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1.  Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort 
Brain and Behavior  2015;5(3):e00313.
Despite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G-protein-coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently.
Data were obtained from 1010 elderly men and women from the prospective population-based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12-years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations.
All three variants showed some evidence of an association with late-life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6-fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12-year incidence of depression. In contrast, rs561077 was associated with a 1.8-fold increased risk of incident depression specifically. No significant associations were observed in men.
Our results thus provide only weak support for the involvement of GPR50 variants in late-life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression).
PMCID: PMC4356842  PMID: 25798330
Antidepressants; candidate gene; GPCR; GPR50; late-life depression; lipid levels
2.  Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort 
Brain and Behavior  2015;e00313.
Despite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G‐protein‐coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently.
Data were obtained from 1010 elderly men and women from the prospective population‐based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12‐years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations.
All three variants showed some evidence of an association with late‐life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6‐fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12‐year incidence of depression. In contrast, rs561077 was associated with a 1.8‐fold increased risk of incident depression specifically. No significant associations were observed in men.
Our results thus provide only weak support for the involvement of GPR50 variants in late‐life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression).
PMCID: PMC4356842  PMID: 25798330
Antidepressants; candidate gene; GPCR; GPR50; late‐life depression; lipid levels
3.  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.
4.  Patient and public attitudes to and awareness of clinical practice guidelines: a systematic review with thematic and narrative syntheses 
Clinical practice guidelines are typically written for healthcare providers but there is increasing interest in producing versions for the public, patients and carers. The main objective of this review is to identify and synthesise evidence of the public’s attitudes towards clinical practice guidelines and evidence-based recommendations written for providers or the public, together with their awareness of guidelines.
We included quantitative and qualitative studies of any design reporting on public, patient (and their carers) attitudes and awareness of guidelines written for providers or patients/public. We searched electronic databases including MEDLINE, PSYCHINFO, ERIC, ASSIA and the Cochrane Library from 2000 to 2012. We also searched relevant websites, reviewed citations and contacted experts in the field. At least two authors independently screened, abstracted data and assessed the quality of studies. We conducted a thematic analysis of first and second order themes and performed a separate narrative synthesis of patient and public awareness of guidelines.
We reviewed 5415 records and included 26 studies (10 qualitative studies, 13 cross sectional and 3 randomised controlled trials) involving 24 887 individuals. Studies were mostly good to fair quality. The thematic analysis resulted in four overarching themes: Applicability of guidelines; Purpose of guidelines for patient; Purpose of guidelines for health care system and physician; and Properties of guidelines. Overall, participants had mixed attitudes towards guidelines; some participants found them empowering but many saw them as a way of rationing care. Patients were also concerned that the information may not apply to their own health care situations. Awareness of guidelines ranged from 0-79%, with greater awareness in participants surveyed on national guideline websites.
There are many factors, not only formatting, that may affect the uptake and use of guideline-derived material by the public. Producers need to make clear how the information is relevant to the reader and how it can be used to make healthcare improvements although there were problems with data quality. Awareness of guidelines is generally low and guideline producers cannot assume that the public has a more positive perception of their material than of alternative sources of health information.
PMCID: PMC4119247  PMID: 25064372
Clinical practice guidelines; Patient; Public; Attitudes; Awareness
5.  Metabolic syndrome and localization of white matter hyperintensities in the elderly population 
Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes.
Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique - Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program–Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions.
After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25–6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region.
Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.
PMCID: PMC4108160  PMID: 22682962
Epidemiology; Observational study; Elderly; Metabolic syndrome; White matter hyperintensities; Alzheimer’s disease
6.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
PMCID: PMC4055488  PMID: 24922517
7.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
PMCID: PMC3896259  PMID: 24162737
8.  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
9.  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
10.  War exposure, 5-HTTLPR genotype and lifetime risk of depression 
in 1962, during the Algerian war, approximately one and a half million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These subjects constitute a cohort for the study of the long term impact of gene-environment interaction on depression.
To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by the serotonin transporter gene (5-HTTLPR).
A community sample of elderly persons aged 65 years and over residing in the Montpellier region of the South of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressions were assessed according to DSM-IV criteria.
A significant relationship was observed between exposure to repatriation and subsequent depression (p<0.002), but there was no significant effect of gene alone (p=0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (Repatriation X 5-HTTLPR) was globally significant (p<0.002; OR= 3.21 [2.48–5.12]). Subjects carrying the two short ( S ) alleles of 5-HTTLPR were observed to be at higher risk (p<0.005; OR=2.34 [1.24–4.32]) and particularly when the repatriation occurred before the age of 35 (p<0.002; OR=2.91 [1.44–5.88]) but did not reach significance in subjects who were older at the time of the event (p=0.067).
The association between depression and war repatriation is significantly modulated by 5-HTTLPR genotype but this appears to occur only in persons who were younger at the time of exposure.
PMCID: PMC3909529  PMID: 21593514
Age Factors; Aged; Aged, 80 and over; Algeria; Alleles; Depressive Disorder; epidemiology; genetics; Diagnostic and Statistical Manual of Mental Disorders; Environment; Female; France; epidemiology; Genetic Predisposition to Disease; Genotype; Humans; Life Change Events; Logistic Models; Male; Prospective Studies; Risk Factors; Serotonin Plasma Membrane Transport Proteins; genetics; Time Factors; War
11.  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
12.  Caffeine and cognitive decline in elderly women at high vascular risk 
Journal of Alzheimer's disease : JAD  2013;35(2):10.3233/JAD-122371.
Persons with vascular disorders are at higher risk of cognitive decline.
To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk.
We included 2475 women aged 65+ years in the Women’s Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995–1996) using a validated 116 item-food frequency questionnaire. From 1998–2000 to 2005–2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory and category fluency. The primary outcome was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake.
We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend=0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (> 371 versus < 30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p=0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend=0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02).
Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.
PMCID: PMC3807252  PMID: 23422357
Cognition; Aging; Caffeine; Cohort studies; Risk factors; Epidemiology
13.  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
14.  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.
15.  Retinal Vascular Caliber Is Associated with Cardiovascular Biomarkers of Oxidative Stress and Inflammation: The POLA Study 
PLoS ONE  2013;8(7):e71089.
Retinal vascular caliber has been linked with increased cardiovascular risk and is predictive of cardiovascular pathology, including stroke and coronary heart disease. Oxidative stress, as well as inflammatory mechanisms, plays a major role in the pathogenesis and progression of atherosclerosis, plaque rupture and vascular thrombotic propensity. The purpose of this study is to explore the relationship between retinal vascular calibers and biomarkers of oxidative stress and inflammation, in subjects free of cardiovascular pathology.
Patients and Methods
Cross-sectional analysis from a community-dwelling cohort comprising 1224 individuals aged 60 years and over, without a history of coronary or peripheral artery disease or stroke. Retinal vascular caliber was measured from fundus photographs using semi-automated standardized imaging software. Oxidative stress was evaluated using plasma superoxide dismutase 2 and glutathione peroxidase (GPx-3) activities, and inflammatory state was assessed using plasma high sensitivity C-reactive protein (hsCRP) and orosomucoid.
In a multivariate model controlling for cardiovascular risk factors, larger retinal arteriolar caliber was independently related to higher level of GPx-3 activity (p = 0.003) whereas larger venular caliber was associated with higher levels of hsCRP (p = 0.0001) and orosomucoid (p = 0.01).
In the present study, biomarkers of oxidative stress regulation and inflammation were independently associated with retinal vascular calibers. This suggests that an assessment of retinal vessels may offer early and non-invasive detection of subclinical vascular pathology.
PMCID: PMC3724806  PMID: 23923054
16.  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
17.  Beliefs and attitudes of French family practitioners toward depression: the impact of training in mental health 
To study, in a sample of French Family Practitioners (FPs), beliefs and attitudes toward depression and how they vary according to training received in mental health.
The Depression Attitude Questionnaire (DAQ) was completed by 468 FPs from all regions of France, recruited by pharmaceutical company representatives to attend focus groups on the management of depression in general practice.
A three factor model was derived from the DAQ, accounting for 37.7% of the total variance. The correlations between individual items of each component varied from 0.4 to 0.65 with an overall internal consistency of 0.47 (Cronbach’s alpha). FPs had an overall neutral position on component 1, professional ease, a positive view on the origins of depression and its amenability to change (component 2), and a belief in the necessity of medication and the benefit of antidepressant therapy (component 3). Training in mental health, specifically through continuing medical education and postgraduate psychiatric hospital training, was significantly and positively associated with both professional ease and a medication approach to treating depression.
this study is the first description of the beliefs and attitudes of French FPs towards depression using a standardized measure, the DAQ, despite the instrument’s limited psychometric properties. It shows the positive effect of training in mental health on attitudes towards depression.
PMCID: PMC3596352  PMID: 21675343
Adult; Attitude of Health Personnel; Depressive Disorder; psychology; therapy; Education, Medical, Continuing; Family Practice; methods; Female; France; Health Knowledge, Attitudes, Practice; Humans; Male; Mental Health Services; Middle Aged; Physicians, Family; education; Principal Component Analysis; Psychometrics; methods; Questionnaires
18.  Patient-Reported Outcome Measures for Chronic Obstructive Pulmonary Disease 
The Patient  2013;6(1):11-21.
Patient-reported outcome measures (PROMs) are intended to reflect outcomes relevant to patients. They are increasingly used for healthcare quality improvement. To produce valid measures, patients should be involved in the development process but it is unclear whether this usually includes people with low literacy skills or learning disabilities. This potential exclusion raises concerns about whether these groups will be able to use these measures and participate in quality improvement practices.
Taking PROMs for chronic obstructive pulmonary disease (COPD) as an exemplar condition, our review determined the inclusion of people with low literacy skills and learning disabilities in research developing, validating, and using 12 PROMs for COPD patients. The studies included in our review were based on those identified in two existing systematic reviews and our update of this search.
People with low literacy skills and/or learning disabilities were excluded from the development of PROMs in two ways: explicitly through the participant eligibility criteria and, more commonly, implicitly through recruitment or administration methods that would require high-level reading and cognitive abilities. None of the studies mentioned efforts to include people with low literacy skills or learning disabilities.
Our findings suggest that people with low literacy skills or learning disabilities are left out of the development of PROMs. Given that implicit exclusion was most common, researchers and those who administer PROMs may not even be aware of this problem. Without effort to improve inclusion, unequal quality improvement practices may become embedded in the health system.
PMCID: PMC3585908  PMID: 23417577
19.  Spatial Distribution of Cerebral White Matter Lesions Predicts Progression to Mild Cognitive Impairment and Dementia 
PLoS ONE  2013;8(2):e56972.
White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years.
In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia.
Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia.
Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.
PMCID: PMC3572965  PMID: 23457645
20.  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
21.  Using patient reported outcome measures in health services: A qualitative study on including people with low literacy skills and learning disabilities 
Patient reported outcome measures (PROMs) are self-report measures of health status increasingly promoted for use in healthcare quality improvement. However people with low literacy skills or learning disabilities may find PROMs hard to complete. Our study investigated stakeholder views on the accessibility and use of PROMs to develop suggestions for more inclusive practice.
Taking PROMs recommended for chronic obstructive pulmonary disease (COPD) as an example, we conducted 8 interviews with people with low literacy skills and/or learning disabilities, and 4 focus groups with 20 health professionals and people with COPD. Discussions covered the format and delivery of PROMs using the EQ-5D and St George Respiratory Questionnaire as prompts. Thematic framework analysis focused on three main themes: Accessibility, Ease of Use, and Contextual factors.
Accessibility included issues concerning the questionnaire format, and suggestions for improvement included larger font sizes and more white space. Ease of Use included discussion about PROMs’ administration. While health professionals suggested PROMs could be completed in waiting rooms, patients preferred settings with more privacy and where they could access help from people they know. Contextual Factors included other challenges and wider issues associated with completing PROMs. While health professionals highlighted difficulties created by the system in managing patients with low literacy/learning disabilities, patient participants stressed that understanding the purpose of PROMs was important to reduce intimidation.
Adjusting PROMs’ format, giving an explicit choice of where patients can complete them, and clearly conveying PROMs’ purpose and benefit to patients may help to prevent inequality when using PROMs in health services.
PMCID: PMC3520727  PMID: 23181735
Patient reported outcome measures; Quality improvement; Chronic obstructive pulmonary disease; Low literacy; Learning disabilities
22.  The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease 
BMJ Open  2012;2(6):e001893.
Epidemiological studies indicate that significant decreases in the incidence of Alzheimer's disease (AD) may be obtained by targeting multiple middle-age risk factors. However, as dementia is unlikely to be diagnosed for decades, short-term outcome measures are required. AD biomarker changes precede clinical symptoms by many years, but their sensitivity to mid-life change remains unknown.
Methods and analysis
PREVENT is a prospective cohort study examining biomarker status at mid-life in at least 150 individuals genetically at high, medium or low risk of late-onset AD. Participants are children of individuals with or without a diagnosed AD allocated to high, medium and low-risk groups according to parental clinical status and ApoE genotype. The biomarkers examined over 2 years are plasma and CSF Aβ42 amyloid, Tau and pTau, proinflammatory cytokines, acute-phase proteins, medial temporal-lobe atrophy, white matter lesion volume, cognitive performance related to transentorhinal and hippocampal functioning and hypothalamic−pituitary−adrenal and sympathetic axes regulation.
Ethics and dissemination
Detected pathologies are communicated to the participant's general practitioner with their permission. Risk status by genotype would not be revealed. The results of the study would be published in peer-reviewed journals and validated biomarkers used to construct a randomised controlled intervention study.
PMCID: PMC3533047  PMID: 23166135
Geriatric Medicine; Epidemiology
23.  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
24.  Disability and incident coronary heart disease in older community-dwelling adults: the Three-City Study 
Disability is a common condition in the elderly and has been associated with prevalent coronary heart disease (CHD) and with shorter longevity. However, whether disability predicts the occurrence of CHD has been less studied.
To prospectively assess the association between disability and incident fatal and non-fatal CHD among older adults free of cardiovascular disease (CVD). Design and Settings: The Three-City (3C) Study is a French multicentre prospective population-based cohort of 9294 elderly subjects (3469 men and 5645 women) aged 65 and over at baseline between 1999 to 2001 and followed-up during 6 years.
7354 participants with no history of CVD and with available information on disability status. Disability was assessed at baseline with a three levels of a hierarchical scale : no disability, mild disability (mobility only), moderate or severe disability (mobility plus activities of daily living and/or instrumental activities of daily living).
Main Outcome Measure
Incident fatal and non-fatal coronary events (angina pectoris, myocardial infarction, revascularization procedures and CHD death).
At baseline, the mean level of the risk factors increased gradually with the severity of disability. After a median follow-up of 5.2 years, 264 first coronary events including 55 fatal events occurred. Participants with moderate or severe disability had a 1.8-fold (95%CI: 1.1–2.9) increased risk of overall CHD compared to non-disabled subjects in multivariate analysis, while those with mild disability were not at increased CHD risk. The association was found for fatal CHD only, for which the risk increased gradually with the severity of disability (mild disability: HR = 1.8, 95%CI: 0.9–3.8; moderate/severe disability: HR = 4.5, 95%CI: 1.8–11.3; p for trend = 0.002).
These data suggest that the association of disability with incident CHD is mostly due to an association with fatal CHD in community-dwelling elderly subjects.
PMCID: PMC3369834  PMID: 20345869
Activities of Daily Living; Aged; Coronary Disease; epidemiology; etiology; Disabled Persons; classification; statistics & numerical data; Female; France; epidemiology; Geriatric Assessment; Hospitalization; statistics & numerical data; Humans; Incidence; Kaplan-Meier Estimate; Logistic Models; Male; Proportional Hazards Models; Prospective Studies; Questionnaires; Risk Assessment; Risk Factors; Severity of Illness Index; Urban Health; statistics & numerical data; epidemiology; elderly; risk factors; disability; coronary heart disease; atherosclerosis.
25.  Clinical usefulness of the metabolic syndrome for the risk of coronary heart disease does not exceed the sum of its individual components in older men and women. The Three-City (3C) Study 
Heart  2012;98(8):650-655.
To investigate the respective associations and clinical usefulness of the metabolic syndrome (MetS) and its individual components to predict the risk of first coronary heart disease (CHD) events in elderly.
The Three-City is a French prospective multisite community-based cohort.
Three large French cities: Bordeaux, Dijon and Montpellier.
7612 subjects aged 65 and over who were free of CHD at baseline.
Main outcome measures
The MetS was defined by the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria.
During a median follow-up of 5.2 years, 275 first CHD events were adjudicated. The MetS was associated with increased risks of total (adjusted HR: 1.78; 95% CI 1.39 to 2.28), fatal (HR: 2.40; 95% CI 1.41 to 4.09) and non-fatal (HR: 1.64; 95% CI 1.24 to 2.17) CHD events. The association with total CHD was significant in women (HR: 2.56; 95% CI 1.75 to 3.75) but not in men (HR: 1.39; 95% CI 0.99 to 1.94; p for interaction=0.012). When in the same multivariable model, hyperglycemia and abdominal adiposity in women, hyperglycemia, lower HDL cholesterol and abdominal adiposity (inverse association) in men were the components significantly associated with CHD. The components of the MetS but not the MetS itself improved risk prediction beyond traditional risk factors (NRI= 9.35%, p<0;001).
The MetS is a risk marker for CHD in community-dwelling elderly subjects but may not be useful for CHD risk prediction purposes compared to its individual components.
PMCID: PMC3328398  PMID: 22505463
Metabolic syndrome; coronary heart disease; elderly; risk stratification; psychology/psychiatry; epidemiology

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