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.

Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study.

BACKGROUND: The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. METHODS AND FINDINGS: We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54-105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2-16 assessment waves (median = 3) and a follow-up duration of 2-15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. CONCLUSIONS: Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data.

Nutrition and mortality in the elderly over 10 years of follow-up: the Three-City study.

In the last 20 years, many prospective cohort studies have assessed the relationships between food consumption and mortality. Result interpretation is mainly hindered by the limited adjustment for confounders and, to a lesser extent, the small sample sizes. The aim of this study was to investigate the association between dietary habits and all-cause mortality in a multicentre prospective cohort that included non-institutionalised, community-based elderly individuals (Three-City Study). A brief FFQ was administered at baseline. Hazard ratios (HR) and 95 % CI for all-cause mortality were estimated relative to the consumption frequency of several food groups, using Cox proportional hazards models adjusted for sex, centre, socio-demographic characteristics and health status indicators. Among the 8937 participants (mean age: 74·2 years, 60·7 % women), 2016 deaths were recorded during an average follow-up of 9 years. The risk of death was significantly lower among subjects with the highest fruit and vegetable consumption (HR 0·90; 95 % CI 0·82, 0·99, P=0·03) and with regular fish consumption (HR 0·89; 95 % CI 0·81, 0·97, P=0·01). The benefit of olive oil use was found only in women (moderate olive oil use: HR 0·80; 95 % CI 0·68, 0·94, P=0·007; intensive use: HR 0·72; 95 % CI 0·60, 0·85, P=0·0002). Conversely, daily meat consumption increased the mortality risk (HR 1·12; 95 % CI, 1·01, 1·24, P=0·03). No association was found between risk of death and diet diversity and use of various fats. These findings suggest that fruits/vegetables, olive oil and regular fish consumptions have a beneficial effect on the risk of death, independently of the socio-demographic features and the number of medical conditions.

Hypnotics and mortality in an elderly general population: a 12-year prospective study.

BACKGROUND: Hypnotics are widely used by the elderly, and their impact on mortality remains controversial. The inconsistent findings could be due to methodological limitations, notably the lack of control for underlying sleep symptoms or illness associated with hypnotic use, for example, insomnia symptoms and excessive daytime sleepiness, depression and anxiety. Our objective was to examine the association between the use of hypnotics and mortality risk in a large cohort of community-dwelling elderly, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders and sleep complaints. METHODS: Analyses were carried out on 6,696 participants aged 65 years or older randomly recruited from three French cities and free of dementia at baseline. Adjusted Cox proportional hazards models with delayed entry, and age of the participants as the time scale, were used to determine the association between hypnotic use and 12-year survival. RESULTS: At baseline, 21.7% of the participants regularly used at least one hypnotic. During follow-up, 1,307 persons died, 480 from cancer and 344 from cardiovascular disease. Analyses adjusted for study center, age and gender showed a significantly greater risk of all-cause and cardiovascular-related mortality with hypnotics, particularly benzodiazepines, and this increased with the number of hypnotics used. None of these associations were significant in models adjusting for sociodemographic and lifestyle characteristics, chronic disorders including cardiovascular pathologies, sleep and psychiatric disorders. Results remained unchanged when duration of past hypnotic intake or persistent versus intermittent use during follow-up were taken into account. CONCLUSIONS: When controlling for a large range of potential confounders, the risk of mortality was not significantly associated with hypnotic use regardless of the type and duration. Underlying psychiatric disorders appear to be the principal confounders of the observed association.

Anxiety and mortality risk in community-dwelling elderly people.

BACKGROUND: There are conflicting data on the role of anxiety in predicting mortality. AIMS: To evaluate the 10-year mortality risk associated with anxiety in community-dwelling elderly people. METHOD: Using data from 718 men and 1046 women aged 65 years and over, gender-stratified associations of anxiety symptoms (Spielberger State-Trait Anxiety Inventory, third tertile) and current DSM-IV anxiety disorder including generalised anxiety disorder (GAD) and phobia with all-cause and cardiovascular mortality were determined. RESULTS: In women, mortality risk was increased for anxiety disorder and GAD in multivariate Cox models (hazard ratio (HR) = 1.53, 95% CI 1.02-2.27 and HR = 2.04, 95% CI 1.08-3.86 respectively), whereas for phobia it was nearly significant (HR = 1.52, 95% CI 0.94-2.47). Anxiety trait symptoms became non-significant as a result of the confounding effect of depressive symptoms. Anxiety disorder was associated with cardiovascular mortality in univariate analysis (HR = 2.42, 95% CI 1.16-5.07). No significant associations were found in men. CONCLUSIONS: Our study suggests a gender-specific association of anxiety and mortality.

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.

Oestrogen receptor polymorphisms and late-life depression.

BACKGROUND: Evidence suggests a role for oestrogen in depression but the involvement of oestrogen receptor polymorphisms remains unknown. AIMS: To determine the association between oestrogen receptor polymorphisms and late-life depression and the modifying effect of hormone treatment. METHOD: Depression was assessed using the Mini-International Neuropsychiatric Interview, according to DSM-IV criteria and the Centre for Epidemiologic Studies - Depression Scale. The association between oestrogen receptor α and ß (ER-α and ER-ß) polymorphisms with severe depression was examined in 6017 community-dwelling elderly people using multivariate logistic regression. RESULTS: In women, the ER-α rs2234693 and rs9340799 polymorphisms were significantly associated with the risk of late-life depression. The A allele of ER-ß rs1256049 increased the risk of depression, but only for non-current users of hormone treatment. In men, only the ER-ß rs4986938 polymorphism showed a weak association with depression risk. CONCLUSIONS: Oestrogen receptor polymorphisms are associated with severe late-life depression risk in women only.

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).

The extent to which childhood adversity and recent stress influence all-cause mortality risk in older adults.

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.

Life-time estrogen exposure and cognitive functioning in later life.

CONTEXT: While recent studies suggest that exogenous estrogen treatment could help reduce age-related cognitive decline and delay the onset of dementia, this has not been found consistently. Few studies have considered the influence of life-time estrogen exposure which may have an independent effect on cognition and/or modulate treatment response. OBJECTIVE: The aim of this study was to examine whether factors related to estrogen exposure across the life-time were associated with cognitive function in postmenopausal women. DESIGN: A battery of cognitive tests were administered at baseline and at 2 and 4 years of follow-up to evaluate cognitive performance among a population-based cohort of 996 French women aged 65 years or older, who were recruited as part of the ESPRIT study. Detailed reproductive histories were also obtained. Logistic regression models, controlling for an extensive range of potential confounding factors, were generated to determine whether hormone-related factors across a woman's lifetime were associated with poor cognitive performance in later life. RESULTS: Age at first menses was negatively associated with performance on the tasks of visual memory and psychomotor speed, while a longer reproductive period was associated with better verbal fluency. Likewise, women who had their first child at a young age performed significantly worse on each of these tasks, as well as on a measure of global cognitive function. The results also suggest that current hormone therapy may be beneficial for a number of cognitive domains, however, in multivariate analysis, women performed significantly better on the task of visual memory only. In contrast, in analysis adjusted for baseline cognitive performance and a range of other factors, none of the reproductive variables were associated with a decline in cognitive performance or the incidence of dementia during the 4-year follow-up period. CONCLUSIONS: In addition to hormone therapy, certain hormone-related events across the lifetime are also associated with cognitive functioning in later life. They were not observed in this study to modulate dementia risk; however, this should be verified over a longer follow-up period. Further studies will also be required to determine whether lifetime hormonal exposure may modify women's response to hormone therapy after the menopause.

Hormonal therapy and depression: are we overlooking an important therapeutic alternative?

OBJECTIVE: This review aimed to examine evidence for the role of hormonal changes in the onset and course of depressive symptomatology and to assess the possible future role of hormonal therapies in the treatment of depression. METHODS: A Medline and PsycINFO search of the literature published between 1965 and 2006 was made of studies of depressive symptoms and hormonal treatment in women at all stages of reproductive life. RESULTS: The cyclic fluctuation of gonadal steroids at menarche coincides with the beginning of gender-based differences in depression rates, which continue throughout reproductive life until menopause. Modifications in hormonal status, whether related to endogenous or exogenous exposure or to hormone deprivation, appear to be associated with affective disorder in a subgroup of women. For these women, a growing body of evidence indicates a biological pattern of vulnerability to mood disorders in response to hormonal fluctuations. This could have three major implications: that women vary in vulnerability to mood disorder when abrupt change in steroid levels occur, that these effects could be cumulative across the female life span, and that women do not arrive at menopause with equal risk of mood disorders or equal susceptibility to the effects of hormonal replacement therapy as has been assumed by current clinical research and practice. CONCLUSION: While hormonal therapies could have positive effects in the treatment and prevention of depressive disorders, further research is required to differentiate hormone-responsive subgroups of women for whom specific hormonal treatments may be most beneficial. To this end, we suggest that a multifactorial model of cumulative vulnerability, which takes into account hormonal exposure throughout life, genetic vulnerability, and environmental factors, may provide better prediction of treatment response.

The effect of an adverse psychological environment on salivary cortisol levels in the elderly differs by 5-HTTLPR genotype.

BACKGROUND: An adverse psychological environment (e.g. stressful events or depression) has been shown to influence basal cortisol levels and cortisol response to stress. This differs depending on the adverse stimuli, but also varies across individuals and may be influenced by genetic predisposition. An insertion/deletion polymorphism in the serotonin transporter gene (5-HTTLPR) is a strong candidate in this regard. OBJECTIVE: To investigate how stressful life events and depression are associated with diurnal cortisol levels in community-dwelling elderly and determine whether this varies according to genetic variability in the 5-HTTLPR. METHODS: This population-based study included 334 subjects aged 65 and older (mean (SD) = 76.5 (6.3)). Diurnal cortisol was measured on two separate days, under quiet (basal) and stressful conditions. The number of recent major stressful events experienced during the past year was assessed from a 12-item validated questionnaire as an index of cumulative recent stressful events. Lifetime trauma was evaluated using the validated Watson's PTSD inventory, which evaluates the most severe traumatic or frightening experience according to DSM criteria. Depression was defined as having a Mini-International Neuropsychiatric Interview (MINI) diagnosis of current major depressive disorder or high levels of depressive symptoms (Center for Epidemiologic Studies-Depression Scale ≥16). 5-HTTLPR genotyping was performed on blood samples. RESULTS: Exposure to stressful life events was associated with lower basal evening cortisol levels overall, and in the participants with the 5-HTTLPR L allele but not the SS genotype. The greatest effects (over 50% decrease, p < 0.001) were observed for the LL participants having experienced multiple recent stressful events or severe lifetime traumas. Participants with the L allele also had higher evening cortisol stress response. Conversely, depression tended to be associated with a 42% higher basal morning cortisol in the SS participants specifically, but did not modify the association between stressful events and cortisol levels. CONCLUSION: An adverse psychological environment is associated with basal cortisol levels and cortisol stress response, but this differs according to 5-HTTLPR genotype.

Heterogeneity in HPA axis dysregulation and serotonergic vulnerability to depression.

Variability in the serotonin transporter (5-HTTLPR) gene can influence the risk of depression associated with adversity, as well as cortisol stress reactivity, although not consistently. No study has examined the impact of both a stressful environment and corticotropic-axis dysfunction on depression, as a function of 5-HTTLPR. This population-based study included 334 subjects aged 65 and older. Depression was measured at both diagnostic (major depression according to DSM-IV) and symptomatic (subthreshold depression) levels of caseness, in addition to 5-HTTLPR and rs25531 genotyping and diurnal cortisol measures. For participants with the SS genotype, higher morning cortisol levels were associated with a 4-fold increased risk of depression. Among LL participants, both evening cortisol levels and recent stressful events increased depression risk, although only the latter remained significant after multivariable adjustment. Conversely, SL individuals appeared somewhat resilient to depression in terms of cortisol and recent stress. These findings indicate that 5-HTTLPR genetic variability appears to influence the association between stress-related factors and late-life depression, although the gene-environment interactions failed to reach statistical significance levels. Participants homozygous for the short allele appeared to have a cortisol-related neuroendocrine vulnerability to depression, while long allele homozygotes were more reactive to stressful events in terms of depression risk.

Brain volumes in late life: gender, hormone treatment, and estrogen receptor variants.

Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.

Measuring resilience in adult women using the 10-items Connor-Davidson Resilience Scale (CD-RISC). Role of trauma exposure and anxiety disorders.

PURPOSE: Resilience is the ability of individuals to adapt positively in the face of trauma. Little is known, however, about lifetime factors affecting resilience. METHODS: We assessed the effects of psychiatric disorder and lifetime trauma history on the resilience self-evaluation using the Connor-Davidson Resilience Scale (CD-RISC-10) in a high-risk-women sample. Two hundred and thirty eight community-dwelling women, including 122 participants in a study of breast cancer survivors and 116 participants without previous history of cancer completed the CD-RISC-10. Lifetime psychiatric symptoms were assessed retrospectively using two standardized psychiatric examinations (Mini International Neuropsychiatric Interview and Watson's Post-Traumatic Stress Disorder Inventory). RESULTS: Multivariate logistic regression adjusted for age, education, trauma history, cancer, current psychiatric diagnoses, and psychoactive treatment indicated a negative association between current psychiatric disorder and high resilience compared to low resilience level (OR = 0.44, 95% CI [0.21-0.93]). This was related to anxiety and not mood disorder. A positive and independent association with a trauma history was also observed (OR = 3.18, 95% CI [1.44-7.01]). CONCLUSION: Self-evaluation of resilience is influenced by both current anxiety disorder and trauma history. The independent positive association between resilience and trauma exposure may indicate a "vaccination" effect. This finding need to be taken into account in future studies evaluating resilience in general or clinical populations.

Estrogen receptor alpha gene variants and major depressive episodes.

BACKGROUND: Despite evidence of estrogen's mood-enhancing effects, the association between estrogen receptor (ER) gene variants and lifetime major depression has been insufficiently studied. METHODS: 3987 community-dwelling women aged 65years and over were recruited in France as part of the Three City Study. Current and past major depressive disorders (MDD) were diagnosed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. The association between two common estrogen receptor alpha (ESR1) polymorphisms with lifetime MDD was examined using adjusted logistic regression models, taking into account the age at first depressive episode and the recurrence of depression. RESULTS: Women homozygous for the variant G allele of ESR1 rs9340799 had a 1.6-fold increased risk of MDD across their lifetime compared with women who were homozygous for the A allele (p=0.009). There was a similar non-significant trend for the C allele of rs2234693 being associated with an increased risk (p=0.09). Polytomous regression analysis further indicated that the GG genotype of rs9340799 was specifically associated with an increased risk of recurrent depressive episodes, regardless of the age at first onset of depression relative to the menopause. LIMITATIONS: The duration and severity of depressive episodes was not considered in the analysis. CONCLUSIONS: This is the first study to examine the association between ESR1 gene variants and lifetime MDD. Our findings indicate a significant association between common variants and the risk of recurrent depressive episodes. This suggests that certain depressed women could be most responsive to hormone-based treatment.

Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study.

BACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.

Estrogen receptor gene variants are associated with anxiety disorders in older women.

BACKGROUND: Estrogen is thought to play a key role in anxiety, but it remains unknown whether genetic variants in the estrogen receptors (ERs) can influence the risk of anxiety. This study investigated whether ESR1 and ESR2 gene variants were associated with specific anxiety disorders in postmenopausal women and evaluated the potential modifying effect of hormone treatment (HT) on these associations. METHODS: One thousand and ninety-two community-dwelling women aged 65 years and older were recruited as part of the ESPRIT Study in Montpellier, France. Anxiety was assessed using the Mini-International Neuropsychiatry Interview (MINI), according to DSM-IV criteria. Two ESR1 and three ESR2 polymorphisms were genotyped. RESULTS: The most common anxiety disorders were phobia (14.2%) and generalised anxiety disorder (GAD, 8%). The A allele of ESR2 rs1256049 was associated with an increased risk of GAD [OR: 2.06, 95% CI: 1.09-3.87], while both ESR1 polymorphisms were specifically associated with phobia. The C allele of ESR1 rs2234693 decreased the risk of phobia by 42% [95% CI: 0.41-0.83], and this remained significant even after Bonferroni correction. The G allele of ESR1 rs9340799 was associated with a 31% decreased phobia risk [95% CI: 0.49-0.96]. There was also evidence of a significant gene-environment interaction, where only women who were currently using HT had a reduced risk of phobia with these ESR1 gene variants. CONCLUSIONS: This study confirms earlier findings of an association between ESR1 and global anxiety in older women, however these associations varied depending on the anxiety syndrome and the use of HT. The results also suggest that the ESR2 may contribute to the genetic vulnerability to GAD, but these findings require further confirmation.

A prospective study of hormone therapy and depression in community-dwelling elderly women: the Three City Study.

BACKGROUND: The potential benefits of hormone therapy (HT) in treating depressed postmenopausal women are controversial, and data on depression (re)emergence in the context of HT discontinuation are lacking. OBJECTIVE: To determine whether HT is associated with a modified risk of new-onset depressive symptoms in elderly women. METHOD: Current depressive symptomatology was evaluated in 4,069 community-dwelling postmenopausal women aged 65 years and over who were randomly recruited from 3 French cities between 1999 and 2001. Depressive symptomatology was assessed using the Center for Epidemiologic Studies-Depression Scale at baseline and as part of the 2- and 4-year follow-up. RESULTS: Over the follow-up period, multivariate logistic regression analyses adjusted for sociodemographic variables, measures of physical health, and cognitive impairment failed to find a significant association between HT at baseline and the incidence of depressive symptoms. However further analysis indicated an increased risk of incident depressive symptoms for women using transdermal estradiol treatment combined with synthetic progestin specifically (odds ratio [OR] = 1.59; 95% CI, 1.01-2.50; P = .046). In addition, while women taking HT continuously over the 4-year follow-up did not show an increased risk of depressive symptoms, women who stopped their treatment early after study inclusion, had a significantly higher risk (OR = 2.63; 95% CI, 1.52-4.55; P = .0005). CONCLUSIONS: Hormone therapy was not associated with a protective effect against the emergence of depressive symptoms in elderly postmenopausal women. However, discontinuing treatment could increase the risk of depressive symptoms. Data on the appropriate management of depression in the context of HT discontinuation among postmenopausal women require further investigation.

Long-term post-operative cognitive decline in the elderly: the effects of anesthesia type, apolipoprotein E genotype, and clinical antecedents.

Cognitive dysfunction in the elderly commonly observed following anesthesia has been attributed to age-related neuronal changes exacerbated by pharmacotoxic effects. However, the extent to which these changes may persist following recovery from surgery is still largely unknown. This study investigates the long-term effects of anesthesia on cognitive functioning after orthopedic surgery in 270 elderly patients over the age of 65 who completed a computerized cognitive battery before and 8 days, 4 and 13 months after surgery. Their performance was compared to those of 310 elderly controls who completed the same neuropsychiatric evaluation at baseline and one-year interval. Multivariate analyses adjusted for socio-demographic variables, depressive symptomatology, vascular pathology as well as baseline cognitive performance. We found early and transient post-operative decline in reaction time and constructional praxis. With regard to long-term changes we observed improvement compared to controls in most verbal tasks (probably due to learning effects). On the other hand, a clear dissociation effect was observed for several areas of visuospatial functioning which persisted up to the 13-month follow-up. This specific pattern of visuospatial deficit was found to be independent of apolipoprotein E genotype and closely resembles what has recently been termed vascular mild cognitive impairment, in turn associated with subtle sub-cortical vascular changes. The observation of only minor differences between persons operated by general and regional anesthesia makes it difficult to attribute these changes directly to the anesthetic agents themselves, suggesting that cognitive dysfunction may be attributable at least in part to peri-operative conditions, notably stress and glucocorticoid exposure.