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1.  Sex differences in the associations between lipid levels and incident dementia 
Journal of Alzheimer's Disease  2013;34(2):519-528.
Cholesterol is a risk factor for developing vascular pathologies, which is in turn an important risk factor for dementia. Previous studies linking lipids and dementia have yielded inconsistent results, which may be attributable to sex differences in the etiology of both vascular disease and dementia. The aim of this study was to evaluate the associations between lipids and incident dementia in 7053 community-dwelling elderly. Dementia was diagnosed at baseline, and 2, 4, and 7-year follow-up. Multivariate Cox models stratified by sex and history of vascular pathologies at baseline were adjusted for sociodemographic, mental and physical health variables and genetic vulnerability. In men without vascular pathologies, an increased incidence of all-cause dementia but not Alzheimer’s disease (AD) was associated with high triglyceride (TG) (HR=1.55, 95%CI=1.04–2.32, p=0.03) and low HDL-cholesterol levels (HR=1.49, 95%CI=0.99–2.23, p=0.05). In women without vascular pathologies, low TG levels were associated with a decreased risk of AD (HR=0.65, 95%CI=0.43–0.97, p=0.03). A decreased risk was also found with high TG levels which may depend on genetic vulnerability to dyslipidemia related to APOA5. For both sexes, no significant associations were found between total- or LDL-cholesterol and dementia or AD. Low HDL-cholesterol and high TG levels may be risk factors of dementia in elderly men whereas low TG is associated with decreased incident AD in women. This data suggests a complex sex-specific etiology of vascular dementia and AD.
PMCID: PMC3966213  PMID: 23254630
Lipids; Dementia; Alzheimer's disease; Elderly; Apolipoprotein; Atherosclerosis; Prospective cohort
2.  Lipid lowering agents, cognitive decline, and dementia: the three-city study 
Journal of Alzheimer's Disease  2012;30(3):629-637.
The aim of this prospective cohort study was to evaluate the effects of lipid lowering agent (LLA) intake on cognitive function in 6830 community-dwelling elderly persons. Cognitive performance (global cognitive functioning, visual memory, verbal fluency, psychomotor speed and executive function), clinical diagnosis of dementia, and fibrate and statin use, were evaluated at baseline, and 2, 4, and 7 year follow-up. Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics, mental and physical health including vascular risk factors, and genetic vulnerability (apolipoprotein E and cholesteryl ester transfer protein). For women but not men, fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only (HR=1.29, 95%CI=1.09–1.54, p=0.004), and did not increase risk for incident dementia. This association was independent of genetic vulnerability related to ApoE and Cholesteryl Exchange Transfer Protein polymorphisms and occurred only in women with higher LDL-cholesterol levels and treated with fibrate (HR=1.39, 95%CI=1.08–1.79, p=0.01) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment. For both sexes, no significant associations were found between statins (irrespective of their lipophilicity) and either cognitive decline or dementia incidence. This prospective study, adjusting for multiple confounders, found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia, but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory.
PMCID: PMC3743740  PMID: 22451317
Fibrate; Statin; Cognitive aging; Alzheimer's disease; Elderly; Apolipoprotein E; Cholesteryl Exchange Transfer Protein; Prospective cohort.
3.  Insomnia, Daytime Sleepiness and Cardio-Cerebrovascular Diseases in the Elderly: A 6-Year Prospective Study 
PLoS ONE  2013;8(2):e56048.
To examine 1) the associations between history of cardio-cerebrovascular diseases (CVD) and insomnia complaints and excessive daytime sleepiness (EDS), and 2) the relationships between sleep complaints and future CVD in persons over 65.
CVD was assessed at baseline and during two, four, and six-year follow-up in 5494 non-demented subjects. Self-reported insomnia complaints (poor sleep quality, difficulty in initiating sleep, difficulty in maintening sleep, and early morning awakening), EDS and sleep medication use were evaluated at baseline. Logistic regression models and Cox proportional hazard models, with delayed entry and age of participants as the time scale, were adjusted for socio-demographic, lifestyle and clinical variables.
At baseline, 748 participants had a past-history of CVD. A past-history of CVD was associated with EDS (OR = 1.28 95%CI = [1.05–1.57]) and the number of insomnia complaints (OR = 1.26 95%CI = [1.03–1.55] for 1–2 insomnia complaints; OR = 1.32 95%CI = [1.03–1.71] for ≥3 complaints). In longitudinal analyses, neither the four components of insomnia nor the number of insomnia complaints were significantly associated with first or recurrent CVD events (n = 391 events). EDS was independently associated with future CVD events even after adjusting for prescribed sleep medication and past-history of CVD (HR = 1.35 95%CI = [1.06–1.71]).
Our results suggest that the relationships between sleep complaints and CVD could be complex. Insomnia complaints are more likely a consequence of CVD, whereas EDS appears to be a determinant of CVD independently of past-history of CVD. EDS screening may thus constitute a means of detecting persons at high risk of CVD.
PMCID: PMC3573087  PMID: 23457496
4.  A prospective study of hormone therapy and depression in community-dwelling elderly women: the Three City Study 
The Journal of Clinical Psychiatry  2010;71(12):1673-1679.
The potential benefits of hormone therapy in treating depressed postmenopausal women are controversial and data on depression (re)emergence in the context of HT discontinuation are lacking.
To determine whether hormone therapy is associated with a modified risk of new onset of depressive symptoms in elderly women.
Current depressive symptomatology was evaluated in 4069 community-dwelling postmenopausal women aged 65 years and over, randomly recruited from three French cities. Depressive symptomatology was assessed using the Centre for Epidemiologic Studies Depression Scale at baseline and as part of the 2- and 4-year follow-up.
Over the follow-up period, multivariate logistic regression analyses adjusted for socio-demographic 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 specifically transdermal estradiol treatment combined with synthetic progestin (OR=1.59, 95%CI 1.01–2.50, p=0.046). In addition, while women taking hormone therapy continuously over the 4-year follow-up did not show an increased risk of depressive symptoms, women who stopped their treatment early after inclusion, had a significantly higher risk (OR= 2.63 95%CI 1.52–4.55, p=0.0005).
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 hormone therapy discontinuation among postmenopausal women requires further investigation.
PMCID: PMC3078521  PMID: 20816026
Administration, Cutaneous; Aged; Aged, 80 and over; Depression; chemically induced; diagnosis; epidemiology; etiology; Drug Therapy, Combination; Estradiol; administration & dosage; adverse effects; Estrogen Replacement Therapy; adverse effects; methods; Estrogens; administration & dosage; adverse effects; Female; Follow-Up Studies; France; epidemiology; Humans; Incidence; Logistic Models; Medication Adherence; psychology; statistics & numerical data; Multivariate Analysis; Odds Ratio; Postmenopause; Progesterone Congeners; administration & dosage; adverse effects; Prospective Studies; Risk Factors; Depression, estradiol, postmenopausal, progestogen, transdermal
5.  A prospective study of diurnal cortisol and cognitive function in community-dwelling elderly people 
Psychological Medicine  2009;40(6):1039-1049.
Elevated cortisol levels due to hypothalamic-pituitary-adrenal axis stress response have been associated with cognitive impairment. The causal relationship between stress and subsequent cognitive impairment remains, however, unclear notably due to small number of gender stratified prospective studies.
Salivary cortisol secretion was evaluated in 197 non-depressed community-dwelling elderly at three time points on the day of hospital attendance for a clinical examination and again on the following day at home, in distinct environment context. Cognitive performance was evaluated at baseline and 2- and 4-year follow-up.
Cross-sectional logistic analyses adjusted for age and education indicated that men with high morning cortisol at the hospital had higher risk of low cognitive performance in verbal fluency (OR=3.0, p=0.05) and visuo-spatial performance (OR=5.1, p=0.03). Impairment in verbal fluency was observed in women with moderate high morning cortisol (OR=3.6, p=0.05) or moderate slow diurnal rhythm (OR=3.7, p=0.04). In longitudinal analyses, slow diurnal rhythm (flatter slope) was associated with decline over 4 years in visuo-spatial performance (OR=7.7, p=0.03) and visual memory (OR=4.1, p=0.03) in men, and in verbal fluency (OR=6.0, p=0.01) in women. High morning cortisol was associated with decline in visual memory in women (OR=5.1, p=0.06).
Hypothalamic-pituitary-adrenal axis dysregulation appears associated with low cognitive performance in the elderly. Slower cortisol elimination rates could predict cognitive decline affecting principally non-verbal functioning in men and verbal functioning in women. The effects appeared independent of environmental context, apolipoprotein E genotype or psychopathology. Interventions blocking this pathway may provide new therapeutic options to prevent cognitive decline.
PMCID: PMC2894868  PMID: 19814852
Cognition; cortisol; elderly; HPA axis; stress
6.  Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study 
Archives of Internal Medicine  2009;169(14):1317-1324.
To examine the association between use of medications with anticholinergic properties, cognitive decline and incident dementia in a large community-based sample of subjects aged 65 years and over.
Participants were 4128 women and 2784 men from a population-based cohort recruited from three French cities. Cognitive performance, clinical diagnosis of dementia and anticholinergic use were evaluated at base-line, 2 and 4 year later.
7.5% of subjects reported anticholinergic drug use at base-line. Multivariate adjusted logistic regression indicated that women reporting anticholinergic drugs at base-line showed greater decline over four years in verbal fluency scores (OR=1.41, CI=1.11–1.79) and in global cognitive functioning (OR=1.22, CI=0.96–1.55) than women not using anticholinergic drugs. In men, an association was found with decline in visual memory (OR=1.63, CI=1.08–2.47) and to a lesser extent in executive function (OR=1.47, CI=0.89–2.44). Significant interactions were observed in women between anticholinergic use and age, apolipoprotein E, or hormone replacement therapy. A significantly 1.4–2 fold higher risk of cognitive decline was observed for continuous anticholinergic users but not for those having discontinued. The risk of incident dementia over the four-year followup was also increased in continuous users (HR=1.65, CI=1.00–2.73) but not in those having discontinued anticholinergic drugs (HR=1.28, CI=0.59–2.76).
Elderly people taking anticholinergic drugs were at increased risk for cognitive decline and dementia. Discontinuing anticholinergic treatment was associated with a decreased risk. Physicians should carefully consider prescription of anticholinergic drugs in elderly people especially in the oldest old and persons at high genetic risk of cognitive disorder.
PMCID: PMC2933398  PMID: 19636034
Aged; Aged, 80 and over; Cholinergic Antagonists; adverse effects; Cognition; drug effects; Dementia; chemically induced; genetics; Female; Genetic Predisposition to Disease; Humans; Longitudinal Studies; Male; Sex Factors; Anticholinergics; apolipoprotein E; cognitive decline; dementia; elderly; gender.
7.  Hormonal treatment, mild cognitive impairment and Alzheimer's disease 
A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer’s disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women’s Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using hormonal replacement therapy compared to controls. Apart from methodological differences, one key short-coming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.
PMCID: PMC2662345  PMID: 18072983
Administration, Cutaneous; Aged; Alzheimer Disease; diagnosis; drug therapy; prevention & control; Cognition Disorders; diagnosis; drug therapy; prevention & control; Estradiol; administration & dosage; therapeutic use; Estrogen Replacement Therapy; methods; Estrogens; administration & dosage; therapeutic use; Estrogens, Conjugated (USP); therapeutic use; Female; Humans; Memory Disorders; diagnosis; drug therapy; prevention & control; Middle Aged; Neuroprotective Agents; administration & dosage; therapeutic use; Progestins; therapeutic use; Randomized Controlled Trials as Topic; statistics & numerical data; Receptors, Estrogen; genetics; Research Design; standards; trends; Severity of Illness Index; Treatment Outcome; Cognition; equine estrogens; transdermal estradiol; estrogen receptor; lifetime hormonal status; observation study; randomized controlled trial
8.  COSMIC (Cohort Studies of Memory in an International Consortium): An international consortium to identify risk and protective factors and biomarkers of cognitive ageing and dementia in diverse ethnic and sociocultural groups 
BMC Neurology  2013;13:165.
A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders.
Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress.
The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.
PMCID: PMC3827845  PMID: 24195705
Cohort studies; Cognitive ageing; Data harmonisation; Dementia; International consortium; Mild cognitive impairment
9.  Hypnotics and mortality in an elderly general population: a 12-year prospective study 
BMC Medicine  2013;11:212.
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.
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.
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.
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.
PMCID: PMC3849429  PMID: 24070457
Cohort studies; Elderly; Hypnotics; Mortality; Sleep disorders
10.  Metabolic Syndrome and Disability: Findings From the Prospective Three-City Study 
Metabolic syndrome (MetS) is a potentially reversible cause of disability in the elderly people. The published literature suggests that the MetS–disability association is likely to be complex, depending on co-existing risk factors and with possible variation for each of the specific MetS components. Further evidence is needed to understand the specific consequences of the MetS as a whole and as a function of its components.
Prospective analyses included data from 6,141 participants (60.9% women) aged 65 and older from the Three-City cohort. Mixed logistic models were used to determine associations between MetS (National Cholesterol Education Program Adult Treatment Panel III criteria) and 7-year incident disability measured as social restriction, mobility limitations (Rosow and Breslau scale), and limitations in instrumental and basic activities of daily living.
MetS was associated with incident social restriction (odds ratio = 1.55, 95% CI: 1.14–2.09), limited mobility (odds ratio = 1.52, 95% CI: 1.21–1.90), and instrumental activities of daily living limitations (odds ratio = 1.62, 95% CI: 1.24–2.10) after adjustment for a range of potential sociodemographic, health behavior, and health status confounders at baseline. These associations were independent of chronic conditions, including cardiovascular disease and dementia. There was evidence of associations between MetS components: central obesity, high triglycerides, and elevated fasting glucose and incidence of limitations in mobility and instrumental activities of daily living.
Our results suggest that the increased risk of mobility and instrumental activities of daily living limitations in the elderly people associated with MetS is over and above that associated with its components.
PMCID: PMC3859359  PMID: 23833203
Metabolism; Frailty; Epidemiology.
11.  Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age 
Diabetes Care  2013;36(4):928-934.
The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).
In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.
Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.
Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.
PMCID: PMC3609527  PMID: 23230097
12.  Oestrogen receptor polymorphisms and late-life depression 
The British Journal of Psychiatry  2011;199(2):126-131.
Evidence suggests a role for estrogen in depression but the involvement of estrogen receptor (ER) polymorphisms remains unknown.
To determine the association between ER polymorphisms and late-life depression and the modifying effect of hormone treatment (HT).
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 ER-α and ER-β polymorphisms with severe depression was examined in 6017 community-dwelling elderly using multivariate logistic regression.
In women, the ER-α rs2234693 and rs9340799 polymorphisms were significantly associated with the risk of late-life depression. The A allele of ER-β rs1256049 increased the risk of depression, but only for non-current users of HT. In men, only the ER-β rs4986938 polymorphism showed a weak association with depression risk.
ER polymorphisms are associated with severe late-life depression risk in women only.
PMCID: PMC3623726  PMID: 21804148
Age Factors; Aged; Aged, 80 and over; Alleles; Depressive Disorder, Major; epidemiology; genetics; Effect Modifier, Epidemiologic; Estrogen Replacement Therapy; Female; Gene Frequency; Genetic Predisposition to Disease; epidemiology; Genotype; Humans; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Postmenopause; psychology; Psychiatric Status Rating Scales; Receptors, Estrogen; genetics
13.  Measuring Resilience in Adult Women Using the 10-Items Connor-Davidson Resilience Scale (CD-RISC). Role of Trauma Exposure and Anxiety Disorders 
PLoS ONE  2012;7(6):e39879.
Resilience is the ability of individuals to adapt positively in the face of trauma. Little is known, however, about lifetime factors affecting resilience.
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).
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]).
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.
PMCID: PMC3387225  PMID: 22768152
14.  Metabolic Syndrome and Onset of Depressive Symptoms in the Elderly 
Diabetes Care  2011;34(4):904-909.
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and the onset of depressive symptoms according to different age-groups in a large, general elderly population.
This was a prospective cohort study of 4,446 men and women aged 65–91 years who were free of depression or depressive symptoms at baseline (the Three-City Study, France). MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale score ≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
After adjusting for a large range of potential confounders, we observed MetS to be associated with 1.73-fold (95% CI 1.02–2.95) odds for new-onset depressive symptoms in the youngest age-group (65–70 years at baseline), independently of cardiovascular diseases. No such association was seen in older age-groups.
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged people can be extended to older adults but not to the oldest ones. Additional research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65–70 years.
PMCID: PMC3064049  PMID: 21346185
15.  Hormone Treatment, Estrogen Receptor Polymorphisms and Mortality: A Prospective Cohort Study 
PLoS ONE  2012;7(3):e34112.
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.
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.
PMCID: PMC3311587  PMID: 22457817
16.  Insomnia symptoms in older adults: associated factors and gender differences 
The aim of this study was to examine the factors associated with insomnia in community-dwelling elderly as a function of the nature and number of insomnia symptoms (IS) e.g. difficulty with initiating sleep (DIS), difficulty with maintaining sleep (DMS) and early morning awakening (EMA).
IS were assessed in a sample of 2673 men and 3213 women aged 65 years and over. The participants were administered standardized questionnaires regarding the frequency of IS and other sleep characteristics (snoring, nightmares, sleeping medication, sleepiness) as well as various socio-demographic, behavioral and clinical variables, and measures of physical and mental health.
More than 70% of men and women reported at least one IS, DMS being the most prevalent symptom in both men and women. Women reported more frequently two or three IS whereas men reported more often only one IS. Multivariate regression analyses stratified by gender showed that men and women shared numerous factors associated with IS, sleeping medication, nightmares, sleepiness, chronic diseases, and depression being independently associated with two or three IS. For both sexes, age was associated with only one IS in all age categories. Loud snoring was strongly associated with increased DMS in men only. High body mass index increased the risk for DIS in men but tended to decrease it in women. In women, hormonal replacement therapy, Mediterranean diet, caffeine and alcohol intake had a protective effect.
Our data suggest that women may have specific predisposition factors of multiple IS which may involve both behavioral and hormonal factors. Identification and treatment of these risk factors may form the basis of an intervention program for reduction of insomnia symptoms in the elderly..
PMCID: PMC3179987  PMID: 20808113
Age Factors; Aged; Aged, 80 and over; Female; France; epidemiology; Humans; Male; Prevalence; Risk Factors; Self Report; Sex Characteristics; Sex Factors; Sleep Initiation and Maintenance Disorders; diagnosis; epidemiology
17.  Retrospective identification and characterization of mild cognitive impairment from a prospective population cohort 
Mild Cognitive Impairment (MCI) case-finding criteria have low specificity in general population studies. The present study retrospectively identifies cases of MCI and determines baseline criteria giving the highest discriminability. The ability of these criteria to increase current case-detection specificity is estimated.
A population-based cohort was recruited from electoral rolls from three French cities. Clinical and environmental characteristics were evaluated at baseline and 2 and 4 year follow-up. The clinical characterisitics of incident cases of dementia were examined retrospectively.
8919 persons over 65 without dementia (60.8% women). The mean age (SD) of the participants was 74.2 (5.6) for men and 74.4 (5.6) for women.
320 persons (3.6%) were retrospectively classified as MCI at baseline. This MCI group had poorer performance on all cognitive tests compared to the rest of the cohort and a sub-sample undergoing MRI were found to have more white matter hyperintensities. The group were also characterized by the presence of an ApoE 4 genotype (OR=2.17 CI 1.44–3.29 for men; OR=2.27 CI 1.59–3.24 for women), and IADL loss (OR=1.72 CI 1.01–3.0 for men and OR=1.49 CI 0.97–2.3 for women). Women with MCI also had high depressive symptomatology (OR=1.96; CI 1.34–2.87), anticholinergic drug use (OR=1.59; CI 1.05–2.28) and low BMI (OR=1.54; CI 1.05–2.28) and men a history of stroke (OR=2.17 CI 1.16–4.05) and glycemia (OR=1.72 CI 1.13–2.71). Addition of these characteristics to conventional MCI definitions increases their specificity.
This general population study employing a retrospective method for classifying persons with MCI identified gender-specific non-cognitive clinical variables which may increase specificity.
PMCID: PMC3173751  PMID: 21491628
Activities of Daily Living; Aged; Apolipoprotein E4; genetics; Cognition Disorders; diagnosis; Dementia; diagnosis; Disease Progression; Female; Genotype; Geriatric Assessment; methods; Humans; Male; Nerve Fibers, Myelinated; pathology; Neuropsychological Tests; Retrospective Studies; Risk Factors; MCI; diagnosis; cohort studies; gender; dementia; ApoE; cardiovascular disorder
18.  Metabolic syndrome and onset of depressive symptoms in the elderly: findings from the three-city study 
Diabetes Care  2011;34(4):904-909.
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and onset of depressive symptoms according to different age-groups in a large general elderly population.
Research Design and Methods
Prospective cohort study of 4446 men and women aged 65 to 91 and free of depression or depressive symptoms at baseline (the Three-City study, France). MetS was defined using the NCEP-ATP III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale (CES-D) score≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
After adjusting for a large range of potential confounders, we observed MetS to be associated with a 1.73-fold (95% CI: 1.02–2.95) odds for new-onset depressive symptoms in the youngest age group (65 to 70 at baseline), independently of cardiovascular diseases. No such association was seen in older age groups.
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged can be extended to older adults but not to the oldest ones. Further research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65 to 70.
PMCID: PMC3064049  PMID: 21346185
Depressive symptoms; metabolic syndrome; elderly; prospective study
19.  Association of adverse childhood environment and 5-HTTLPR Genotype with late-life depression 
The Journal of Clinical Psychiatry  2009;70(9):1281-1288.
Neurobiological and clinical studies suggest that childhood maltreatment may result in functional and structural nervous system changes which predispose the individual to depression. This vulnerability appears to be modulated by a polymorphism in the serotonin linked promoter region (5-HTTLPR). Little is known however, about the persistence of this vulnerability across the life-span although clinical studies of adult populations suggest that gene-environment interaction may diminish with ageing.
Depressive symptomatology and adverse and protective childhood events were examined in a population of 942 persons aged 65 years and over, taking into account socio-demographic characteristics and proximal competing causes of depression (widowhood, recent life-events, vascular and neurological disorder, and disability). Subjects were diagnosed as depressed if they met one of three criteria: a diagnosis of major depression on the Mini International Neuropsychiatric Interview (MINI), over 16 on the CES-D or anti-depressant treatment
Exposure to traumatic events in childhood doubled the risk of late-life depression and increased the risk of repeated episodes. Not all events were found to be pathogenic; significant risk being associated with excessive sharing of parental problems, poverty, mental disorder in parents, excessive punishment, verbal abuse, humiliation and mistreatment by an adult outside the family. Interactions were observed between the 5-HTTLPR ‘L’ allele, poverty and excessive sharing of parental problems.
Certain types of childhood trauma continue to constitute risk factors for depression in old age, outweighing more proximal causes. Gene-environment vulnerability interaction is linked in older age to the L-carrying genotype, modulating the effects of general environmental conditions rather than aggressive acts on the individual, perhaps due to increased cardiac reactivity.
PMCID: PMC3078522  PMID: 19573496
Adult; Adult Survivors of Child Abuse; psychology; statistics & numerical data; Age Factors; Aged; Aged, 80 and over; Child; Child of Impaired Parents; psychology; statistics & numerical data; Depressive Disorder, Major; epidemiology; genetics; Female; France; epidemiology; Genotype; Humans; Life Change Events; Longitudinal Studies; Male; Polymorphism, Genetic; Psychiatric Status Rating Scales; statistics & numerical data; Retrospective Studies; Risk Factors; Serotonin Plasma Membrane Transport Proteins; genetics; Social Environment; Stress, Psychological; depression; elderly; child abuse; 5-HTTLPR; gene-environment interaction
20.  Long-term post-operative cognitive decline in the elderly: the effects of anesthesia type, apolipoprotein E genotype, and clinical antecedents 
Journal of Alzheimer's Disease  2010;22 Suppl 3:105-113.
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 that of 310 elderly controls who completed the same neuro-psychiatric 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.
PMCID: PMC3078520  PMID: 20858969
Aged; Aged, 80 and over; Anesthesia; adverse effects; Anesthesia, Conduction; adverse effects; Anesthesia, General; adverse effects; Apolipoproteins E; genetics; Arthroplasty, Replacement; Attention; physiology; Choice Behavior; physiology; Cognition; physiology; Cognition Disorders; etiology; genetics; psychology; Female; Humans; Language; Male; Memory; physiology; Mental Processes; physiology; Neuropsychological Tests; Postoperative Complications; genetics; psychology; Questionnaires; Socioeconomic Factors; Space Perception; physiology; Visual Perception; physiology; Anesthesia; Apolipoprotein E; Mild cognitive impairment; Post-operative cognitive decline
21.  Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study 
Neurology  2009;73(21):1729-1737.
To examine the association between hormone therapy (HT) and cognitive performance or dementia, focusing on the duration and type of treatment used, as well as the timing of initiation of HT in relation to the menopause.
Women 65 years and older were recruited in France as part of the Three City Study. At baseline and 2 and 4 year follow-up, women were administered a short cognitive test battery and a clinical diagnosis of dementia was made. Detailed information was also gathered relating to current and past HT use. Analysis was adjusted for a number of socio-demographic, behavioural, physical and mental health variables, as well as Apolipoprotein ε4 (Apoe-ε4).
Among 3130 naturally postmenopausal women, current HT users performed significantly better than never users on verbal fluency, working memory and psychomotor speed. These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial. However, initiation of HT close to the menopause was not associated with better cognition. HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with Apoe-ε4.
Current HT was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used. We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life. Current HT may decrease the risk of dementia associated with the Apoe-ε4 allele.
PMCID: PMC2993903  PMID: 19933973
Aged; Aged, 80 and over; Apolipoproteins E; genetics; Cognition Disorders; drug therapy; etiology; genetics; Cohort Studies; Dementia; complications; genetics; Estrogen Replacement Therapy; methods; Female; Humans; Logistic Models; Neuropsychological Tests; Retrospective Studies
22.  Neurological signs and late-life depressive symptoms in a community population: the ESPRIT study 
Depression in the elderly is common and often resistant to treatment. It has been suggested that late-life depression may be related to underlying neurobiological changes, however these observations are derived from diverse clinical samples and as yet have not been confirmed in a more representative population study.
Our aim was to investigate associations between neurological signs as markers of underlying brain dysfunction and caseness for depression in an elderly community sample, controlling for physical health and comorbid/past neurological disorders.
A cross-sectional analysis of 2102 older people without dementia from the ESPRIT project. Depressive symptomatology was ascertained using the CES-D and abnormal neurological signs/comorbidity from a full neurological examination according to ICD-10 criteria.
Pyramidal, extrapyramidal, cranial nerve and sensory deficit signs were significantly associated with case-level depressive symptoms, but were more likely to be present in participants with a previous history of neurological disorder.
We confirmed previous findings of an association between neurological signs and case-level depressive symptoms in late-life. However, this suggests that depression in late-life may reflect either the severity of comorbid neurological disorder or perhaps widespread neurodegeneration.
PMCID: PMC2980503  PMID: 19823983
Neurological signs; Late-life Depression; Depressive symptoms; Old age; Neurodegenerative theory
23.  Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence 
Journal of Alzheimer's Disease   2010;20 Suppl 1:S161-S166.
The present study examines the epidemiological evidence for a causal relationship between caffeine consumption and cognitive deterioration in the elderly.
A population study of 641 elderly persons examining cognitive functioning, caffeine consumption, magnetic resonance imaging volumetrics and other factors known to affect cognitive performance.
Our findings demonstrate that the association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, taking into account multiple confounders, to be dose-dependent and temporarily related (caffeine consumption precedes cognitive change). Mean log transformed white matter lesion/cranial volume ratios were found to be significantly lower in women consuming more than 3 units of caffeine per day after adjustment for age (−1.23 SD=0.06) than women consuming 2–3 units (−1.04 SD=0.04) or one unit or less (−1.04 SD=0.07, −35% in cm3 compared to low drinkers). This observation is coherent with biological assumptions that caffeine through adenosine is linked to amyloid accumulation and subsequently white matter lesion formation.
The significant relationship observed between caffeine intake in women and lower cognitive decline is highly likely to be a true causal relationship and not a spurious association.
PMCID: PMC2929398  PMID: 20164564
cognitive decline, white matter lesions, caffeine, cohort study
24.  A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women 
Menopause (New York, N.y.)  2009;16(3):509-517.
Across a woman’s lifetime, variations in hormone levels are known to influence mood and well-being. Whether absolute or changes in hormone levels over time are associated with depression among postmenopausal women remains unclear.
The Melbourne Women’s Midlife Health Project is a longitudinal population based study of women, who were followed through the menopause transition. This analysis is based on data collected from 138 postmenopausal women in years 11 and 13 of the study, who were assessed for the presence of depressive symptoms using the Centre for Epidemiological Studies Depression Scale. Logistic regression models were developed to determine whether absolute or changes in hormone levels were associated with depression.
No significant associations were found between depressive symptoms and the absolute levels of sex-hormone binding globulin, testosterone, free androgen index, estradiol, free estradiol or FSH. On the other hand, women with a decline in total serum estradiol over the 2-year period had a more than 3-fold increased risk of depressive symptoms (OR: 3.5; 95% CI: 1.2–9.9). A large increase in FSH levels over this period was also associated with depressive symptoms (OR: 2.6; 95% CI: 1.0–6.7). These associations remained even after adjustment for initial depression score, as well as a range of potential confounding factors.
Changes in estradiol and to a lesser extent follicle-stimulating hormone levels are associated with an increased risk of depressive symptoms in postmenopausal women. These results further support a role for fluctuating rather than absolute hormone levels in later life depression.
PMCID: PMC2814239  PMID: 19169164
Aged; Depression; blood; Estradiol; blood; Female; Follicle Stimulating Hormone; blood; Humans; Logistic Models; Longitudinal Studies; Middle Aged; Odds Ratio; Postmenopause; blood; psychology
25.  Modelling complex pathways between late-life depression and disability: evidence for mediating and moderating factors 
While previous research has consistently shown an association between depression and disability in the elderly, less is known about the mechanisms linking the two. Recent longitudinal population studies showed considerable inconsistency in the criteria used to establish causality and terms such as mediation and effect modification were frequently incorrectly applied in terms of the inferences drawn.
We underlines the necessity to adopt more stringent theoretical criteria for the establishment of intermediary effects in the relationship between depression and disability in order to better identify cross-validated potential intervention points for reducing the risk of disablement and depression.
PMCID: PMC2691412  PMID: 19243645
Aged; Longitudinal studies; Disability evaluation; Depression

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