Childhood adverse events and BDNF promoter methylation in later-life.

Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.

Brain-derived neurotrophic factor (BDNF) variants and promoter I methylation are associated with prolonged nocturnal awakenings in older adults.

Brain-derived neurotrophic factor (BDNF) is important for sleep physiology. This study investigates whether BDNF variants and promoter I methylation may be implicated in sleep disturbances in older adults. Genotyping was performed for seven BDNF single nucleotide polymorphisms (SNPs) in 355 community-dwelling older adults (aged ≥65 years) and BDNF exon 1 promoter methylation was measured in blood samples at baseline (n = 153). Self-reported daytime sleepiness and insomnia, ambulatory polysomnography measures of sleep continuity and architecture, and psychotropic drug intake were assayed during follow-up. Logistic regression adjusted for age, sex, comorbidities, body mass index, and psychotropic drug intake. Associations were found specifically between wake time after sleep onset (WASO) and four SNPs in the participants not taking psychotropic drugs, whereas in those taking drugs, the associations were either not significant (rs6265 and rs7103411) or in the reverse direction (rs11030101 and rs28722151). Higher BDNF methylation levels were found at most CpG units in those with long WASO and this varied according to psychotropic drug use. The reference group with short WASO not taking drugs showed the lowest methylation levels and the group with long WASO taking treatment, the highest levels. Some SNPs also modified the associations, the participants carrying the low-risk genotype having the lower methylation levels. This genetic and epigenetic study demonstrated blood BDNF promoter methylation to be a potential biomarker of prolonged nocturnal awakenings in older people. Our results suggest the modifying effect of psychotropic drugs and BDNF genetic variants in the associations between methylation and WASO.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium.

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

Objectively Assessed Weight Change and All-Cause Mortality among Community-Dwelling Older People.

Later life changes in body weight may be associated with an increased risk of mortality in older adults. The objective of this study was to examine whether weight change over four years was associated with a 17-year mortality risk in older adults. Participants were 1664 community-dwelling adults aged ≥65 years in the longitudinal Enquete de Sante' Psychologique-Risques, Incidence et Traitement (ESPRIT) study. Outcomes were all-cause mortality, cardiovascular disease (CVD) and cancer mortality. Weight change was defined as difference between weight at baseline and 4 years, categorised into: weight stable (±<5% weight change), weight loss (≥5%) and weight gain (≥5%). Association between weight change and mortality risk was evaluated using Cox proportional hazards models. Over 17 years of follow-up (median 15 years), 565 participants died. Compared to stable weight participants, those with ≥ 5% weight loss had an increased risk of all-cause mortality (HR: 1.24, 95% CI: 1.00−1.56, p = 0.05) and CVD mortality (HR: 1.53, 95% CI: 1.10−2.14, p = 0.01), but not cancer mortality (HR: 0.83, 95% CI: 0.50−1.39, p = 0.49). Weight gain of ≥5% was not associated with increased mortality (HR: 1.05, 95% CI: 0.76−1.45, p = 0.74). Weight monitoring in older adults could help identify weight loss at its early stages to better target interventions to maintain nutritional reserve and prevent premature mortality.

The association between adverse childhood events and later-life cognitive function and dementia risk.

BACKGROUND: Considerable work exists in the literature to describe the negative impacts of early-life stress exposures on health in adulthood. This study investigated whether the accumulation of adverse childhood events is associated with later-life cognitive function and incident dementia. METHODS: Participants were 1562 community-dwelling older adults, who were enrolled in the ESPRIT cohort in France. Adverse childhood events were measured using a modified version of the Childhood Trauma Questionnaire. Cognition was measured using tests of global cognition, visual memory, verbal fluency, psychomotor speed and executive function. Fourteen-year incident dementia was diagnosed using DSM-IV criteria. RESULTS: In comparison to participants with two or less adverse childhood events, increased risk of poor psychomotor speed at baseline was observed in individuals with multiple adverse childhood events (3-4 events OR: 1.39, 95% CI: 1.00-1.93); ≥5 events (OR: 1.52, 95% CI: 1.07-2.17), particularly in women but not in men. Worse verbal fluency was also observed in individuals who experienced between three and four adverse childhood events (OR: 1.34, 95% CI: 1.00-1.78). Amongst the individual factors investigated, early-life abuse/maltreatment (OR: 1.47, 95% CI: 1.02-2.14) and poverty/financial difficulties (OR: 1.53, 95% CI: 1.12-2.08) was associated with worse psychomotor speed. No associations were observed with incident dementia. LIMITATIONS: Participants most at risk (those with baseline dementia) were excluded. CONCLUSION: Multiple adverse childhood events are associated with worse psychomotor speed, and verbal fluency in later-life, however further research is needed to determine the mechanisms underlying this association and whether it results from unmeasured confounding, including social disadvantage.

The Association of Weight Loss, Weight Status, and Abdominal Obesity with All-Cause Mortality in Older Adults.

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 <18.5 kg/m2), 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.

A Prospective Study of Diurnal Cortisol and Incident Dementia in Community-Dwelling Older Adults.

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).

Steroid 21-hydroxylase gene variants and late-life depression.

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.

Structural brain alterations in older adults exposed to early-life adversity.

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.

Late-life cynical hostility is associated with white matter alterations and the risk of Alzheimer's disease.

BACKGROUND: Cynical 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. METHODS: In 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. RESULTS: Eighty-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. CONCLUSIONS: High 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.

Time-dependent depression and anxiety symptoms as risk factors for recurrent cardiac events: findings from the UPBEAT-UK study.

BACKGROUND: Depression 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. METHODS: Data (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. RESULTS: In 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]. CONCLUSIONS: Anxiety is an important short-term preventable and potentially causal risk factor for RCEs, to be targeted in secondary cardiac disease prevention programmes.

11ß-Hydroxylase (CYP11B1) gene variants and new-onset depression in later life.

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.

Estimating prevalence of subjective cognitive decline in and across international cohort studies of aging: a COSMIC study.

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.

The long-term consequences of trauma and posttraumatic stress disorder symptoms on later life cognitive function and dementia risk.

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.

A cross-national study of depression in preclinical dementia: A COSMIC collaboration study.

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.

Does parity matter in women's risk of dementia? A COSMIC collaboration cohort study.

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.

Testosterone levels and cause-specific mortality in the older French men without metabolic syndrome.

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.

Structural brain changes with lifetime trauma and re-experiencing symptoms is 5-HTTLPR genotype-dependent.

Background: Findings on structural brain alterations following trauma are inconsistent due probably to heterogeneity in imaging studies and population, clinical presentations, genetic vulnerability, and selection of controls. This study examines whether trauma and re-experiencing symptoms are associated with specific alterations in grey matter volumes and if this varies according to 5-HTTLPR genotype. Methods: Structural MRI was used to acquire anatomical scans from 377 community-dwelling older adults. Quantitative regional estimates of 22 subregional volumes were derived using FreeSurfer software. Lifetime trauma was assessed using the validated Watson's PTSD inventory, which evaluates the most severe trauma experienced according to DSM criteria. Analyses adjusted for age, sex, total brain volume, head injury, and comorbidities. Results: Of the 212 participants reporting lifetime trauma, 35.4% reported re-experiencing symptoms and for 1.9%, this was severe enough to meet criteria for full threshold PTSD. In participants with the SS 5-HTTLPR genotype only, re-experiencing symptoms were associated with smaller volumes in middle and superior temporal, frontal (lateral orbital, rostral and caudal middle) and parietal (precuneus, inferior and superior) regions. The trauma-exposed participants without re-experiencing symptoms were not significantly different from the non-trauma-exposed participants except for smaller precuneus and superior parietal region in traumatized participants and a larger amygdala in traumatized women specifically. Conclusions: In the non-clinical sample, lifetime trauma and re-experiencing symptoms were associated with smaller volume in prefrontal, temporal and parietal cortex subregions, and this varied according to serotonergic genetic vulnerability, 5-HTTLPR SS individuals being most susceptible.

Antecedentes: Los hallazgos sobre las alteraciones estructurales cerebrales luego del trauma son inconsistentes debido probablemente a heterogeneidad en los estudios de imagen y población, presentaciones clínicas, vulnerabilidad genética y selección de los controles. Este estudio examina si el trauma y los síntomas de reexperimentación están asociados con alteraciones específicas en los volúmenes de materia gris y si esto varía de acuerdo al genotipo 5-HTTLPR.Métodos: Se utilizó IMR estructural para adquirir mapeos anatómicos de 377 adultos mayores residentes en viviendas comunitarias. Se derivaron estimados regionales cuantitativos de 22 volúmenes sub-regionales usando el software FreeSurfer. Se evaluó trauma a través de la vida utilizando el inventario para TEPT validado de Watson, que evalúa el trauma más severo experimentado de acuerdo a criterios DSM. Se ajustaron los análisis por edad, sexo, volumen cerebral total, trauma encefálico y comorbilidades.Resultados: De los 212 participantes que reportaron trauma en la vida, un 35.4% reportó síntomas de reexperimentación y para el 1,9% fueron lo suficientemente severos para cumplir los criterios para el umbral completo del TEPT. Sólo en los participantes con el genotipo SS 5-HTTLPR, los síntomas de reexperimentación se asociaron con menores volúmenes en las regiones temporal media y superior, frontal (orbitolateral, rostral y caudal medial) y parietal (precúneo, inferior y superior). Los participantes expuestos a trauma sin síntomas de reexperimentación no variaron significativamente respecto a los no expuestos a trauma excepto por menor tamaño del precúneo y región superior parietal en los participantes traumatizados y un mayor tamaño de la amígdala específicamente en mujeres traumatizadas.Conclusiones: En una muestra no-clínica, el trauma a través de la vida y los síntomas de reexperimentación se asociaron con menor tamaño en sub-regiones corticales prefrontales, temporales y parietales, y esto varía de acuerdo a la vulnerabilidad genética serotoninérgica, siendo más susceptibles los individuos 5-HTTLPR SS.

Is Peripheral BDNF Promoter Methylation a Preclinical Biomarker of Dementia?

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.

Aromatase (CYP19A1) gene variants, sex steroid levels, and late-life depression.

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.