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Bien que leur efficacite n’ait pas souvent ete etudiee et de surcroit demontree, les traitements non medicamenteux font partie integrante de la prise en charge des personnes atteintes de demence neurodegenerative, en particulier de maladie d’Alzheimer. Une evaluation correcte et rigoureuse est pourtant essentielle pour: connaitre avec fiabilite les traitements non medicamenteux qui sont reellement efficaces, savoir comment les mettre en place, definir quels patients pourront en beneficier reellement et determiner, le cas echeant, quels effets indesirables ou inconvenients y sont associes. Si le schema d’etude classique de l’essai comparatif randomise reste la reference pour evaluer un traitement non medicamenteux, d’autres types d’etudes (avant- apres, ici-ailleurs, etudes d’observation) peuvent etre employes meme si leurs biais potentiels doivent etre scrupuleusement evalues. Les essais evaluant des traitements non medicamenteux ont des aspects methodologiques specifiques, comme la difficulte a respecter l’insu, ou encore la complexite dans le choix du comparateur et dans la standardisation de l’intervention. Il existe neanmoins des solutions pour faire face a ces difficultes et pour contribuer a ameliorer la qualite des essais. Enfin, un traitement non medicamenteux ne devrait pas etre mis en oeuvre sans disposer d’informations prealables sur son efficacite potentielle et ses eventuels effets indesirables.

OBJECTIVE To assess the 1-year risk of developing sustained hypertension in untreated elderly with white-coat hypertension (WCHT) or masked hypertension (MHT), and the 1-year risk of developing uncontrolled hypertension in treated elderly with office or home uncontrolled hypertension (OUHT or HUHT). METHODS We studied the 1-year risk of developing sustained or uncontrolled hypertension in a community-based cohort of 1481 individuals aged at least 73 years. The same BP device was used throughout the entire study. WCHT was defined as high blood pressure (BP) at office and normal home BP without antihypertensive intake, OUHT as high office BP and normal home BP with antihypertensive intake, MHT as high BP at home and normal office BP without antihypertensive intake, and HUHT as high home BP and normal office BP with antihypertensive intake. Sustained hypertension was defined as high office and home BP without antihypertensive intake and uncontrolled hypertension as high office and home BP with antihypertensive intake. RESULTS Sustained or uncontrolled hypertension at 1 year was diagnosed in 13% of participants with high office BP and in 26% of those with high home BP. Compared to participants with normal office and home BP, risk of sustained/uncontrolled hypertension was increased about three-fold in individuals with high office BP [OR = 2.9; 95% confidence interval (CI) = 1.5-5.5; P = 0.002] and about seven-fold in those with high home BP (OR = 6.8; 95% CI = 3.8-12.2; P < 0.0001). These risks were higher in individuals not treated by antihypertensive (OR(WCHT) = 4.3, P = 0.03; OR(MHT) = 16.8, P < 0.0001). CONCLUSION In this community-based study, elderly individuals with high office or home BP had an increased risk of hypertension 1 year later. This risk was higher among individuals not treated by antihypertensive and particularly in those with MHT. As these high-risk individuals would be otherwise undetected our results strongly support the large use of home blood pressure measurement in the elderly.

OBJECTIVE Home blood pressure (BP) monitoring is one of the tools recommended in hypertension management. However, its influence in older adults is seldom investigated. We aimed to assess whether regular home BP monitoring leads to a reduction of BP and an improvement in hypertension control in older adults. METHODS In a 24-month trial, individuals aged 73-97 years were randomized in a control (office and home BP measured at 0, 12, and 24 months) or an intervention (office measured at 0, 12, and 24 months; home BP measured every 3 months) group. The primary outcome was the difference in means office BP over 24 months in hypertensive patients. Secondary outcomes included differences in mean home BP over follow-up in hypertensive patients, and frequency of hypertension and of drug use at 24 months in the total sample. Intention-to-treat analyses comprised 1733 persons, among which 1043 were hypertensive. RESULTS Hypertensive patients in the intervention group experienced a significantly greater fall in office systolic BP (SBP) [mean between-group difference -2.1 mmHg, 95% confidence interval (CI) -4.1; -0.2, P = 0.03], home SBP (mean between-group difference -3.4, 95% CI -4.8; -2.1, P

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

Recent studies suggest dilated Virchow-Robin Spaces (dVRS) could be a manifestation of cerebral small-vessel disease, but little is known about their risk factors. As inflammation has been associated with other brain MRI findings, we investigated whether interleukin-6 and C-reactive protein were associated with the severity of dVRS in the eldery. dVRS were assessed in basal ganglia and white matter and rated on a severity scale. We found that elevated interleukin-6 levels were associated with higher severity of dVRS in basal ganglia, suggesting that inflammation might be associated with the burden of dVRS in the elderly.

Objective: Longitudinal studies of dementia rely on the assumption that individuals who drop out are comparable to those who remain in the study, adjusting for measured covariates. Existing methods to handle dropouts account for differences based on past health and cognitive measures. We assess whether such adjustments fully account for differences in future dementia risk. Methods: Among Three-City Study participants in Dijon, France, with 1 (n = 1,633) or 2 (n = 1,168) brain MRI scans, we tested whether white matter lesion volume (WMLV), hippocampal volume, or brain CSF volume predicted dropout (“unable to contact” or “refused interview”) in repeated-measures logistic regression with up to 4 follow-ups (average 3.5 waves). Using linear regression, we also estimated differences in MRI volumes and MRI changes by subsequent dropout status and estimated plausible ranges for selective attrition bias based on these associations. Models were adjusted for demographic, health, and cognitive score covariates. Results: Baseline greater WMLV predicted increased odds of dropping out (adjusted odds ratio = 1.71; 95% confidence interval [CI] 1.20−2.43). Among participants with 2 MRI scans, individuals who subsequently dropped out had significantly worse declines in hippocampal volume (−0.30 SD difference; 95% CI −0.43 to −0.17) between the first and second MRI scans. Conclusions: Higher future dementia risk, indicated by worse past brain MRI findings, predicted future study dropout. Adjustment for selective attrition, based on MRI markers when available, may help reduce bias in estimates of dementia incidence and improve research on dementia risk factors. MRI findings may also help prospectively identify cohort members at elevated risk of attrition.

Objective: The relation between inflammation and brain MRI findings in the elderly remains poorly known. We investigated the association of circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels with baseline and longitudinal white matter hyperintensities (WMH), silent brain infarction, and brain volumes in community-dwelling elderly free of dementia. Methods: We included 1,841 participants aged 65 to 80 years from the Three City-Dijon cohort. Participants followed an MRI examination at baseline and after a 4-year follow-up (n = 1,316). IL-6 and CRP concentrations were measured at baseline from fasting blood samples. WMH were detected with an automatic imaging processing method and gray matter, hippocampal, white matter, and CSF volumes were estimated with voxel-based morphometry. Silent brain infarctions were assessed visually and defined as focal lesions of ≥3 mm in the absence of stroke. We used analysis of covariance and logistic regression to model the associations between inflammatory biomarkers and brain MRI findings adjusting for potential confounders. Results: In cross-sectional analyses, higher IL-6 levels were associated with higher WMH volumes ( p p = 0.001) and hippocampal ( p = 0.01) volumes, and increasing CSF volumes ( p = 0.002) in a dose-relationship pattern. Similar but weaker relations were observed for CRP. We observed no associations between baseline inflammatory biomarker levels and the evolution of MRI findings over 4 years. Conclusions: IL-6, and, to a lesser degree, CRP levels were associated with WMH severity as well as global markers of brain atrophy. These results suggest that an inflammatory process may be involved in both age-associated brain alterations.

Objectives: We examined the relationship between self-rated health and incident dementia, and investigated the impact of cognitive complaints, depressive symptoms, and functional status on this relationship. Methods: Participants of the 3C Study, a prospective cohort study composed of 8,169 community-dwelling persons aged ≥65 years, were asked to rate their health at the baseline examination in 1999–2001. They were followed for a median of 6.7 years during which dementia was screened and diagnosed. Hazard ratios (HR) of dementia according to baseline self-rated health (good, fair, or poor) were estimated with a Cox model adjusted for potential confounders. Results: During the 46,990 person-years of follow-up, 618 participants developed dementia. Risk of dementia was increased in participants with poor (adjusted HR 1.70, 95% confidence interval [CI] 1.22–2.37) or fair (adjusted HR 1.34, 95% CI 1.13–1.59) self-rated health compared to those with good self-rated health. Poor self-rated health was associated with both AD (1.48, 1.00–2.24) and vascular dementia (3.38, 1.25–9.17). Self-rated health was a stronger predictor of dementia in participants without cognitive complaints (risk of dementia in subjects without cognitive complaints rating their health as poor: 1.96 [1.24–3.09], p = 0.004) and in those without functional disability. Conclusions: Participants rating their health as poor or fair at baseline were at increased risk of incident dementia during follow-up. Self-rated health could help raise awareness of medical doctors about a patient9s risk of dementia, especially in those without conditions indicative of potential cognitive impairment.

OBJECTIVE Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and the onset of depressive symptoms according to different age-groups in a large, general elderly population. RESEARCH DESIGN AND METHODS This was a prospective cohort study of 4,446 men and women aged 65–91 years who were free of depression or depressive symptoms at baseline (the Three-City Study, France). MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale score ≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups. RESULTS After adjusting for a large range of potential confounders, we observed MetS to be associated with 1.73-fold (95% CI 1.02–2.95) odds for new-onset depressive symptoms in the youngest age-group (65–70 years at baseline), independently of cardiovascular diseases. No such association was seen in older age-groups. CONCLUSIONS Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged people can be extended to older adults but not to the oldest ones. Additional research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65–70 years.

The clinical significance of dilated Virchow-Robin spaces (dVRS) remains unclear and their impact on cognitive performances has only been reported in small sample studies. Our aim was to assess the association between severity of dVRS and risk of incident dementia and cognitive decline in an elderly cohort. The degree of dVRS in both white matter and basal ganglia were ranked using high-resolution 3D MRI in a population-based sample of 1,778 non-demented participants from 65 to 80 years of age, who had a cerebral MRI at baseline. Cognitive function was assessed and dementia was diagnosed during a 4-year follow-up period. Cox proportional hazard models were used to examine the association between dVRS degree on a four-level severity score and incident dementia. The relat ionship between dVRS degree and change in cognition was examined using linear mixed effect models. During 6,135 person-years of follow-up, 27 individuals developed dementia. The highest degree of dVRS was associated with a strong increase in the risk of incident dementia independently of other standard risk factors of dementia, both for dVRS in white matter (HR = 9.8, 95% CI 1.7-55.3) and in basal ganglia (HR = 5.8, 95% CI 1.2-28.4). After further adjustment on white matter hyperintensity volume and brain infarcts, this association remained signific ant for dVRS in white matter. Higher rate of cognitive decline was found to be related to high degree of dVRS in basal ganglia but not in white matter. These results need confirmation but they suggest tha t assessment of the severity of dVRS may help identify groups of individuals that are at increased risk of dementia.

The authors evaluated the association of low-to-moderate alcohol consumption with risk of cognitive decline in a census-based cohort study of men and women aged ≥55 years conducted in Zaragoza, Spain (1994-1999). Participants free of dementia at baseline (N = 3,888) were examined after 2.5 and 4.5 years of follow-up. Information on alcohol intake was collected with the EURODEM Risk Factors Questionnaire and the History and Aetiology Schedule. The study endpoint was severe cognitive decline, defined as loss of ≥1 point/year on the Mini-Mental State Examination or a diagnosis of incident dementia (Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, Text Revision criteria). Compared with those for abstainers, the multivariate-adjusted odds ratios for severe cognitive decline for male drinkers of12 g alcohol/day, drinkers of 12-24 g alcohol/day, and former drinkers were 0.61 (95% confidence interval (CI): 0.31, 1.20), 1.19 (95% CI: 0.61, 2.32), and 1.03 (95% CI: 0.59, 1.82), respectively. The corresponding odds ratios for women were 0.88 (95% CI: 0.45, 1.72), 2.38 (95% CI: 0.98, 5.77), and 1.03 (95% CI: 0.48, 2.23). This study did not support the hypothesis that low-to-moderate alcohol consumption prevents cognitive decline. The inverse association between low-to-moderate alcohol intake and cognitive decline observed in other studies may have been due to inclusion of former drinkers in the abstainers reference category.

Introduction L’alteration des fonctions executives (FE) est un des signes les plus precoces de la maladie d’Alzheimer (MA). Son pattern anatomique precis demeure indetermine. Objectifs L’objectif etait d’etudier l’association entre l’epaisseur cortical (EC) et les FE dans la cohorte francaise Memento (participants ayant une plainte cognitive subjective (PCS) ou un trouble cognitif leger [TCL]). Methodes Les 1924 participants (femmes : 62,1 %) de MEMENTO (Dufouil et al., 2017) avec une evaluation initiale des FE (fluence verbale litterale [FVL] et semantique [FVS] et trail making test [TMT]) et de l’epaisseur corticale (IRM) composent l’echantillon analytique. Le MMSE moyen etait de 28,02 (± 1,6). Les scores standardises sur les facteurs demographiques ont ete calcules pour les FVL/S et la difference de temps de realisation entre parties B et A du TMT (TMTb-at). Des regressions lineaires pas a pas ont ete conduites. Resultats Le MMSE moyen etait de 28,02 (± 1,6). Une FVL faible etait associee a une diminution de la fraction cerebrale parenchymateuse (FCP), de l’EC de la region pars-orbitalis gauche (R2 = 0,017 ; p p p Discussion Le correlat anatomique des troubles dysexecutifs dans le TCL et la PCS etait l’atrophie cerebrale globale et les regions parsorbitalis gauche, l’isthme cingulaire droit et le precuneus droit. C’est la 1 re etude, a notre connaissance, qui determine dans une large cohorte de TCL et PCS, avec une methodologie standardisee, precisement les regions corticales liees aux FE. Conclusion L’atrophie de ces 3 regions rend compte des troubles dysexecutifs des TCL et PCS et ce pattern pourrait constituer un marqueur precoce de risque evolutif. Informations complementaires MEMENTO est sponsorisee par la Fondation Plan Alzheimer (Plan Alzheimer 2008–2012).

Introduction Le diabete de type 2 est un facteur de risque de demence. L’identification d’interactions avec d’autres caracteristiques pourrait permettre de cibler des sous-groupes a haut-risque. Objectifs Estimer si l’association entre diabete et demence est modifiee par d’autres facteurs de risque, en tenant compte des biais potentiels de selection (donnees et suivi manquants, risques competitifs de deces). Methodes Dans la cohorte des 3 cites (population generale ≥ 65 ans, francaise, vivant a domicile), des modeles de Cox ont permis d’estimer l’association entre diabete a l’inclusion et risque de demence jusqu’a 12 ans de suivi. L’analyse a ete stratifiee selon les facteurs de risque suivants : âge ≥ 70 ans, sexe feminin, bas niveau d’etudes, tabagisme actif, hypertension arterielle, hypercholesterolemie, obesite, allele E4 de l’ApoE et insuffisance renale, et les interactions ont ete testees. Resultats Parmi les 7834 participants inclus dans l’analyse (âge moyen : 74 ans, 61 % femmes, 10 % diabetiques), 863 cas de demence incidente ont ete diagnostiques : suivi median 9 ans. Les personnes diabetiques a l’inclusion avaient un risque superieur de demence (hazard ratio = 1,8, intervalle de confiance a 95 % : [1,51–2,25]). L’association diabete/demence n’etait modifiee par aucun des autres facteurs de risque, et etait robuste a la prise en compte des biais potentiels de selection. Discussion Dans une large cohorte francaise de personnes de plus de 65 ans, les diabetiques ont un risque de demence superieur de 80 % par rapport aux non-diabetiques. Ce risque n’est pas significativement modifie en presence ou non d’autres facteurs de risques de demence. Conclusion Un depistage systematique et precoce du diabete, associe a une prise en charge appropriee, pourrait retarder ou prevenir la survenue de demence.

Background and Purpose— White matter lesions (WMLs) have been shown to be associated with the risk of stroke in previous studies but little is known about the prediction of other vascular events. We evaluated the risk of stroke and other vascular events according to WML volume in a large population-based sample. We also studied WML volume by type (deep or periventricular) in relation to these events. Methods— The 3-City Study is a population-based prospective cohort of people aged ≥65 years followed up for, on average, 4.9 years. Among them, 1643 participants free of prevalent vascular events had quantitative measurements of WML volume at baseline using a fully automatic method. The risks of incident major vascular events according to WML volume were evaluated using Cox proportional hazards models. Results— The risk of incident stroke significantly increased with increasing baseline WML volume and was multiplied by 5 for those in the highest quartile of WML volume. Nonstroke vascular events’ incidence was not associated with WML volumes, whatever their type. Conclusions— WMLs are an independent predictor of stroke in the elderly. This association is specific because WMLs are not associated with the risk of other vascular events.

Background and Purpose— External validation of the Framingham stroke risk function has been rarely performed. We assessed its predictive ability in a population-based cohort of French elderly. Methods— The sample comprised 6913 subjects from the 3C Study, aged 65 to 84 at baseline, who were followed up to 6 years. Predictive accuracy of the original Framingham stroke risk function was assessed in a 3-step procedure: comparison between the Framingham and 3C cohorts of the prevalence of selected risk factors and the associated relative risks (RR) for stroke, comparison of the predicted to the observed number of stroke events (calibration), and ability to separate high-risk from low-risk participants (discrimination). We also compared predictive performances of the original Framingham, the recalibrated Framingham, and the local stroke risk functions. Results— During follow-up, 110 incident strokes occurred. For most risk factors, RRs were comparable between the 2 cohorts, except for age in women. The original Framingham stroke risk function applied to the 3C cohort overestimated the 6-year absolute risk for stroke by a factor of 3.7 for men and 4.4 for women. However, the recalibrated Framingham and 3C functions did not show any over- or underestimation of stroke risk. The 3 stroke risk functions (original, recalibrated, and 3C) provided acceptable discrimination with areas under the ROC curve ranging from 0.67 to 0.73. Conclusions— The original Framingham stroke risk function strongly overestimated the stroke risk for 3C participants. Derived Framingham stroke score sheets should not be directly used by physicians in the French elderly population.

We report on a method for the longitudinal follow-up of individual white matter hypersignals (WMH) and on its application to the study of WMH natural evolution in a cohort of 1,118 elderly over a 4-year period. For each subject, automated WMH detection was performed on T2-weighted MR images acquired both at baseline and at follow-up after registration in a common space. The detection algorithm was designed both to track WMH previously existing at baseline and to identify newly formed WMH. The average annual change in WMH load was found to be 0.25 cm3/year, 36% of this change being attributable to newly formed WMH. Quantitative analyses showed that change in WMH was mainly explained by progression of juxtaventricular and periventricular WMH while the load of WMH in the deep white matter zones was found stable over 4 years of the study. Statistical parametric mapping confirmed these spatial WMH change distributions in the juxta- and periventricular zones. High blood pressure was not a significant predictor of the annual change in WMH. This study proposes a new scheme for the longitudinal study of WMH change by dissociating worsening of existent WMH from surfacing of new WMH and may thus contribute to help understanding and characterizing the neurological and etiological bases of these two processes and their potential differences.

OBJECTIVE To examine the relationship between blood pressure and depression in a large sample of noninstitutionalized elderly people. METHODS Cross-sectional community-based study in 9294 participants aged 65 years and over, living at home, in three French cities (Bordeaux, Dijon and Montpellier). Participants were categorized as depressive, based on three different markers of depression. Multiple linear regression analyses of the relation between depression and mean systolic and diastolic blood pressure values were conducted, taking into account potential confounders like age, sex, education, smoking, alcohol consumption, body mass index and history of cardiovascular events. RESULTS Our working sample had a mean age (SD) of 73.7 (5.0) years, and included 60.7% of women. Overall, 31% of participants met the criteria for depression, 77.5% had hypertension, and 49.5% were on antihypertensive drugs. Analyses showed lower systolic and diastolic blood pressure values in depressive individuals compared with nondepressive ones, in both men (systolic blood pressure 148.2 versus 151.8 mmHg, P < 0.002; diastolic blood pressure 83.0 versus 84.7 mmHg, P = 0.003) and women (systolic blood pressure 141.7 versus 144.7 mmHg, P < 0.0001; diastolic blood pressure 80.7 versus 81.4 mmHg, P < 0.02). These associations were independent of age and of use of antihypertensive or psychotropic agents. CONCLUSION In a large sample of elderly individuals from the general population, depressive individuals had lower blood pressure values than nondepressive ones, independent of medications and of history of cardiovascular events.

Background: Hyperhomocysteinemia is associated with an increased risk of cognitive impairment in the elderly. Recent studies suggest that folate level may also influence the course of cognitive decline. Objective: We performed the cross-sectional analysis of the relationship between homocysteine and folate levels and cognitive performances in a population-based study including 3,914 subjects aged 65 years and older. Method: Subjects had an evaluation of their cognitive level using five neuropsychological tests. A Cognitive Summary Score was computed as the sum of each of the 5 cognitive tests score standardized. Relations of folate and homocysteine levels with cognition were first studied separately in a covariance analysis. Stratified analyses were also performed because of interaction between folate and homocysteine in relation to cognition. Results: Subjects in the higher quartile of homocysteine (high homocysteine group) and subjects in the lower quartile of folate (low folate group) had consistently lower cognitive performances in all tests. When stratified on folate level, high homocysteinemia was associated with lower cognitive performances only in subjects with a low folate level. Conclusion: In this large population-based sample of elderly people, the association between high homocysteinemia and decreased cognition was only seen in participants with low folate levels.

Backround Baseline depressive symptoms have been consistently associated with the onset of cardiovascular disease (CVD). Objectives Since depressive symptoms vary over time in elderly persons, and to help clarify whether or not depression is an etiological factor for CVD, we quantified the association between the course of depressive symptoms and occurrence of first coronary heart disease (CHD) and stroke events in older adults. Design A population-based prospective observational study. Setting Participants were randomly selected from the electoral rolls of three large French cities. Participants A total of 9,294 participants were examined at baseline between 1999 and 2001, and thereafter at repeated study visits over 10 years. Measurements High levels of depressive symptoms (HLDS) were defined as a score ≥16 on the 20-item Center for Epidemiologic Studies Depression Scale. The number of study visits with HLDS was used as a time dependent variable in Cox proportional hazard models. Results There were 7,313 participants (36.6% males) aged 73.8 ± 5.4 years with no history of CHD, stroke or dementia at baseline. After a median follow-up of 8.4 years (SD 2.3 years), 629 first CHD or stroke events occurred. After adjustment for sociodemographic characteristics and vascular risk factors, the risk of CHD and stroke combined increased 1.15-fold (95% CI: 1.06 to 1.25) per each additional study visit with HLDS. The results remained unchanged when accounting for the presence of disability and antidepressant intake at baseline and during follow-up. Conclusion Elderly persons exposed to HLDS at several occasions over 10 years showed substantial increased risk of coronary heart disease and stroke events.

Introduction/purpose In vivo detection of cerebral microbleeds (CMBs) from T2* gradient recalled echo (GRE) magnitude image suffers from low specificity, modest inter-rater reproducibility and is biased by its sensitivity to acquisition parameters. New methods were proposed for improving this identification, but they mostly rely on 3D acquisitions, not always feasible in clinical practice. A fast 2D phase processing technique for computing internal field maps (IFM) has been shown to make it possible to characterize CMBs through their magnetic signature in routine clinical setting, based on 2D multi-slice acquisitions. However, its clinical interest for CMBs identification with respect to more common images remained to be assessed. To do so, systematic experiments were undertaken to compare the ratings obtained by trained observers with several image types, T2* magnitude, Susceptibility Weighted Imaging reconstructions (SWI) and IFM built from the same T2*-weighted acquisition. Materials/methods 15 participants from the MEMENTO multi-center cohort were selected: six subjects with numerous CMBs (20 ± 6 CMBs), five subjects with a few CMBs (2 ± 1 CMBs) and four subjects without CMB. 2D multi-slice T2* GRE sequences were acquired on Philips and Siemens 3T systems. After pilot experiments, T2* magnitude, Susceptibility Weighted Imaging (SWI) minimum intensity projection (mIP) on three slices and IFM were considered for the rating experiments. A graphical user interface (GUI) was designed in order to consistently display images in random order. Six raters of various background and expertise independently selected “definite” or “possible” CMBs. Rating results were compared with respect to a specific consensus reference, on both lesion and subject type points of view. Results IFM yielded increased sensitivity and decreased false positives rate (FPR) for CMBs identification compared to T2* magnitude and SWI-mIP images. Inter-rater variability was decreased with IFM when identifying subjects with numerous lesions, with only a limited increase in rating time. IFM thus appears as an interesting candidate to improve CMBs identification in clinical setting., Highlights • We introduce an evaluation of phase-contrast for CMBs detection in clinical setting. • Comparison included T2* magnitude, SWI-mIP and IFM images using a specific GUI. • Rating results showed an improved sensitivity of IFM compared to T2*and SWI-mIP. • A decreased false positive rate with IFM with respect to T2*and SWI-mIP was proved. • We demonstrate a decreased inter-rater variability with IFM.

International audience; Objective: Low socioeconomic position (SEP) has been linked to an increased risk of dementia and cognitive decline. However, little is known about the association between SEP and morphologic brain changes in older age. This study examines the relationships between indicators of life-course SEP with both hippocampal volume (HcV) and HcV loss in a population-based cohort of 1328 older adults aged 65 to 80 years.Methods: Multivariable linear regression models were used to estimate the associations of SEP with baseline HcV and the annual rate of HcV atrophy according to three life-course conceptual models: the sensitive/critical periods model (which explored SEP in specific periods: in childhood [using parental education], early adulthood [based on participants' education], and midlife [based on participants' socioprofessional group]); the accumulation-of-risk model (life-course cumulative SEP), and the social mobility model (life-course SEP trajectories).Results: Participants with lower midlife SEP had smaller HcV (-0.08 cm3; 95% confidence interval, -0.15 to -0.01) and 0.17% (95% confidence interval, 0.04%-0.30%) faster hippocampal atrophy than participants with higher midlife SEP. Childhood and early adulthood SEPs were not related to hippocampal measures. The accumulation-of-risk and the social mobility models revealed that the accumulation of socioeconomic disadvantage and declining socioeconomic trajectories were related to faster hippocampal atrophy.Conclusions: In this cohort of older adults, lower socioprofessional attainment in midlife and disadvantageous life-course socioeconomic position were associated with faster hippocampal atrophy, a cerebral change linked to cognitive disorders. Results support the hypothesized links between socioenvironmental exposures related to stress and/or cognitive enrichment and brain/cognitive reserve capacities.

Background Education, a marker for cognitive reserve, is thought to be associated with low risks of dementia, but less is known about its association with cognitive decline in preclinical stages of dementia. This study aimed to see whether higher education level could have a protective effect against faster cognitive decline in preclinical stages of dementia and whether this protection is consistent across six different studies around the world. Methods We assessed the association between education and change in mini-mental state examination (MMSE) in people who developed dementia during the study period before the time of dementia diagnosis in six international studies of ageing: Newcastle 85+, UK; Three-City (3C), France; Leiden 85+ and Longitudinal Aging Study Amsterdam (LASA), the Netherlands; Octogenarian Twins (OCTO-Twin), Sweden; and Memory and Ageing Study (MAS), Australia. Using a coordinated analysis approach, we used multilevel models to investigate the role of education in the change in MMSE independently within each cohort, while controlling for common covariates such as age at baseline, sex, and time to dementia diagnosis from study entry within each cohort. Each individual's cognitive scores were aligned according to distance (years) to dementia diagnosis. Findings High levels of education (>12 years) were associated with steeper linear rates of decline in MMSE scores from study entry to time of dementia diagnosis in most cohorts—3C, Leiden 85+, LASA, OCTO-Twin, and MAS. However, in one cohort (Newcastle 85+), higher education was associated with a slow rate of decline in the preclinical stages of dementia (β=0·93, 95% CI 0·09–1·77) compared with lower education, suggesting perhaps a difference in the educational system between the UK and the rest of Europe or Australia during the early 1990s. A random-effects meta-analysis across data from all six studies showed a non-significant steeper cognitive decline with time for those with higher education (β=–0·08, 95% CI –0·17 to 0·003; see appendix for forest plot). Interpretation This coordinated approach analysis revealed no consistent protection for people with higher education in terms of lowering the rate of cognitive decline in the preclinical stages of dementia, which is a major public health burden. This work only partly supports the cognitive reserve hypothesis—ie, the clinical manifestation of dementia is delayed in people with higher education but that a steeper decline occurs once a certain threshold has been reached. Funding The funding sources of this work were the Alzheimer's Society (grant number 144) and the Medical Research Council (unit programme number MC_UU_12019/1).

Background and Purpose— White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods— Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results— A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance ( P −8 ). Four loci were suggestive ( P −5 ) of an association with WML progression: 10q24.32 (rs10883817, P =1.46×10 −6 ); 12q13.13 (rs4761974, P =8.71×10 −7 ); 20p12.1 (rs6135309, P =3.69×10 −6 ); and 4p15.31 (rs7664442, P =2.26×10 −6 ). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions— Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Background: Slow gait is common in dementia, but it remains unknown whether the slowing happens many years prior to dementia onset. We therefore examined the relationship between slow baseline gait speed (GS), change in GS, and the hazard of incident dementia in a community dwelling of elderly people. Methods: A total of 3,663 participants dementia-free at baseline (mean age, 73.5 years) were followed up for 9 years from a prospective cohort (Three-City study, France) for incident dementia (all-cause, Alzheimer's disease, vascular dementia, and other causes). GS over 6 m was assessed 4 times over the follow-up using two photoelectric cells. We used a multistate model to estimate the hazard ratio (HR) of dementia for baseline GS and tested a washout period of 4 to 7 years. The role of GS change between 65 and 85 years was examined using linear mixed models and joint models for survival and longitudinal data. Results: A total of 296 participants developed dementia during the follow-up. In age/sex-adjusted models, 1-SD (0.204 m/s) lower GS was associated with an increased hazard of dementia (HR = 1.59, 95% confidence interval [CI] = 1.39, 1.81, p < .001), with associations evident when gait assessments were taken from 4 years (HR = 1.46; CI = 1.26, 1.68) and 7 years (HR=1.30; CI = 1.00, 1.70) prior to dementia onset. Independently of baseline GS, those with a steeper decline had a higher hazard of dementia (HR per 1 SD [0.007 m/s/year] decrease = 3.39 [1.37-8.43], p = .009). Conclusions: Gait is slower up to 7 years prior to clinical onset of dementia. Decline in GS is also more accelerated, suggesting strong links between cognitive and motor function in older adults.

International audience; Cerebral β-amyloid (Aβ) deposition and atrophy are central features of Alzheimer disease. Studies of Alzheimer disease biomarkers have largely focused on Aβ in cerebrospinal fluid (CSF), and there is uncertainty as to what plasma Aβ may be a marker. We examined the association of Aβ levels in the plasma with magnetic resonance imaging (MRI)-markers of brain aging, including longitudinal changes in global and regional brain volumes, in dementia-free persons. We studied 1530 participants of the Three-City-Dijon cohort, aged 65-80 years. Plasma Aβ measurement and magnetic resonance imaging were performed at baseline and after a 4-year follow up. Total brain, gray matter, and hippocampal volume were estimated using voxel-based morphometry, and annualized change in brain volumes was calculated. Increased plasma Aβ1-40 was associated with lower baseline hippocampal volume. Although baseline plasma Aβ levels were not associated with longitudinal change in brain volumes, consistently high plasma Aβ1-40 levels were associated with faster total brain atrophy and consistently low plasma Aβ1-42/Aβ1-40 ratio, with increased total brain atrophy and gray matter atrophy. In dementia-free older adults, high plasma Aβ1-40 and low plasma Aβ1-42/Aβ1-40 ratio were associated with smaller hippocampal volume and accelerated global and regional brain atrophy respectively.

International audience; INTRODUCTION:The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD).METHODS:A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method.RESULTS:Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups.DISCUSSION:A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

BackgroundSeveral studies have reported smaller hippocampal volume (HcV) in depression patients; however, the temporality of the association remains unknown. One proposed hypothesis is that depression may cause HcV loss. This study evaluates whether previous depression and recent depressive symptoms are associated with HcV and HcV loss.MethodWe used a prospective cohort of older adults (n= 1328; age = 65–80 years) with two cerebral magnetic resonance imaging examinations at baseline and 4-year follow-up. Using multivariable linear regression models, we estimated, in stratified analyses by gender, the association between indicators of history of depression and its severity (age at onset, recurrence, hospitalization for depression), proximal depressive symptoms [Center for Epidemiologic Studies-Depression (CES-D) scale], baseline antidepressant use, and the outcomes: baseline HcV and annual percentage change in HcV.ResultsAt baseline, women with more depressive symptoms had smaller HcV [−0.05 cm3, 95% confidence interval (CI) −0.1 to −0.01 cm3per 10-unit increase in CES-D scores]. History of depression was associated with a 0.2% faster annual HcV loss in women (95% CI 0.01–0.36%). More baseline depressive symptoms and worsening of these symptoms were also associated with accelerated HcV loss in women. No associations were observed in men. Treatment for depression was associated with slower HcV loss in women and men.ConclusionsWhile only concomitant depressive symptoms were associated with HcV, both previous depression and more proximal depressive symptoms were associated with faster HcV loss in women.

To determine whether the addition of data derived from magnetic resonance imaging (MRI) of the brain to a model incorporating conventional risk variables improves prediction of dementia over 10 years of follow-up.Population based cohort study of individuals aged ≥ 65.The Dijon magnetic resonance imaging study cohort from the Three-City Study, France.1721 people without dementia who underwent an MRI scan at baseline and with known dementia status over 10 years' follow-up.Incident dementia (all cause and Alzheimer's disease).During 10 years of follow-up, there were 119 confirmed cases of dementia, 84 of which were Alzheimer's disease. The conventional risk model incorporated age, sex, education, cognition, physical function, lifestyle (smoking, alcohol use), health (cardiovascular disease, diabetes, systolic blood pressure), and the apolipoprotein genotype (C statistic for discrimination performance was 0.77, 95% confidence interval 0.71 to 0.82). No significant differences were observed in the discrimination performance of the conventional risk model compared with models incorporating data from MRI including white matter lesion volume (C statistic 0.77, 95% confidence interval 0.72 to 0.82; P=0.48 for difference of C statistics), brain volume (0.77, 0.72 to 0.82; P=0.60), hippocampal volume (0.79, 0.74 to 0.84; P=0.07), or all three variables combined (0.79, 0.75 to 0.84; P=0.05). Inclusion of hippocampal volume or all three MRI variables combined in the conventional model did, however, lead to significant improvement in reclassification measured by using the integrated discrimination improvement index (P=0.03 and P=0.04) and showed increased net benefit in decision curve analysis. Similar results were observed when the outcome was restricted to Alzheimer's disease.Data from MRI do not significantly improve discrimination performance in prediction of all cause dementia beyond a model incorporating demographic, cognitive, health, lifestyle, physical function, and genetic data. There were, however, statistical improvements in reclassification, prognostic separation, and some evidence of clinical utility.

International audience; Several genetic polymorphisms have been associated with Late Onset Alzheimer’s Disease (LOAD), but there has been limited evidence on whether these polymorphisms predict intermediary stage outcomes such as cognitive changes in prospective community-based studies. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also predict worse cognitive function and accelerated decline across multiple cognitive domains. We analyzed data from the 3C-Dijon study, in which 4931 respondents aged 65+ were examined up to 5 times over 10 years with a neuropsychological assessment. We evaluated the associations of polymorphisms in APOE, CR1, BIN1, CLU, PICALM, ABCA7, MS4A6A, CD33, MS4A4E and CD2AP with level and change in 5 neuropsychological tests, assuming a dominant effect model. To optimize measurement, we used a mixed regression model with a latent process for each cognitive domain: global cognition (Mini Mental State Examination); verbal fluency (Isaac’s Set Test); visual memory (Benton Visual Retention Test); information processing (Trail Making Test B) and literacy (National Adult Reading Test). APOE was associated with accelerated decline in global cognition and verbal fluency. Only two non-APOE genetic polymorphisms were associated with cognitive decline: CR1 was associated with rate of change in verbal fluency and BIN1 was associated with rate of change in global cognition. In a large prospective population-based study of dementia-free individuals, only a few cognitive domains were associated with established LOAD risk alleles. The most consistent associations were for global cognition and verbal fluency.

Background— The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results— We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 ( P =2.7×10 −19 ) and identified novel loci on chr10q24 ( P =1.6×10 −9 ) and chr2p21 ( P =4.4×10 −8 ). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 ( P =2.0×10 −8 ) and chr2p16 ( P =1.5×10 −8 ). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions— We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

White matter lesions (WML) on MRI of the brain are common in both demented and nondemented older persons. They may be due to ischemic events and are associated with cognitive and physical impairments. It is not known whether the prevalence of these WML in the general population differs across European countries in a pattern similar to that seen for coronary heart disease. Here we report the prevalence of WML in 1,805 men and women drawn from population-based samples of 65- to 75-year-olds in ten European cohorts. Data were collected using standardized methods as a part of the multicenter study CASCADE (Cardiovascular Determinants of Dementia). Centers were grouped by region: south (Italy, Spain, France), north (Netherlands, UK, Sweden), and central (Austria, Germany, Poland). In this 10-year age stratum, 92% of the sample had some lesions, and the prevalence increased with age. The prevalence of WML was highest in the southern region, even after adjusting for differences in demographic and selected cardiovascular risk factors. Brain aging leading to disabilities will increase in the future. As a means of hypothesis generation and for health planning, further research on the geographic distribution of WML may lead to the identification of new risk factors for these lesions.

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4 ± 3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

Objectives: To describe the prevalence of and characteristics associated with major and minor depression in older medical inpatients and to compare associated characteristics by sex and history of depression. Design: Cross-sectional study of two patient samples, with and without a screening diagnosis of major or minor depression. Setting: The medical services of two acute care hospitals. Participants: Medical admissions of people aged 65 and older with at most mild cognitive impairment (N=380). Measurements: Diagnoses of major and minor depression (Diagnostic Interview Schedule), cognitive impairment (Mini-Mental State Examination), premorbid disability, sociodemographic variables (including social networks and support), comorbidity, severity of illness, history of depression. Results: The prevalence of major depression differed by hospital, ranging from 14.2% (95% confidence interval (CI)=11.7–17.1) in Hospital A to 44.5% (95% CI=33.1–56.4) in Hospital B. The prevalence of minor depression was similar in the two hospitals, ranging from 9.4% (95% CI=7.4–11.9) in Hospital A to 7.9% (95% CI=2.9–16.3) in Hospital B. After adjustment for hospital, the same characteristics (history of depression, premorbid disability, cognitive impairment, perceived adequacy of support, and visits from friends) were associated with major and minor depression, although most of these associations tended to be weaker for minor depression. Most of these factors were also associated with depression in multivariate analyses. The most important characteristics in women were premorbid disability, history of depression, and adequacy of emotional support; in men they were history of depression, cognitive impairment, and adequacy of emotional support. A cerebrovascular or other cardiovascular diagnosis did not explain the association between depression and cognitive impairment. Conclusion: Major and minor depression occur frequently in older medical inpatients and are associated with similar patient characteristics. A history of depression and the patient's sex should be considered in the identification and interpretation of these associated factors.

OBJECTIVES: To explore whether more cognitive complaints are associated with previous or future cognitive decline. DESIGN: Longitudinal; epidemiology vascular aging study. SETTING: Community in Nantes, France. PARTICIPANTS: Seven hundred thirty-three subjects, aged 59 to 71. MEASUREMENTS: Subjective cognitive complaints were recorded at 4-year follow-up examination in a prospective study of people aged 59 to 71 at study entry. Participants' cognitive performances were assessed repeatedly at each wave (baseline, 4 years, and 6 years) of the study using a series of neuropsychological tests including the Mini-Mental State Examination. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale. Subjects also had a cerebral magnetic resonance imaging scan at 4-year follow-up to evaluate presence and severity of white matter hyperintensities (WMHs). RESULTS: Subjects with more cognitive complaints had greater cognitive decline. This significant relationship persisted after adjusting for potential confounders, including depressive symptoms. Multivariate analysis also showed that, in subjects without measured cognitive decline between study entry and 4-year follow-up, those with more cognitive complaints at 4-year follow-up had significantly greater measured cognitive decline during the subsequent 2 years. In the presence of severe WMH, more cognitive complaints were an even stronger predictor of future cognitive decline. CONCLUSION: Cognitive complaints reflect measured cognitive decline, but they also predict cognitive decline at an earlier stage than objective tests that are not able to detect cognitive deficits. They need to be taken into account in clinical practice.

This paper presents the cognitive test battery used in the Cascade Study (Cardiovascular Determinants of Dementia) for examining the consequences of cerebral white matter lesions and atrophy. The test battery includes nine different tasks assessing memory, executive function, and global cognitive function. Three episodic memory tasks were used in combinations to assess the role of attention and speed on encoding. Estimates of short- and long-term memory capacity were also derived from these three memory tasks. Semantic memory production / frontal lobe functions were assessed by means of a word fluency test. The Letter Digit Substitution test and the Stroop test were used to assess speed of processing and attention. Motor speed was measured with the Purdue Pegboard test, and global cognitive function was assessed by the Mini Mental State Examination. Overall performance data for the whole Cascade sample and for each of eight study centers are presented for each test. Possible reasons for performan...

Diabetic patients are at increased risk for stroke, but little is known about the presence of other brain lesions. We studied the association of magnetic resonance imaging–detected brain lesions to diabetes in 1,252 individuals aged 65–75 years who were randomly selected from eight European population registries or defined working populations. All scans were centrally read for brain abnormalities, including infarcts, white matter lesions, and atrophy. We used a three-point scale to rate periventricular white matter lesions, and the volume of subcortical lesions was calculated according to their number and size. Subjective grading of cortical atrophy by lobe and summation of the lobar grades resulted in a total cortical atrophy score. The mean of three linear measurements of the ventricular diameter relative to the intracranial cavity defined the severity of subcortical atrophy. After adjustment for possible confounders, diabetes was associated with cortical brain atrophy but not with any focal brain lesions or subcortical atrophy. There was a strong interaction of diabetes and hypertension, such that the association between diabetes and cortical atrophy existed only in hypertensive but not in normotensive participants. Cognitive and pathological data are needed to determine the clinical significance of these findings as well as to understand the mechanisms underlying these associations.

Resume On dispose aujourd’hui de donnees scientifiques solides indiquant que l’hypertension arterielle et a un moindre degre d’autres facteurs de risque vasculaire pourraient etre la cible d’interventions visant a diminuer l’incidence de la demence. Deux essais ont demontre l’effet des antihypertenseurs sur le risque de demence, maladie d’Alzheimer pour l’un et demence post accident vasculaire cerebral pour l’autre. Par ailleurs, plusieurs grandes etudes epidemiologiques ont mis en evidence une association entre facteurs vasculaires et demence. Ces resultats permettent d’envisager des strategies de prevention de la demence. Il reste, par des etudes epidemiologiques appropriees, a estimer quel impact pourraient avoir ces interventions sur l’incidence et la prevalence de la demence. Si l’impact espere est important, les etudes permettant de demontrer l’efficacite de la prevention de la demence devraient etre mises en place.

Background Accurate identification of individuals at high risk of dementia influences clinical care, inclusion criteria for clinical trials and development of preventative strategies. Numerous models have been developed for predicting dementia. To evaluate these models we undertook a systematic review in 2010 and updated this in 2014 due to the increase in research published in this area. Here we include a critique of the variables selected for inclusion and an assessment of model prognostic performance. Methods Our previous systematic review was updated with a search from January 2009 to March 2014 in electronic databases (MEDLINE, Embase, Scopus, Web of Science). Articles examining risk of dementia in non-demented individuals and including measures of sensitivity, specificity or the area under the curve (AUC) or c-statistic were included. Findings In total, 1,234 articles were identified from the search; 21 articles met inclusion criteria. New developments in dementia risk prediction include the testing of non-APOE genes, use of non-traditional dementia risk factors, incorporation of diet, physical function and ethnicity, and model development in specific subgroups of the population including individuals with diabetes and those with different educational levels. Four models have been externally validated. Three studies considered time or cost implications of computing the model. Interpretation There is no one model that is recommended for dementia risk prediction in population-based settings. Further, it is unlikely that one model will fit all. Consideration of the optimal features of new models should focus on methodology (setting/sample, model development and testing in a replication cohort) and the acceptability and cost of attaining the risk variables included in the prediction score. Further work is required to validate existing models or develop new ones in different populations as well as determine the ethical implications of dementia risk prediction, before applying the particular models in population or clinical settings.

We investigated the relationship of diabetes and prediabetes with cognitive performances, assessed through raw test and z scores and according to neurocognitive impairment (NCI) classification in a cohort of individuals infected with HIV.The ANRS CO3 Aquitaine cohort is a prospective hospital-based cohort of HIV-1-infected patients under routine clinical management in 6 public hospitals in southwestern France. Between 2007 and 2009, an ancillary study consisted of a neuropsychological battery of 10 tests at baseline and 2-year follow-up. The severity of NCI (normal, asymptomatic, mild, HIV dementia) was assessed according to international guidelines.At baseline (400 patients, 33 with prediabetes, 39 with diabetes), in cross-sectional multivariable analyses, patients with diabetes performed significantly worse on 9 neuropsychological tests that assessed memory, executive functions, attention, psychomotor speed, language, and manual dexterity. Participants with prediabetes had worse performances compared with those who had normal glycemia in 5 tests. The longitudinal analysis of the association between glycemia status at baseline and change in cognitive performances over 2-year follow-up (n = 283) suggested that patients with diabetes also showed a slightly higher decline on 5 of the 10 tests, those involving executive functions and memory functioning. Glycemia status at baseline was not significantly associated with NCI severity in cross-sectional (p = 0.44) and longitudinal (p = 0.64) analyses.In this hospital-based cohort of people living with HIV, diabetes, but not the other cardiovascular risk factors, is associated with worse cognitive performances in several cognitive domains and with larger decline in fewer domains over the short term.

Hyperhomocysteinemia is associated with an increased risk of vascular disease, and recent results suggest that it also could increase the risk of dementia. We examined the relationship between homocysteine and cognitive decline in 1,241 subjects aged 61 to 73 years, followed up over 4 years. Plasma homocysteine levels were determined in all participants as well as cardiovascular risk factors, apolipoprotein E genotype, plasma levels of folate, and vitamin B12. Cognitive performances were assessed repeatedly by using Mini-Mental State Examination, Trail Making Test, Digit Symbol Substitution Test, and Finger Tapping Test. At 2-year follow-up, 841 subjects underwent cerebral magnetic resonance imaging, and white matter hyperintensities were rated visually. Analyses were adjusted for all cardiovascular risk factors. Cross-sectional analyses showed that higher concentrations of homocysteine were significantly related to poorer performances at all neuropsychological tests. Longitudinal analyses confirmed this finding. The odds of cognitive decline was 2.8-fold (p < 0.05) higher in subjects with homocysteine levels above 15 micromol/L compared with those with homocysteine levels below 10 micromol/L. In participants who underwent magnetic resonance imaging, the relationship between homocysteine and cognition was unchanged after taking into account white matter hyperintensities suggesting that white matter hyperintensities do not mediate the association between homocysteine and cognition.

Objective To evaluate the association between white matter lesion (WML) volume, silent infarcts and restless legs syndrome (RLS) in a population-based study of elderly individuals. Design Cross-sectional study. Setting Population-based Three-City study. Participants 1035 individuals from the Dijon, France, centre of the Three-City study who had available information on volume of WMLs from MRIs and who answered questions about the prevalence of RLS. Primary outcome measure Prevalence of RLS. Results WML volume was measured using an automated tissue segmentation method. Logistic regression was used to evaluate adjusted associations between tertiles of WML volume and RLS and between silent infarcts and RLS. 218 individuals (21.1%) were determined to have RLS. Compared with those in the first tertile of WML volume, individuals in the second tertile (OR=1.09; 95% CI 0.75 to 1.60) or third tertile (OR=1.17; 95% CI 0.79 to 1.74) did not have an increased prevalence of RLS. We also did not observe associations between the volume of deep or periventricular WML and RLS; nor did we observe an association between silent brain infarcts and RLS (OR=0.74; 95% CI 0.40 to 1.39). These findings were not modified by age or gender. Conclusions Higher volume of WML and the presence of silent infarcts were not associated with an increased prevalence of RLS in this population-based cohort of elderly individuals.