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Background: To use neuropsychological assessments for studying the underlying disease processes contributing to dementia, it is crucial that they correspond to magnetic resonance imaging (MRI)-based measures of dementia, regardless of educational level., Methods: French 3-City Dijon MRI study cohort members (n=1782) with assessments of white matter lesion volume (WMLV), hippocampal volume (HCV), and cerebrospinal fluid volume (CSFV), and 6 waves of neuropsychological assessments over 11 years, including Mini-Mental State Examination (MMSE), plus 5 other tests combined using a Z-score or item-response theory (IRT-cognition) comprised the study cohort. We evaluated, testing interactions, whether education modified associations of MRI markers with intercept or rate of change of MMSE, Z-score composite, or IRT-cognition., Results: In linear models, education modified the associations of WMLV and CSFV with MMSE and CSFV and Z-score composite. In mixed models, education modified the associations of WMLV and CSFV with level of MMSE and the association of HCV with slope of MMSE. Education also modified the association with CSFV and slope of Z-score composite decline. There was no evidence that education modified associations between MRI measures and level or slope of IRT-cognition., Conclusions: Longitudinal analysis of correctly scaled neuropsychological assessments may provide unbiased proxies for MRI-based measures of dementia risk.

Improvements in cognitive test scores upon repeated assessment due to practice effects (PEs) are well documented, but there is no empirical evidence on whether alternative specifications of PEs result in different estimated associations between exposure and rate of cognitive change. If alternative PE specifications produce different estimates of association between an exposure and rate of cognitive change, this would be a challenge for nearly all longitudinal research on determinants of cognitive aging. Using data from 3 cohort studies-the Three-City Study-Dijon (Dijon, France, 1999-2010), the Normative Aging Study (Greater Boston, Massachusetts, 1993-2007), and the Washington Heights-Inwood Community Aging Project (New York, New York, 1999-2012)-for 2 exposures (diabetes and depression) and 3 cognitive outcomes, we compared results from longitudinal models using alternative PE specifications: no PEs; use of an indicator for the first cognitive visit; number of prior testing occasions; and square root of the number of prior testing occasions. Alternative specifications led to large differences in the estimated rates of cognitive change but minimal differences in estimated associations of exposure with cognitive level or change. Based on model fit, using an indicator for the first visit was often (but not always) the preferred model. PE specification can lead to substantial differences in estimated rates of cognitive change, but in these diverse examples and study samples it did not substantively affect estimated associations of risk factors with change., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Restless legs syndrome has been speculated to be linked to cognitive impairment through vascular risk factors or through its effect on sleep deprivation. Previous studies on the association between restless legs syndrome and cognitive function have been inconclusive. We performed a cross-sectional analysis of the association between restless legs syndrome and cognitive function using data from a large population-based study of elderly individuals residing in France., Methods: We used information from 2070 individuals from the Dijon, France center of the Three-City study who had available information on restless legs syndrome and cognitive functioning measures. Restless legs syndrome was assessed using the 4 minimal diagnostic criteria of the International Restless Legs Study Group. During the same wave in which restless legs syndrome status was assessed, cognitive functions also were assessed using 4 tests: Isaacs' test of verbal/category fluency, the Benton Visual Retention Test, the Trail Making Test B, and the Mini-Mental State Examination. We created a summary global cognitive score by summing the z scores for the 4 tests and used analysis of covariance to explore the association between restless legs syndrome and cognitive function., Results: We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. The mean global z-score after multivariate adjustment was -0.003 (SE 0.173) for those with restless legs syndrome and -0.007 (SE 0.129) for those without restless legs syndrome (P-value = .98)., Conclusion: Data from this large, population-based study do not suggest that restless legs syndrome is associated with prevalent cognitive deficits in elderly individuals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

To test the hypothesis that age at retirement is associated with dementia risk among self-employed workers in France, we linked health and pension databases of self-employed workers and we extracted data of those who were still alive and retired as of December 31st 2010. Dementia cases were detected in the database either through the declaration of a long-term chronic disease coded as Alzheimer's disease and other dementia (International Classification of Disease codes G30, F00, F01, F03) or through the claim for reimbursement of one of the anti-dementia drugs. Data were analyzed using Cox proportional hazard model adjusting for potential confounders. Among the 429,803 retired self-employed workers alive on December 31st 2010, prevalence of dementia was 2.65 %. Multivariable analyses showed that the hazard ratio of dementia was 0.968 [95 % confidence interval = (0.962-0.973)] per each extra year of age at retirement. After excluding workers who had dementia diagnosed within the 5 years following retirement, the results remained unchanged and highly significant (p < 0.0001). We show strong evidence of a significant decrease in the risk of developing dementia associated with older age at retirement, in line with the "use it or lose it" hypothesis. Further evidence is necessary to evaluate whether this association is causal, but our results indicate the potential importance of maintaining high levels of cognitive and social stimulation throughout work and retiree life.

Background: The Mini-Mental State Examination (MMSE) is widely used in population-based longitudinal studies to quantify cognitive change. However, its poor metrological properties, mainly ceiling/floor effects and varying sensitivity to change, have largely restricted its usefulness. We propose a normalizing transformation that corrects these properties, and makes possible the use of standard statistical methods to analyze change in MMSE scores., Methods: The normalizing transformation designed to correct at best the metrological properties of MMSE was estimated and validated on two population-based studies (n = 4,889, 20-year follow-up) by cross-validation. The transformation was also validated on two external studies with heterogeneous samples mixing normal and pathological aging, and samples including only demented subjects., Results: The normalizing transformation provided correct inference in contrast with models analyzing the change in crude MMSE that most often lead to biased estimates of risk factors and incorrect conclusions., Conclusions: Cognitive change can be easily and properly assessed with the normalized MMSE using standard statistical methods such as linear (mixed) models., (© 2014 S. Karger AG, Basel.)

The authors examined the associations of participants' and their parents' educational levels with cognitive decline while addressing methodological limitations that might explain inconsistent results in prior work. Residents of Dijon, France (n = 4,480) 65 years of age or older who were enrolled between 1999 and 2001 were assessed using the Isaacs' verbal fluency test, Benton Visual Retention Test, Trail Making Test B, and Mini-Mental State Examination up to 5 times over 9 years. The authors used random-intercepts mixed models with inverse probability weighting to account for differential survival (conditional on past performance) and quantile regressions to assess bias from measurement floors or ceilings. Higher parental educational levels predicted better average baseline performances for all tests but a faster average decline in score on the Isaacs' test. Higher participant educational attainment predicted better baseline performances on all tests and slower average declines in Benton Visual Retention Test, Trail Making Test B, and Mini-Mental State Examination scores. Slope differences were generally small, and most were not robust to alternative model specifications. Quantile regressions suggested that ceiling effects might have modestly biased effect estimates, although the direction of this bias might depend on the test instrument. These findings suggest that the possible impacts of educational experiences on cognitive change are small, domain-specific, and potentially incorrectly estimated in conventional analyses because of measurement ceilings.

Aims/hypothesis: The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial., Methods: Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis., Results: Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p

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., (Copyright 2008 S. Karger AG, Basel.)

Objectives: The relationship between depression and dementia in the elderly has been extensively studied but the tools used to define depressed subjects are heterogeneous between studies. The objective of this study was to examine the relationship between depression and cognitive performances by using multiple measures of depressive state., Methods: A sample of 7,869 nondemented community-dwelling persons aged >or=65 years participated in the study. Depressive symptoms were evaluated by the Center for Epidemiological Study Depression Scale and the Mini-International Neuropsychiatric Interview was used to assess history of major depressive episodes (MDE). Cognitive function was evaluated by several tests including the Mini-Mental State Examination (MMSE), Trail Making Test, Isaacs Set Test and Benton Visual Retention Test., Results: When studied in separate models, depressive symptoms were significantly related to lower cognitive performances for all neuropsychological tests after adjusting for potential confounders (p<0.0001), whereas subjects with current MDE had significantly lower performances in MMSE and Isaacs Set Test. When studied concomitantly, only high levels of depressive symptoms were related to lower cognitive performance, whereas existence of MDE (past or current) was no longer associated with cognitive performances., Conclusions: These data suggest that once current depressive symptoms are taken into account, major depression (past or current) is not associated with lower cognitive performances in a community-based sample of elderly people aged >or=65 years., ((c) 2007 S. Karger AG, Basel.)

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.

Spouse correlations for cognitive functions and psychological state were investigated using data on 31 spouse pairs. Subjects were part of the Epidemiology of Vascular Aging (EVA) study, a longitudinal study on cognitive and vascular aging. Between July 1991 and June 1993, 1389 subjects aged 59 to 71 years old were recruited, including 318 couples. Cognitive tests assessed global functioning, verbal fluency, attention, verbal memory, psychomotor speed, and logical intelligence. Depressive symptoms and anxiety levels were assessed by the Center for Epidemiological Studies Depression Scale and Spielberger Scale, respectively. Statistically significant positive spouse correlations were found for both psychological scales, spousal similarity being higher for depressive symptoms (r = 0.31, P < 0.0001) than anxiety level (r = 0.13, P = 0.04). When controlling for age, education level, and psychotropic drug use, these associations were not modified. Except for attention and psychomotor speed, significant positive spouse correlations, ranging from 0.18 for logical intelligence to 0.36 for global functioning, were observed for all cognitive performances. When adjusting for age, education level, and depressive symptoms, correlation coefficients decreased and spouse correlations remained significant for global assessments and verbal fluency. These results suggest that, in the elderly, spouse correlations are high for depressive symptoms and rather moderate for anxiety levels and cognitive performances.

Objective: To measure cognitive change using a brief measure over a period of 9 years and to adjust for attrition in the sample., Design: The Cambridge City over 75 Cohort (CC75C), a complete sample of the 75 years and older age group from five group general practices in the city of Cambridge with a systematic one-third of a further practice, all followed on four occasions., Setting: Cambridge city, UK, the respondents' place of residence., Participants: A total of 2106 subjects were included at study entry., Measurements: A brief interview, administered by a trained interviewer, containing a short cognitive scale and the Mini-Mental State Examination (MMSE) at baseline, 2.4 years, 6 years, and 9 years., Results: Decline in MMSE scores occurred across the population and was greater in the oldest age groups. Attrition at later stages of the follow-up was associated with greater decline at earlier stages. Adjusting the results for loss to the sample leads to considerably higher estimates of decline, with the older age groups declining faster from lower levels., Conclusions: To date, cognitive decline in the very old has been considerably underestimated by longitudinal studies. If studies of population samples are to reflect the health and social needs of this frail group accurately, adjustments for the effect of attrition must be included before true decline can be estimated.

Heavy alcohol drinking is associated with cognitive impairment, but little is known concerning the cognitive effect of moderate alcohol consumption. The Epidemiology of Vascular Aging (EVA) Study is a longitudinal study of cognitive and vascular aging. Between June 1991 and June 1993, 1,389 subjects aged 59-71 years (574 men and 815 women) who had been recruited from the electoral rolls of Nantes, France, were examined. Trained psychologists administered a battery of 10 neuropsychological tests assessing most areas of cognitive functioning. Detailed information on alcohol intake was collected during a structured interview. A multiple linear regression model was used to examine the relations between test scores and alcohol consumption at baseline in men and women separately, controlling for age, education, income, depressive symptoms, and smoking status. Odds ratios for being a high cognitive performer (i.e., being in the top 10% of the distribution of summary scores from the neuropsychological battery) were calculated. Among men, neuropsychological test scores were not associated with alcohol consumption in either univariate or multivariate analysis; nor did the proportion of high cognitive performers vary by alcohol consumption. In contrast, among women, significant positive associations between alcohol consumption and cognitive performance were observed for most tests in multivariate analysis. For example, for the Mini-Mental State Examination, the adjusted mean score for female nondrinkers was 27.5 and that for the heaviest drinkers 28.2 (p < 0.001). The odds ratio for being a high cognitive performer was 2.5 (95% confidence interval 1.1-5.7) for women who usually consumed two or more drinks per day in comparison with nondrinkers. These findings suggest that, among women, moderate alcohol consumption may have a beneficial effect on cognitive function.

We examined the association between apolipoprotein E (ApoE) epsilon 4 allele and cognitive performances in a population sample of 1174 high functioning volunteers aged 59-71 years. The neuropsychological battery included the Mini Mental State Examination (MMSE) and nine tests assessing visual attention, verbal memory, visual processing, logical reasoning, psychomotor rapidity, visual memory, auditory attention and verbal fluency. The ratio of genotypes with zero, one or two epsilon 4 alleles was 70.6%, 21.4% and 1.9%, respectively. The epsilon 4 allele was significantly associated with lower scores for visual attention, psychomotor rapidity and MMSE. In the best performer subgroup (MMSE score above 25, n = 1028), all relationships persisted. Our findings demonstrate that the ApoE-epsilon 4 allele is early associated with low normal cognitive performances in areas which are not specifically affected at the subclinical onset of dementia.

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. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]