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1.  Convergent genetic and expression data implicate immunity in Alzheimer's disease 
Jones, Lesley | Lambert, Jean-Charles | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Vedernikov, Alexey | Escott-Price, Valentina | Stone, Timothy | Richards, Alexander | Bellenguez, Céline | Ibrahim-Verbaas, Carla A | Naj, Adam C | Sims, Rebecca | Gerrish, Amy | 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 | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | 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 | Letteneur, Luc | Kornhuber, Johanes | Tárraga, Lluís | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Emilsson, Valur | 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 | Kehoe, Pat | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleὀ, Alberti | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick | Hardy, John | Naranjo, Maria Candida Deniz | Razquin, Cristina | Bosco, Paola | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Moebus, Susanne | Mecocci, Patrizia | del Zompo, Maria | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Jessen, Frank | Dichgans, Martin | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alavarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | 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 FAG | 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 SK | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Pastor, Pau | 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 | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broekhoven, Christine | Ramirez, Alfredo | Schellenberg, Gerard D | Seshadri, Sudha | Amouyel, Philippe | Williams, Julie | Holmans, Peter A
Background
Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis.
Methods
The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
Results
ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05).
Conclusions
The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.
doi:10.1016/j.jalz.2014.05.1757
PMCID: PMC4672734  PMID: 25533204
Alzheimer's disease; dementia; neurodegeneration; immune response; endocytosis; cholesterol metabolism; uniquitination; pathway analysis; ALIGATOR; Weighted gene coexpression network analysis
2.  Shared genetic contribution to ischemic stroke and Alzheimer's disease 
Traylor, Matthew | Adib‐Samii, Poneh | Harold, Denise | Dichgans, Martin | Williams, Julie | Lewis, Cathryn M. | Markus, Hugh S. | Fornage, Myriam | Holliday, Elizabeth G | Sharma, Pankaj | Bis, Joshua C | Psaty, Bruce M | Seshadri, Sudha | Nalls, Mike A | Devan, William J | Boncoraglio, Giorgio | Malik, Rainer | Mitchell, Braxton D | Kittner, Steven J | Ikram, M Arfan | Clarke, Robert | Rosand, Jonathan | Meschia, James F | Sudlow, Cathie | Rothwell, Peter M | Levi, Christopher | Bevan, Steve | Kilarski, Laura L | Walters, Matthew | Thijs, Vincent | Slowik, Agnieszka | Lindgren, Arne | de Bakker, Paul I W | 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‐Thçrèse | 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 | Fiçvet, 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 | Del Zompo, Maria | 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
Annals of Neurology  2016;79(5):739-747.
Objective
Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.
Methods
Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred.
Results
We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response.
Interpretation
Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747
doi:10.1002/ana.24621
PMCID: PMC4864940  PMID: 26913989
3.  Excessive daytime sleepiness and antipathogen drug consumption in the elderly: a test of the immune theory of sleep 
Scientific Reports  2016;6:23574.
The evolutionary reasons for sleep remain controversial. The immune theory of sleep suggests that sleep is essential to the immune system, allowing organisms to allocate more energy to their immunity. This hypothesis was tested by exploring the links between excessive daytime sleepiness (EDS) and vulnerability to infectious diseases in a large (n = 9294) cohort of elderly individuals, with information on socio-demographics, daily habits, and medical characteristics. At the two-year and four-year follow-ups, we obtained individual data from the national healthcare insurance about all medications prescribed to the participants between 2001 and 2003 (n = 2865). We found an independent positive association between EDS and the consumption of some anti-pathogen drugs. This relationship was mostly explained by fungal and parasitic infections rather than by viral and bacterial ones. These results, although based on correlations, are consistent with the idea that EDS as a proxy of altered sleep quality/quantity may affect the efficiency of the immune system, and hence vulnerability to infections.
doi:10.1038/srep23574
PMCID: PMC4800730  PMID: 26996205
4.  The Prevalence of Mild Cognitive Impairment in Diverse Geographical and Ethnocultural Regions: The COSMIC Collaboration 
PLoS ONE  2015;10(11):e0142388.
Background
Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI).
Methods
Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment.
Results
The published range of MCI prevalence estimates was 5.0%–36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%–10.8%); Clinical Dementia Rating of 0.5 (1.8%–14.9%); Mini-Mental State Examination score of 24–27 (2.1%–20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01).
Conclusion
Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally.
doi:10.1371/journal.pone.0142388
PMCID: PMC4634954  PMID: 26539987
5.  Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia 
Objectives
Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of Mild Cognitive Impairment (MCI) or dementia.
Methods
We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia.
Results
The interaction between education level and WML volume reached significance (p=0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p=0.02, HR= 3.77 [1.29–10.99]), but not in the high education group (>8 years) (p=0.82, HR=1.07 [0.61–1.87]).
Conclusions
Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.
doi:10.1016/j.jagp.2013.06.002
PMCID: PMC4143478  PMID: 24021219
Alzheimer’s disease; dementia; mild cognitive impairment (MCI); white matter lesions; Magnetic Resonance Imaging (MRI); cognitive reserve; cohort studies
6.  APOE-ε4 and risk for Alzheimer’s disease: Do regionally distributed white matter hyperintensities play a role? 
Background
We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase risk for Alzheimer’s disease (AD). Here, we examined whether individuals with APOE*4have increased parietal WMH volume.
Methods
Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n=694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n=539, 8 with dementia) in Montpellier. The association between regional WMH and APOE*4 was examined separately in each group and then in a combined analysis.
Results
In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE*4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH.
Conclusions
APOE*4 is associated with increased parietal lobe WMH.
doi:10.1016/j.jalz.2014.07.155
PMCID: PMC4252241  PMID: 25304991
APOE; Alzheimer disease; white matter hyperintensities
7.  Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort 
Brain and Behavior  2015;5(3):e00313.
Introduction
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.
Methods
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.
Results
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.
Discussion
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).
doi:10.1002/brb3.313
PMCID: PMC4356842  PMID: 25798330
Antidepressants; candidate gene; GPCR; GPR50; late-life depression; lipid levels
8.  Involvement of GPR50 polymorphisms in depression: independent replication in a prospective elderly cohort 
Brain and Behavior  2015;e00313.
Abstract
Introduction
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.
Methods
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.
Results
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.
Discussion
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).
doi:10.1002/brb3.313
PMCID: PMC4356842  PMID: 25798330
Antidepressants; candidate gene; GPCR; GPR50; late‐life depression; lipid levels
9.  Metabolic Syndrome and Disability: Findings From the Prospective Three-City Study 
Background.
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.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1093/gerona/glt101
PMCID: PMC3859359  PMID: 23833203
Metabolism; Frailty; Epidemiology.
10.  If patient‐reported outcome measures are considered key health‐care quality indicators, who is excluded from participation? 
Abstract
Patient‐reported outcome measures have received increasing attention with regard to ensuring quality improvement across the health service. However, there is a risk that people with disabilities and low literacy are systematically excluded from the development of these measures as well as their application in clinical practice. This editorial highlights some of these risks and the potential consequences of exclusion for these groups.
doi:10.1111/j.1369-7625.2012.00772.x
PMCID: PMC5060906  PMID: 22512658
disability; exclusion; low literacy; patient‐reported outcomes
11.  Patient and public attitudes to and awareness of clinical practice guidelines: a systematic review with thematic and narrative syntheses 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6963-14-321
PMCID: PMC4119247  PMID: 25064372
Clinical practice guidelines; Patient; Public; Attitudes; Awareness
12.  Metabolic syndrome and localization of white matter hyperintensities in the elderly population 
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.
doi:10.1016/j.jalz.2011.11.007
PMCID: PMC4108160  PMID: 22682962
Epidemiology; Observational study; Elderly; Metabolic syndrome; White matter hyperintensities; Alzheimer’s disease
13.  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.
Background
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.
Significance
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.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
14.  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.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
15.  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.
doi:10.3233/JAD-121228
PMCID: PMC3966213  PMID: 23254630
Lipids; Dementia; Alzheimer's disease; Elderly; Apolipoprotein; Atherosclerosis; Prospective cohort
16.  Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age 
Diabetes Care  2013;36(4):928-934.
OBJECTIVE
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).
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.
doi:10.2337/dc12-0239
PMCID: PMC3609527  PMID: 23230097
17.  War exposure, 5-HTTLPR genotype and lifetime risk of depression 
Background
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.
Aims
To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by the serotonin transporter gene (5-HTTLPR).
Method
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.
Results
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).
Conclusion
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.
doi:10.1192/bjp.bp.110.087924
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
18.  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.
Background
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.
Methods/Design
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.
Discussion
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.
doi:10.1186/1471-2377-13-165
PMCID: PMC3827845  PMID: 24195705
Cohort studies; Cognitive ageing; Data harmonisation; Dementia; International consortium; Mild cognitive impairment
19.  Caffeine and cognitive decline in elderly women at high vascular risk 
Journal of Alzheimer's disease : JAD  2013;35(2):10.3233/JAD-122371.
Background
Persons with vascular disorders are at higher risk of cognitive decline.
Objective
To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk.
Methods
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.
Results
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).
Conclusions
Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.
doi:10.3233/JAD-122371
PMCID: PMC3807252  PMID: 23422357
Cognition; Aging; Caffeine; Cohort studies; Risk factors; Epidemiology
20.  Hypnotics and mortality in an elderly general population: a 12-year prospective study 
BMC Medicine  2013;11:212.
Background
Hypnotics are widely used by the elderly, and their impact on mortality remains controversial. The inconsistent findings could be due to methodological limitations, notably the lack of control for underlying sleep symptoms or illness associated with hypnotic use, for example, insomnia symptoms and excessive daytime sleepiness, depression and anxiety. Our objective was to examine the association between the use of hypnotics and mortality risk in a large cohort of community-dwelling elderly, taking into account a wide range of potential competing risks including sociodemographic characteristics, lifestyle, and chronic disorders as well as underlying psychiatric disorders and sleep complaints.
Methods
Analyses were carried out on 6,696 participants aged 65 years or older randomly recruited from three French cities and free of dementia at baseline. Adjusted Cox proportional hazards models with delayed entry, and age of the participants as the time scale, were used to determine the association between hypnotic use and 12-year survival.
Results
At baseline, 21.7% of the participants regularly used at least one hypnotic. During follow-up, 1,307 persons died, 480 from cancer and 344 from cardiovascular disease. Analyses adjusted for study center, age and gender showed a significantly greater risk of all-cause and cardiovascular-related mortality with hypnotics, particularly benzodiazepines, and this increased with the number of hypnotics used. None of these associations were significant in models adjusting for sociodemographic and lifestyle characteristics, chronic disorders including cardiovascular pathologies, sleep and psychiatric disorders. Results remained unchanged when duration of past hypnotic intake or persistent versus intermittent use during follow-up were taken into account.
Conclusions
When controlling for a large range of potential confounders, the risk of mortality was not significantly associated with hypnotic use regardless of the type and duration. Underlying psychiatric disorders appear to be the principal confounders of the observed association.
doi:10.1186/1741-7015-11-212
PMCID: PMC3849429  PMID: 24070457
Cohort studies; Elderly; Hypnotics; Mortality; Sleep disorders
21.  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.
doi:10.3233/JAD-2012-120064
PMCID: PMC3743740  PMID: 22451317
Fibrate; Statin; Cognitive aging; Alzheimer's disease; Elderly; Apolipoprotein E; Cholesteryl Exchange Transfer Protein; Prospective cohort.
22.  Retinal Vascular Caliber Is Associated with Cardiovascular Biomarkers of Oxidative Stress and Inflammation: The POLA Study 
PLoS ONE  2013;8(7):e71089.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0071089
PMCID: PMC3724806  PMID: 23923054
23.  Oestrogen receptor polymorphisms and late-life depression 
The British Journal of Psychiatry  2011;199(2):126-131.
Background
Evidence suggests a role for estrogen in depression but the involvement of estrogen receptor (ER) polymorphisms remains unknown.
Aims
To determine the association between ER polymorphisms and late-life depression and the modifying effect of hormone treatment (HT).
Method
Depression was assessed using the Mini-International Neuropsychiatric Interview, according to DSM-IV criteria and the Centre for Epidemiologic Studies-Depression Scale. The association between ER-α and ER-β polymorphisms with severe depression was examined in 6017 community-dwelling elderly using multivariate logistic regression.
Results
In women, the ER-α rs2234693 and rs9340799 polymorphisms were significantly associated with the risk of late-life depression. The A allele of ER-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.
Conclusions
ER polymorphisms are associated with severe late-life depression risk in women only.
doi:10.1192/bjp.bp.111.091751
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
24.  Beliefs and attitudes of French family practitioners toward depression: the impact of training in mental health 
Objective
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.
Methods
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.
Results
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.
Conclusion
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
25.  Patient-Reported Outcome Measures for Chronic Obstructive Pulmonary Disease 
The Patient  2013;6(1):11-21.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s40271-013-0004-5
PMCID: PMC3585908  PMID: 23417577

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