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1.
Depress Anxiety ; 37(2): 146-155, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31730745

RESUMO

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.

2.
J Alzheimers Dis ; 73(2): 645-655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31839607

RESUMO

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.

3.
Psychoneuroendocrinology ; 111: 104492, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31704635

RESUMO

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.

4.
Transl Psychiatry ; 9(1): 291, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712553

RESUMO

Late-life depression, as a potential marker of pre-dementia, has seldom been explored by symptom dimension and sex, despite sexual dimorphic differences. This study aimed to examine whether specific depressive dimensions were associated with pre-Alzheimer's disease dementia (pre-AD), separately for women and men. Data were drawn from 5617 (58% women) community-dwellers aged 65+ recruited in 1999-2000 and followed at 2-year intervals for 12 years. We used Cox proportional hazard models to study associations between time-dependent Centre for Epidemiologic Studies-Depression Scale (CES-D) symptom dimensions (namely somatic, depressed, positive affect, and interpersonal challenge) and pre-AD, defined retrospectively from validated diagnoses established 3.5 (IQR: 3.2-4.0) years onwards. Analyses were performed according to overall depressive symptomatology (DS+: CES-D score ≥ 16) and antidepressant/anxiolytic medication use (AA). Results indicated that in DS+ women only, all four dimensions were significantly associated with pre-AD in the AA- group, in particular somatic item 'Mind' and depressed affect items 'Depressed' and 'Blues'. The most depression-specific dimension, depressed affect, was also significantly associated with pre-AD in the DS- AA- women (HR:1.28, 95%CI: 1.12;1.47). In both sexes, in the DS- groups somatic affect was the most robust pre-AD marker, irrespective of treatment (women: HR = 1.22, 95%CI: 1.08;1.38; men: HR = 1.30, 95%CI: 1.14;1.48). Our findings highlight sex-specific associations between depressive symptom dimensions and pre-AD, modulated by depressive symptomatology and treatment. Assessment of specific symptom dimensions taking into account overall symptomatology and treatment could help identify and target high-risk AD-dementia profiles for interventions.

5.
PLoS Med ; 16(7): e1002853, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31335910

RESUMO

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.


Assuntos
Cognição , Disfunção Cognitiva/etnologia , Grupos Étnicos/psicologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Comorbidade , Diabetes Mellitus/etnologia , Exercício Físico , Feminino , Educação em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/etnologia , Acidente Vascular Cerebral/etnologia
7.
Aging Dis ; 10(2): 463-469, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31011488

RESUMO

Chronic systemic low-grade inflammation is associated with aging, but little is known on whether age-related inflammation affects brain structure, particularly white matter. The current study tested the hypothesis that in older adults without dementia, higher serum levels of high-sensitivity C-reactive protein (hs-CRP) are associated with reduced corpus callosum (CC) areas. French community-dwelling subjects (ESPRIT study) aged 65 and older (N=101) underwent hs-CRP testing and structural magnetic resonance imaging (MRI). Multiple linear regression models were carried out. In the unadjusted model, higher hs-CRP level was significantly associated with smaller anterior, mid, and total midsagittal CC areas, but not with the posterior CC area. These associations were independent of demographic characteristics and intracranial volume. After adjustment for body mass index, diabetes, inflammation-related chronic pathologies and white matter lesions (WML), only the associations between hs-CRP level and smaller anterior and total midsagittal CC areas were still significant, although weaker. These findings suggest that low-grade inflammation is associated with CC structural integrity alterations in older adults independently of physical or neuropsychiatric pathologies.

8.
Stress ; 22(1): 162-168, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30298755

RESUMO

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 (ß = -1.846 ± 0.666, p = .007) and diurnal cortisol (area under curve [AUC]) (ß = -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.


Assuntos
Metilação de DNA , Hidrocortisona/metabolismo , Fator de Células-Tronco/genética , Estresse Psicológico/genética , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Prospectivos , Saliva/química , Saliva/metabolismo , Estresse Psicológico/metabolismo , Inquéritos e Questionários
9.
J Psychiatry Neurosci ; 44(1): 45-53, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565905

RESUMO

Background: There is evidence of structural brain alterations in major depressive disorder (MDD), but little is known about how these alterations might be affected by age at onset or genetic vulnerability. This study examines whether lifetime episodes of MDD are associated with specific alterations in grey-matter volume, and whether those alterations vary according to sex or serotonin transporter-linked promoter region (5-HTTLPR) genotype (LL, SL or SS). Methods: We used structural MRI to acquire anatomic scans from 610 community-dwelling participants. We derived quantitative regional estimates of grey-matter volume in 16 subregions using FreeSurfer software. We diagnosed MDD according to DSM-IV criteria. We adjusted analyses for age, sex, total brain volume, education level, head injury and comorbidities. Results: Lifetime MDD was associated with a smaller insula, thalamus, ventral diencephalon, pallidum and nucleus accumbens and with a larger pericalcarine region in both men and women. These associations remained after adjustment for false discovery rate. Lifetime MDD was also associated with a smaller caudate nucleus and amygdala in men and with a larger rostral anterior cingulate cortex in women. Late-onset first episodes of MDD (after age 50 years) were associated with a larger rostral anterior cingulate cortex and lingual and pericalcarine regions; early-onset MDD was associated with a smaller ventral diencephalon and nucleus accumbens. Some associations differed according to 5-HTTLPR genotype: the thalamus was smaller in participants with MDD and the LL genotype; pericalcarine and lingual volumes were higher in those with the SL genotype. Limitations: This study was limited by its cross-sectional design. Conclusion: Major depressive disorder was associated with persistent volume reductions in the deep nuclei and insula and with enlargements in visual cortex subregions; alterations varied according to age of onset and genotype.

10.
PLoS Med ; 15(11): e1002704, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30481189

RESUMO

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.


Assuntos
Menopausa Precoce , Doenças Ovarianas/epidemiologia , Abandono do Hábito de Fumar , Fumar/efeitos adversos , Adulto , Idade de Início , Idoso , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Doenças Ovarianas/diagnóstico , Doenças Ovarianas/fisiopatologia , Medição de Risco , Fatores de Risco , Fumar/epidemiologia , Fatores de Tempo , Estados Unidos/epidemiologia
11.
J Psychiatry Neurosci ; 43(6)2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30226714

RESUMO

Background: There is evidence of structural brain alterations in major depressive disorder (MDD), but little is known about how these alterations might be affected by age at onset or genetic vulnerability. This study examines whether lifetime episodes of MDD are associated with specific alterations in grey-matter volume, and whether those alterations vary according to sex or serotonin transporter-linked promoter region (5-HTTLPR) genotype (LL, SL or SS). Methods: We used structural MRI to acquire anatomic scans from 610 community-dwelling participants. We derived quantitative regional estimates of grey-matter volume in 16 subregions using FreeSurfer software. We diagnosed MDD according to DSM-IV criteria. We adjusted analyses for age, sex, total brain volume, education level, head injury and comorbidities. Results: Lifetime MDD was associated with a smaller insula, thalamus, ventral diencephalon, pallidum and nucleus accumbens and with a larger pericalcarine region in both men and women. These associations remained after adjustment for false discovery rate. Lifetime MDD was also associated with a smaller caudate nucleus and amygdala in men and with a larger rostral anterior cingulate cortex in women. Late-onset first episodes of MDD (after age 50 years) were associated with a larger rostral anterior cingulate cortex and lingual and pericalcarine regions; early-onset MDD was associated with a smaller ventral diencephalon and nucleus accumbens. Some associations differed according to 5-HTTLPR genotype: the thalamus was smaller in participants with MDD and the LL genotype; pericalcarine and lingual volumes were higher in those with the SL genotype. Conclusion: Major depressive disorder was associated with persistent volume reductions in the deep nuclei and insula and with enlargements in visual cortex subregions; alterations varied according to age of onset and genotype.

12.
BMC Psychiatry ; 18(1): 282, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180828

RESUMO

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 (ß = - 0.44 to ß = - 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.


Assuntos
Metilação de DNA/genética , Transtorno Depressivo Maior/genética , Estudos de Associação Genética/métodos , Genótipo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Distribuição Aleatória , Autorrelato
13.
Clin Endocrinol (Oxf) ; 89(4): 514-525, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29935032

RESUMO

CONTEXT: Although endogenous oestradiol, 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 oestrogen 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 oestradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free oestradiol (fE2) was estimated using Vermeulen and Södergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of oestradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: A total of 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 oestradiol 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.


Assuntos
Estradiol/sangue , Receptores Estrogênicos/genética , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/mortalidade , Polimorfismo Genético/genética , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto Jovem
14.
J Endocr Soc ; 2(4): 322-335, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29577108

RESUMO

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.

15.
Psychoneuroendocrinology ; 88: 1-8, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29132028

RESUMO

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.


Assuntos
Depressão/genética , Peptidil Dipeptidase A/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Metilação de DNA/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário , Estudos Longitudinais , Masculino , Peptidil Dipeptidase A/metabolismo , Sistema Hipófise-Suprarrenal , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Saliva/química
16.
BMC Psychiatry ; 17(1): 354, 2017 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-29070016

RESUMO

BACKGROUND: It 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. METHODS: The 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. RESULTS: Individuals 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. CONCLUSION: This 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.


Assuntos
Metilação de DNA/genética , Transtorno Depressivo Maior/genética , Variação Genética/genética , Interleucina-6/genética , Adulto , Idoso , Transtorno Depressivo Maior/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Seguimentos , França , Genótipo , Humanos , Masculino
17.
BMC Med ; 15(1): 81, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28424070

RESUMO

BACKGROUND: Cognitive impairment is very common in late-life depression, principally affecting executive skills and information processing speed. The aim of the study was to examine the effect of antidepressant treatment on cognitive performances over a 10-year period. METHODS: The community-based cohort included 7381 participants aged 65 years and above. Five cognitive domains (verbal fluency, psychomotor speed, executive function, visuospatial skills and global cognition) were assessed up to five times over 10 years of follow-up. Treatment groups included participants under a specific antidepressant class at both baseline and the first follow-up and their follow-up cognitive data were considered until the last consecutive follow-up with a report of antidepressant use of the same class. Linear mixed models were used to compare baseline cognitive performance and cognitive decline over time according to antidepressant treatment. The models were adjusted for multiple confounders including residual depressive symptoms assessed by the Center for Epidemiologic Studies-Depression scale. RESULTS: At baseline, 4.0% of participants were taking antidepressants. Compared to non-users, tricyclic antidepressant users had lower baseline performances in verbal fluency, visual memory and psychomotor speed, and selective serotonin reuptake inhibitor users in verbal fluency and psychomotor speed. For the two other cognitive abilities, executive function and global cognition, no significant differences were found at baseline irrespective of the antidepressant class. Regarding changes over time, no significant differences were observed in comparison with non-users whatever the cognitive domain, except for a slight additional improvement over the follow-up in verbal fluency skills for tricyclic antidepressant users. CONCLUSIONS: In this large elderly general population cohort, we found no evidence for an association between antidepressant use and post-treatment cognitive decline over 10 years of follow-up in various cognitive domains.


Assuntos
Antidepressivos/efeitos adversos , Disfunção Cognitiva/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino
18.
Neurobiol Stress ; 7: 38-46, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28377990

RESUMO

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.

19.
PLoS Med ; 14(3): e1002265, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28350817

RESUMO

BACKGROUND: Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease [AD] and mixed or vascular dementia) in older community-dwelling persons. METHODS AND FINDINGS: Non-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation [SD] 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC]) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio [HR] per SD increase = 1.13 [95% CI 1.04-1.22], p = 0.0045, and HR = 1.12 [1.03-1.22], p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 [1.03-1.23], p = 0.0110, and HR = 1.12 [1.02-1.23], p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 [1.03-1.19], p = 0.0044) and mixed or vascular dementia (HR = 1.21 [1.04-1.41], p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 [0.98-1.17], p = 0.1374, and HR = 1.17 [0.96-1.42], p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses. CONCLUSIONS: In a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.


Assuntos
Colesterol/sangue , Demência/epidemiologia , Triglicerídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Demência/sangue , Demência Vascular/sangue , Demência Vascular/epidemiologia , Feminino , França/epidemiologia , Humanos , Incidência , Estudos Longitudinais , Masculino , Estudos Prospectivos , Fatores de Risco
20.
PLoS Med ; 14(3): e1002261, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28323832

RESUMO

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.


Assuntos
Apolipoproteínas E/genética , Disfunção Cognitiva/epidemiologia , Escolaridade , Genótipo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais
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