the CYP11B1 gene and late-life depression, taking into account history of depression and potential sex-specific effects. Methods We assessed depression in 1007 community-dwellers aged 65 years or older (60% women) at baseline and over a 14-year follow-up. A clinical level of depression was defined as a score of ≥ 16 on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). We examined incident and recurrent depression in participants without or with a history of major depression, respectively. We genotyped 5 single-nucleotide polymorphisms (SNPs) spanning CYP11B1. We used multivariable analyses to adjust for age, body mass index, cardiovascular ischemic pathologies, hypertension, cognitive impairment and anxiety. Results In women, rs6471580 and rs7016924 were associated with a 50% lower rate of incident (new-onset) late-life depression, and rs11783855 was associated with a 2.4-fold higher rate of late-life depression. These associations remained after correction for multiple testing, but we found no associations for recurrent depression in women or men. Limitations This study focused on the major gene involved in corticosteroid biosynthesis, but other genes may also be implicated in this pathway. Conclusion Variants of the CYP11B1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner.

Background Psychological stress is recognized as a major risk factor for a range of non-communicable diseases and possibly mortality. The extent to which the type and timing of stress exposure influences mortality, and potential differences between genders, remains unknown. Objective To examine the association between early-life and recent stressful experiences and mortality risk in later life, and to determine possible gender differences in these associations. Method Data were obtained from 2152 French community-dwelling participants (aged ≥65). Questionnaires were used to evaluate recent stress, as well as retrospective reporting of childhood adversity. Mortality status was determined through death registries. Adjusted Cox proportional hazards models were used to determine the association between stress and 16-year mortality risk. Results Over a mean 12.9 years, 850 people died. Having a childhood home environment with very serious conflicts was associated with a 54% increased mortality risk (95%CI:1.21-1.96), and childhood abuse/maltreatment with a 34% increased risk (95% CI:1.05-1.70). For females, specific childhood events (serious illness HR:1.91, 95%CI:1.40–2.60; war/natural disaster HR:1.47, 95%CI:1.14-1.88) and the number of events (≥5 adverse events HR:1.91, 95%CI:1.25-2.32), also increased mortality risk. In terms of recent events, mortality risk increased by 66% (95%CI:1.39-2.00) in participants reporting a recent serious illness or physical trauma and by 86% for those reporting problems with the police/justice (95%CI:1.05-3.30). Among males specifically, mortality risk also increased with major financial problems (HR:1.92, 95%CI:1.14-3.21), and when they had a relative with a serious illness (HR:1.26, 95%CI:1.01–1.55). Conclusions Stressful life experiences are associated with all-cause mortality however the associations varied between early-life adversities and recent stress, and were different across the genders. Among females, certain types of childhood adversity continue to predict mortality risk in later life, while in males specific recent stress significantly increased mortality risk.

Additional file 1.

Introduction Depression commonly accompanies Alzheimer's disease, but the nature of this association remains uncertain. Methods Longitudinal data from the COSMIC consortium were harmonized for eight population-based cohorts from four continents. Incident dementia was diagnosed in 646 participants, with a median follow-up time of 5.6 years to diagnosis. The association between years to dementia diagnosis and successive depressive states was assessed using a mixed effect logistic regression model. A generic inverse variance method was used to group study results, construct forest plots, and generate heterogeneity statistics. Results A common trajectory was observed showing an increase in the incidence of depression as the time to dementia diagnosis decreased despite cross-national variability in depression rates. Discussion The results support the hypothesis that depression occurring in the preclinical phases of dementia is more likely to be attributable to dementia-related brain changes than environment or reverse causality.

International audience; OBJECTIVES: Previous studies have reported controversial findings regarding the association of testosterone with mortality in older men. This heterogeneity might be partially explained by comorbidities and the presence of metabolic syndrome, as well as differential associations according to causes of death.METHODS: We used data from a random subsample of the Three-City study, in which hormone levels were measured in 338 men ≥65 years without metabolic syndrome who were followed-up for 12 years. Vital status was determined for all participants from different sources. We used inverse-probability-weighted Cox regression to estimate the hazard ratios (HRs) of cause-specific mortality and 95% confidence intervals (CIs).RESULTS: Over the follow-up period, 130 men died (30 from cardiovascular disease, 45 from cancer, 55 from other causes). The association of testosterone with mortality showed significant heterogeneity across causes of death (p=0.027 and p=0.022 for total and bioavailable testosterone, respectively). Higher testosterone levels were associated with increased cardiovascular mortality (HR for 1-standard deviation increase, 1.86; 95% CI, 1.28 to 2.71 and 1.50; 95% CI, 1.04 to 2.17 for total and bioavailable testosterone, respectively). By contrast, there were no significant associations of testosterone with mortality from cancer and other causes.CONCLUSIONS: Our data suggest that the association of testosterone with mortality in men without metabolic syndrome might be differential according to the cause of death. These findings may partially explain the heterogeneity across studies on the relationship between testosterone levels and mortality.

Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n = 769) and buccal samples during follow-up (n = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ4. Multivariable logistic regression analyses determined the association between BDNF methylation and both prevalent and incident dementia. Adjustment for gender, age, education, APOEɛ4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ-0.5%, 95% CI:-0.9,-0.04, p = 0.03, p = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p = 0.02, p = 0.14 adjusted and Δ-1.5%, OR:0.85, SE:0.06, p = 0.03, p = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r=-0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing.

CONTEXT: Although endogenous estradiol, generally considered as the female hormone, has been little investigated in men, it could play a role in men's health, mortality in particular. The influence of estrogen receptors (ER) genetic polymorphisms on this relationship has never been studied. DESIGN AND PARTICIPANTS: The Three-City cohort study included (1999-2001) 3650 men >/=65 years who were followed for mortality over 12 years. At baseline, total estradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free estradiol (fE2) was estimated using Vermeulen and Sodergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of estradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: 183 men died over the follow-up (cardiovascular disease (CVD), n=44; cancer, n=57; other causes, n=82). After adjustment, there was a quadratic relationship of all-cause mortality with tE2 and fE2 (p-quadratic=0.04 and 0.05, respectively), with higher mortality for the top and bottom tertiles compared to the middle one. These associations were stronger for CVD mortality (p-quadratic=0.01 and 0.02 for tE2 and fE2, respectively) and disappeared for cancer mortality. There was no evidence of an interaction of estradiol with any ER polymorphisms on all-cause mortality. CONCLUSION: In elderly men, we showed a nonlinear association of tE2 and fE2 with all-cause mortality. These quadratic relationships were stronger for CVD mortality and did not exist for cancer mortality. ER genetic polymorphisms did not modify this association. This article is protected by copyright. All rights reserved.

International audience

International audience; Background: Adverse childhood events may have differential effects on the brain that persist into adulthood. Findings on structural brain alterations in older adults exposed to early-life adversity are inconsistent notably due to heterogeneity in imaging studies, population, psychiatric comorbidities, nature of adverse events, and genetic vulnerability. This study examines whether exposure related to physical or sexual maltreatment, emotional maltreatment, and global adverse environment during childhood are associated with specific alterations in grey matter volumes and if this varies according to sex and serotonin transporter-linked promoter region (5-HTTLPR) genotype.Method: Structural MRI was used to acquire anatomical scans from 398 community-dwelling older adults. Quantitative regional estimates of 23 subregional volumes were derived using FreeSurfer software. Retrospective reporting of childhood adversity was collected using structured self-reported questionnaire. Analyses adjusted for age, sex, brain volume, head injury, lifetime depression and anxiety disorder, psychiatric medication, and cardiovascular ischemic pathologies.Results: Exposure to adverse family environment was associated with smaller volumes of several frontal, cingulate, and parietal subregions and larger amygdala in the 5-HTTLPR SS genotype participants specifically but larger volumes of caudate, putamen, pallidum, and nucleus accumbens in the SL genotype participants. Highly significant differences were found with excessive sharing of parent problems with children, associated with larger grey-matter volumes in the thalamus and several frontal and parietal regions in 5-HTTLPR SL male participants specifically.Conclusions: Early-life adversity is associated with grey-matter volume alterations in older adults and this varies according to the type of adversity experienced, sex, and serotonergic genetic vulnerability; 5-HTTLPR SS participants appearing most vulnerable and SL individuals most resilient.

Background With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. Methods and findings We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54–105 (mean = 72.7) years and without dementia at baseline. Studies had 2–15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = −0.1, SE = 0.01), APOE*4 carriage (B = −0.31, SE = 0.11), depression (B = −0.11, SE = 0.06), diabetes (B = −0.23, SE = 0.10), current smoking (B = −0.20, SE = 0.08), and history of stroke (B = −0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = −0.07, SE = 0.01), APOE*4 carriage (B = −0.41, SE = 0.18), and diabetes (B = −0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = −0.24, SE = 0.12), and between diabetes and cognitive decline (B = −0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. Conclusions These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences., Darren Lipnicki and the Sydney COSMIC team analysed cognitive performance and risk factor data from older people from 15 countries to assess associations between risk factors and late-life cognition, Author summary Why was this study done? There is a growing global burden associated with cognitive decline and dementia. Evidence for modifiable risk factors that could be targeted to reduce this burden needs to be improved. Risk factors for cognitive decline and dementia might differ between ethno-regional groups. What did the researchers do and find? We analyzed cognitive performance and risk factor data from 48,522 older individuals, provided by 20 studies of aging representing 15 countries (Australia, Brazil, Cuba, France, Germany, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, The Netherlands, the United Kingdom, and the United States). Cognitive performance was measured as Mini-Mental State Examination (MMSE) and global cognition scores. When controlling for confounding risk factors, the apolipoprotein E ε4 allele (APOE*4), depression, diabetes, current smoking, and history of stroke were associated with poorer cognitive performance, and higher levels of education and vigorous physical activity were associated with better performance. Age, APOE*4, and diabetes were associated with faster cognitive decline. Compared to white people, Asian people showed stronger associations between having ever smoked and cognitive performance, and between diabetes and cognitive decline. What do these findings mean? Modifiable risk factors associated with cognitive decline include education, smoking, physical activity, diabetes, and stroke. If these associations are determined to be causal, interventions targeting these factors may help reduce the global burden of cognitive decline and dementia. Interventions may require tailoring to particular ethno-regional groups.

A recent study reported for the first time, that DNA methylation of the KITLG gene mediates the association between childhood trauma and cortisol stress reactivity. Our study aimed to provide the first independent replication of these findings. ESPRIT is a prospective study of community-dwelling participants (age ≥ 65), randomly selected from the electoral rolls of the Montpellier district, in France. Clinical depression was assessed using the Mini-International Neuropsychiatric Interview (MINI, French version 5.00), and the Centre for Epidemiological Studies Depression Scale (CES-D). Experiences of childhood adversity were ascertained via a 25-item questionnaire. Morning, evening, and diurnal salivary cortisol was measured under basal and stress conditions and determined using direct radioimmunoassay analysis. DNA methylation of the KITLG gene was quantified in whole blood using the SEQUENOM MassARRAY EpiTYPER platform. A significant negative association was observed between KITLG DNA methylation and both morning cortisol (β = −1.846 ± 0.666, p = .007) and diurnal cortisol (area under curve [AUC]) (β = −19.429 ± 8.868, p = .031) under a stress condition. However, only the former association was significant after correcting for multiple testing. Further, this association remained after adjusting for age, sex, and depression status. No significant association was observed between childhood trauma and KITLG DNA methylation in this older population. This study provides support for an association between KITLG methylation and stress cortisol levels, suggesting that DNA methylation of this gene may play a role in the longer term regulation of the stress system.Lay summary The significant negative association between KITLG DNA methylation and morning cortisol, measured under a stressful condition, suggests that individuals with higher KITLG methylation will secrete lower levels of cortisol whilst under stress. The significant negative association between KITLG DNA methylation and morning cortisol, measured under a stressful condition, suggests that individuals with higher KITLG methylation will secrete lower levels of cortisol whilst under stress.

OBJECTIVE Increasing evidence suggests that Alzheimer's disease begins at least a decade before the diagnosis of dementia. Earlier identification of the disease will have important implications for intervention; however, current models of preclinical changes are theoretical and require verification from empirical observations. Furthermore, these models have not incorporated psychiatric features. METHOD Clinical and biological markers were examined at baseline (1999-2001) in 9,076 people aged 65 years and older. A nested case-control study included 830 cases with Alzheimer's disease diagnosed by DSM-IV criteria during the 10-year follow-up and twice as many controls. By taking the distance between baseline and diagnosis as the length of the preclinical period, disease marker trajectories were estimated using nonparametric locally weighted smoothing analysis. RESULTS Significant differences for the cases compared to the controls were observed on both intercept and slope for truncated amyloid β40 (P = .006; P = .003, respectively), C-reactive protein (P = .03; P = .05), verbal fluency (P < .0001; P < .0001), visual recall (P < .0001; P = .007), and hippocampal volume (P = .0002; P = .04) and on the slope only for truncated amyloid β42 (P = .01). The cases showed higher levels of depressive symptoms (P = .003), which remained stable over the 10 years to diagnosis. CONCLUSIONS As hypothesized by existing theoretical models, changes in plasma amyloid β levels, hippocampal atrophy, cognitive loss, and C-reactive protein are already observed up to 10 years before diagnosis. An acceleration in cognitive decline appears to follow a significant increase in amyloid accumulation, and depressive symptomatology remains at a constantly higher level. Overall, clinical and biological markers do not follow the same trajectories; the clinical picture changes according to distance from dementia.

Background Disrupted serotonergic signaling is often a feature of depression and the role of the serotonin transporter gene (SLC6A4), responsible for serotonin re-uptake, has received much attention in this regard. Most studies have focused on the polymorphic 5-HTTLPR upstream repeat, or DNA methylation at the promoter CpG island. Few studies have explored the influence of genetic variation across the gene on DNA methylation, and their combined association with depression risk. The aim of this study was to determine whether genetic variation in the SLC6A4 gene influences promoter DNA methylation, and whether these are associated with depression status. Method The ESPRIT study involves a community-based population of older individuals (> 65 years of age). Major depressive disorder (MDD) was diagnosed according to DSM-IV (American Psychiatric Association, 1994) criteria, and severe depressive symptoms assessed by the Centre for Epidemiological Studies Depression (CES-D) Scale. Sequenom MassARRAY was used to measure SLC6A4 methylation status (n = 302). Results Nominally significant associations were observed between SLC6A4 genetic variants (5-HTTLPR, rs140700, rs4251417, rs6354, rs25528, rs25531) and DNA methylation at several CpG sites. In multivariate regression, DNA methylation was associated with depression status, but only in the presence of specific genotypes. In individuals homozygous for the short 5-HTTLPR and 5-HTTLPR/r25531 alleles, lower methylation at two CpGs was associated with depression (β = − 0.44 to β = − 0.31; p = 0.001 to p = 0.038). Conclusion We present evidence for genotype-dependent associations between SLC6A4 methylation and depression. Genetic variants may also play a role in influencing promoter methylation levels and its association with depression. Electronic supplementary material The online version of this article (10.1186/s12888-018-1850-4) contains supplementary material, which is available to authorized users.

International audience; OBJECTIVE:Frequent Attenders (FAs) have high rates of both common mental disorders (CMD) and physical disorders, partly justifying this service use behaviour. This study examines both case and non-case concordance between CMDs as estimated by a self-report screening questionnaire and as rated by the general practitioner (GP), in FAs compared to Other Attenders (OAs).METHODS:2275 patients of an overlapping sample of 55 GPs from 2 surveys performed 10 years apart, completed in the waiting room the Patient Health Questionnaire (PHQ) and Client Service Receipt Inventory on 6-month service use. For each patient, the GP rated mental health on a 0-4 scale, with a clear indication that scores of 2 and above referred to caseness. PHQ-CMDs included major and other depressive, anxiety, panic, and somatoform disorders, identified using the original PHQ DSM-IV criteria-based algorithms. FA was defined as the top 10% of attenders in age, sex and survey-year stratified subgroups.RESULTS:FAs had higher rates of PHQ-CMDs (42% versus 23% for OAs, p

Previous studies have shown controversial results about the role of testosterone in all-cause mortality in elderly men. We hypothesized that metabolic syndrome (MetS) could partly explain this discrepancy. We therefore examined the association of all-cause mortality with total and bioavailable testosterone, taking into account the MetS. We used data from the Three-City Cohort (3C) study with 12-year follow-up. The 3C study included 3650 men aged >65 years in three French cities. Hormone was measured in a random subsample of 444 men, and MetS was determined as stated by the International Diabetes Federation criteria. We used inverse-probability–weighted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Of 444 men included in the analysis, 106 (23.9%) had MetS at baseline, and 166 died over the follow-up. There was a significant interaction between testosterone level and MetS for all-cause mortality (P = 0.002 and P = 0.008 for total and bioavailable testosterone, respectively). Among men with MetS, a decrease in one standard deviation of testosterone was associated with higher mortality risk [HR 1.78 (95% CI 1.13 to 2.78) and HR 1.83 (95% CI 1.17 to 2.86) for total and bioavailable testosterone, respectively]. By contrast, there was no association of testosterone with mortality risk among men without MetS. Our results suggest that MetS modifies the association between testosterone and mortality in older men. If confirmed, these findings could contribute to improve risk stratification and better manage the health of older men., We evaluated the association of testosterone with mortality in men and found metabolic syndrome (MetS) was an effect modifier of this relationship. Low testosterone increased mortality among men with MetS.

Background Depression is one of the most prevalent psychiatric disorders, and in older persons is associated with high levels of comorbidity and under-treatment. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis is consistently observed in the older population as well as depressed patients, with the angiotensin converting enzyme (ACE) a key regulator of the stress response. Epigenetic regulation of ACE may play an important role in HPA axis (dys)regulation. Objective To investigate ACE promoter methylation as a biomarker of late-life depression, and its association with genetic variation and cortisol secretion. Method The longitudinal general population ESPRIT study is aimed at investigating psychiatric disorders in older persons (n = 1863, average age = 73). Depression was assessed using the Mini International Neuropsychiatric Interview according to DSM-IV criteria and the Centre for Epidemiologic Studies Depression Scale (CES-D). Genotype information for seven polymorphisms across the ACE gene was also available. Blood and saliva samples collected at baseline and used to extract DNA and measure cortisol, respectively. Sequenom MassARRAY was used to measure promoter DNA methylation of the ACE gene (n = 552). Results There was no evidence of an association between ACE promoter methylation and depression. However, there was evidence that ACE genetic variants influenced methylation, and modified the association between depression and methylation (Δ at various sites; ‐2.05% to 1.74%; p = 0.019 to 0.039). Multivariate analyses were adjusted for participants’ lifestyle, health and medical history. Independent of depression status, ACE methylation was inversely correlated with cortisol levels (r = −0.336, p = 0.042). Conclusion This study provides evidence that associations between ACE methylation and depression are genotype-dependent, suggesting that the development of reliable depression biomarkers may need to consider methylation levels in combination with underlying genetic variation. ACE methylation may also be a suitable biomarker of cortisol and/or HPA axis activity.

Table S1. Individual CpG units assayed and analysed in this study. Table S2. Frequency of SLC6A4 genotypes according to depression status in the study population. Figure S1. Flowchart of the quality control process following the generation of SLC6A4 methylation data. Figure S2. Differences in DNA methylation according to depression status, stratified by SLC6A4 genotypes. (DOCX 421 kb)

International audience; BackgroundIt is well established that there is a link between inflammation and depression, with several studies reporting increased circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL6), in depressed individuals. Peripheral epigenetic marks, including DNA methylation, hold promise as biomarkers for a range of complex conditions, with potential to inform diagnosis and tailor interventions. The aim of this study was to determine whether individuals with depression display differential methylation of the IL6 gene promoter compared to individuals without depression.MethodsThe ESPRIT study of later life neuropsychiatric disorders used a random sampling framework to select non-institutionalised participants aged ≥65 years and over living in the Montpellier region of France. Major depressive disorder (MDD) was assessed using the Mini International Neuropsychiatric Interview (MINI) according to DSM-IV criteria. High levels of depressive symptoms were defined as a score of ≥16 on the Centre for Epidemiologic Studies Depression Scale (CES-D). IL6 promoter DNA methylation was measured on a sub-sample of 380 participants who provided buccal samples.ResultsIndividuals with depression (current MDD or high depressive symptoms) had lower IL6 methylation levels at one of the four sites investigated, however the effect size was small (∆ 2.4%, SE 0.009, p = 0.006). Interestingly, antidepressant use was independently associated with higher IL-6 methylation at the same site (∆ 4.6%, SE 0.019, p = 0.015). In multivariate linear regression analyses adjusting for covariates, including sex and smoking status, these associations remained. There was no effect modification when considering IL6 genotype.ConclusionThis study presents evidence that IL6 methylation may be a marker of depression status in older individuals, however further work is now needed to replicate these findings and to assess the association with inflammatory status of individuals.

Background.In elderly general population sub-syndromal clinically significant levels of depressive symptoms are highly prevalent and associated with high co-morbidity and increased mortality risk. However changes in depressive symptoms over time and etiologic factors have been difficult to characterise notably due to methodological shortcomings. Our objective was to differentiate trajectories of depressive symptoms over 10 years in community-dwelling elderly men and women using statistical modelling methods which take into account intra-subject correlation and individual differences as well as to examine current and life-time risk factors associated with different trajectories.Methods.Participants aged 65 and over were administered standardised questionnaires and underwent clinical examinations at baseline and after 2, 4, 7 and 10 years. Trajectories over time of the Center for Epidemiologic Studies Depression scores were modelled in 517 men and 736 women separately with latent class mixed models which include both a linear mixed model to describe latent classes of trajectories and a multinomial logistic model to characterise the latent trajectories according to baseline covariates (socio-demographic, lifestyle, clinical, genetic characteristics and stressful life events).Results.In both genders two different profiles of symptom changes were observed over the 10-year follow-up. For 9.1% of men and 25% of women a high depressive symptom trajectory was found with a trend toward worsening in men. The majority of the remaining men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels of depressive symptoms. In large multivariate class membership models, mobility limitations [odds ratio (OR) = 4.5, 95% confidence interval (CI) 1.6–12.9 and OR = 4.9, 95% CI 2.3–10.7, in men and women respectively], ischemic pathologies (OR = 2.9, 95% CI 1.0–8.3 and OR = 3.1, 95% CI 1.0–9.9), and recent stressful events (OR = 4.5, 95% CI 1.1–18.5, OR = 3.2, 95% CI 1.6–6.2) were associated with a poor symptom course in both gender as well as diabetes in men (OR = 3.5, 95% CI 1.1–10.9) and childhood traumatic experiences in women (OR = 3.1, 95% CI 1.6–5.8).Conclusions.This prospective study was able to differentiate patterns of chronic and remitting depressive symptoms in elderly people with distinct symptom courses and risk factors for men and women. These findings may inform prevention programmes designed to reduce the chronic course of depressive symptomatology.