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Introduction: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown., Methods: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms., Results: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups., Discussion: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics., (© 2021 the Alzheimer's Association.)

Background: The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements., Methods: In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral 18 F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions., Results: The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E ε4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single-domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex., Conclusions: MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs., Trial Registration: Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013.

Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease., (© The Author(s) 2016.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds., Methods: We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis., Results: APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size-weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008)., Conclusions: APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.

Objective: Our aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease., Methods: The study comprised 1,800 participants (aged 72.5 ± 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors., Results: Presence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09-2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02-1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04-1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [β] ± standard error: 0.0003 ± 0.0001, p = 0.024; β ± standard error: 0.005 ± 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04-1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69-0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque., Conclusions: In addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively.

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 < 0.01), lower gray matter (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.

Background and Purpose: Silent brain infarcts (SBIs) have been recognized as common lesions in elderly subjects and their diagnosis relies on brain imaging. In this study, we aimed to evaluate the different MRI parameters and criteria used for their evaluation in the literature to better understand the variation across studies and related limitations., Method: Original MRI studies of SBI performed in human populations and reported in the English literature were reviewed. Analyses were restricted to population-based studies or studies in which at least 50 subjects with SBI were detected. The MRI parameters as well as the MRI criteria of SBI (size, signal characteristics, and criteria for differentiation of dilated Virchow-Robin spaces) were described and analyzed., Result: Magnetic field strength, slice thickness, and gap between slices greatly varied among the 45 articles included in this review. The MRI definition of SBI was inconsistent across studies. In half of them, SBI was defined as hypointense on T1 and hyperintense on T2-weighted images. Exclusion criteria for dilated Virchow-Robin spaces were used only in 7 studies., Conclusions: The variation in MRI characteristics and diagnostic criteria for SBI represent a major limitation for interpretation and comparison of data between studies. Efforts are needed to reach unified imaging criteria for SBI.

Background: Complaints about memory are common in older people but their relationship with underlying brain changes is controversial., Aims: To investigate the relationship between subjective memory impairment and previous or subsequent changes in white matter lesions and brain volumes., Method: In a community cohort study of 1336 people without dementia, 4-year changes in brain magnetic resonance imaging measures were investigated as correlates of subjective memory impairment at baseline and follow-up., Results: Subjective memory impairment at baseline was associated with subsequent change in hippocampal volume and at follow-up impairment was associated with previous change in hippocampal, cerebrospinal fluid and grey matter volume and with subcortical white matter lesion increases. All associations with volume changes were U-shaped with significant quadratic terms - associations between least decline and subjective memory impairment were potentially explained by lower baseline hippocampal volumes in the groups with least volume change. Associations between hippocampal volume change and subjective memory impairment at follow-up were independent of cognitive decline and depressive symptoms, they were stronger in participants with the apolipoprotein E (APOE) ε4 allele and in those without baseline subjective memory impairment., Conclusions: Complaints of poor memory by older people, particularly when new, may be a realistic subjective appraisal of recent brain changes independent of observed cognitive decline.

CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia., (Copyright 2008 Elsevier Inc. All rights reserved.)

Background and Purpose: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium., Methods: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct)., Results: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample., Conclusions: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

Background and Purpose: The relationship between white matter lesions (WMLs) and the apolipoprotein E genotype has been controversial from cross-sectional studies and no longitudinal finding has been reported. We investigated whether the apolipoprotein E genotype influences baseline and evolution over 4-year follow-up of WML volumes in a population-based sample of 1779 nondemented subjects aged 65 to 80 years old at enrollment., Methods: The sample consisted of 3C-Dijon study participants who had 2 cerebral MRIs, at entry and at 4-year follow-up. WML volumes were estimated using a fully automatic procedure. We performed analysis of covariance to evaluate the relationship between apolipoprotein E genotype and WML load and progression., Results: Multivariable analyses showed that epsilon4epsilon4 individuals had both significantly higher WML volume at baseline and higher WML increase over 4-year follow-up than noncarriers and heterozygous of the epsilon4 allele for apolipoprotein E genotype., Conclusion: These findings suggest it might be important to take into account WML severity when assessing the relationship between apolipoprotein E and dementia.

Objectives: To investigate the cross-sectional and longitudinal associations between performance-based measures of motor function and volume of white matter lesions (WMLs), and to examine the influence of the localization of these lesions., Methods: At baseline, motor performances (maximum walking speed, Tinetti gait and balance subscales) were assessed in 1,702 subjects aged 80 years or younger from the Dijon (France), France center of the Three-City study. Volumes of WMLs lesions (total, periventricular, deep) were measured using an automated method of tissue segmentation and quantification of lesion size. At 8-year follow-up, walking speed was evaluated in 1,086 subjects., Results: At baseline, mean and 95% confidence interval (CI) walking speed was lower in subjects with total volumes of WMLs >or=90th percentile (1.50 [1.45-1.55] m/s) than in subjects with lower volumes (1.56 [1.55-1.58] m/s; p = 0.004). Baseline total volumes of WMLs above the 90th percentile predicted walking speed decline during follow-up (odds ratio [95% CI] for having the greatest walking speed decline = 2.3 [1.3-4.1], p = 0.006). Moreover, high volumes of periventricular but not deep WMLs were associated with slower walking speed at baseline (p = 0.005) and over time (p = 0.001), and with lower Tinetti gait subscore (p = 0.02)., Interpretation: Our study shows a cross-sectional and longitudinal association between high total volumes of WMLs, in particular volumes above the 90th percentile, and impaired mobility. These associations were independent of several confounders, including cognition, and were mainly accounted for by volumes of periventricular WMLs. These findings support the hypothesis of a vascular contribution to motor decline in the elderly.

Introduction: 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., Materials and Methods: 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., Results: The average annual change in WMH load was found to be 0.25 cm(3)/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., Conclusion: 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.

Background: Brain atrophy and white-matter lesions (WML) are common features at cerebral MRI of both normal and demented elderly people. In a population-based study of 1,792 elderly subjects aged 65-80 years, free of dementia, who had a cerebral MRI at entry, we investigated the relationship between WML volume and brain atrophy markers estimated by hippocampal, gray matter (GM) and cerebrospinal fluid (CSF) volumes., Methods: An automated algorithm of detection and quantification of WML was developed, and voxel-based morphometry methods were used to estimate GM, CSF and hippocampal volumes. To evaluate the relation between those volumes and WML load, we used analysis of covariance and multiple linear regression models adjusting for potential confounders and total intracranial volumes., Results: Age was highly correlated with WML load and all brain atrophy markers. Total WML volume was negatively associated with both GM (beta = -0.03, p < 0.0001) and hippocampal volumes (beta = -0.75, p = 0.0009) and positively with CSF volumes (beta = 0.008, p = 0.02) after controlling for sex, age, education level, hypertension and apolipoprotein E genotype. Evidence for a relationship between brain atrophy markers and WML was stronger for periventricular WML. We found that the relationship between WML and hippocampal volumes was independent of other brain tissue volumes., Conclusion: These results suggest that, in the brain of nondemented elderly subjects, degenerative processes and vascular changes co-occur and are related independently of vascular risk factors., (2009 S. Karger AG, Basel.)

Background: Subjective memory deficit (SMD) is one of few potential presenting symptoms for people with early cognitive impairment. However, associations with underlying brain changes are unclear., Methods: In a community sample of 1,779 people without dementia, and with neuroimaging (MRI) data, associations were investigated for SMD with white matter lesion volume and with the following volumetric measures: gray and white matter, CSF, hippocampal, parahippocampal, and amygdalar. Covariates included depressive symptoms (Center for Epidemiologic Studies Depression Scale), a battery of cognitive tests, physical health, and social activity., Results: SMD was present in 26.4% of the sample. Of the neuroimaging measures analyzed, SMD was most strongly associated with temporal WML (OR for highest quintile compared to the remainder 1.44, 95% CI 1.12-1.85), and lower hippocampal volume (OR per decreasing quintile 1.22, 1.11-1.35). These associations were independent of all other covariates, including cognitive function., Conclusions: Subjective memory deficit (SMD) was associated with neuroimaging characteristics in the temporal and hippocampal regions, suggesting that SMD may, at least in some cases, represent a realistic appraisal of underlying brain function independent of measured cognition. However, further research is required for volumetric measures and SMD to establish whether the association reflects lifelong structure or neurodegenerative changes.

Background: There is increasing evidence for a link between cerebrovascular disease and depression in the elderly but the mechanisms are still unknown. This study examines the longitudinal relationship between depression and white matter lesions (WML) in a sample of elderly aged 65 years and older., Methods: Three City (3C)-Dijon is a 4-year follow-up population-based prospective study of 1658 subjects. At baseline, lifetime major depressive episode diagnosis was established using the Mini International Neuropsychiatric Interview. At each study wave, severity of depressive symptoms was assessed using Center for Epidemiological Studies-Depression (CES-D), and antidepressants intake was recorded. At baseline, lifetime major depression (LMD) was defined as lifetime major depressive episode or antidepressant medication intake. At follow-up, subjects were classified "incident depression" if scoring high at CES-D or antidepressant users. At baseline, cerebral magnetic resonance imaging (MRI) was performed to quantify WML volumes using an automated method of detection. At 4-year follow-up, 1214 subjects had a second MRI., Results: Cross-sectional analysis showed a significantly higher WML volume in subjects with LMD compared with other subjects. Adjusted longitudinal analysis showed that increase in WML load was significantly higher in subjects with baseline LMD (2.1 cm(3) vs. 1.5 cm(3), p = .004). Among subjects free of depression up to baseline (n = 956), the higher the baseline WML volume, the higher the risk of developing depression during follow-up (odds ratio one quartile increase: 1.3; 95% confidence interval: = 1.1-1.7)., Conclusions: Our data show that depression and WML volumes are strongly related. These results are consistent with the hypothesis of a vascular depression in the elderly.

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.

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.

Background: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease., Methods and Results: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001)., Conclusions: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

Cerebral white matter lesions are frequently observed on magnetic resonance imaging (MRI) scans in elderly people and are associated with stroke and dementia. Elevated blood pressure is presumed one of the main risk factors, although data are almost exclusively derived from cross-sectional studies. We assessed in 10 European cohorts the relation between concurrently and previously measured blood pressure levels, hypertension, its treatment, and severe cerebral white matter lesions. In total, 1805 nondemented subjects aged 65 to 75 years were sampled from ongoing community-based studies that were initiated 5 to 20 years before the MRI. White matter lesions in the periventricular and subcortical region were rated separately using semiquantitative measures. We performed logistic regression analyses adjusted for potential confounders in 1625 people with complete data. Concurrently and formerly assessed diastolic and systolic blood pressure levels were positively associated with severe white matter lesions. Both increases and decreases in diastolic blood pressure were associated with more severe periventricular white matter lesions. Increase in systolic blood pressure levels was associated with more severe periventricular and subcortical white matter lesions. People with poorly controlled hypertension had a higher risk of severe white matter lesions than those without hypertension, or those with controlled or untreated hypertension. Higher blood pressure was associated with an increased risk of severe white matter lesions. Successful treatment of hypertension may reduce this risk; however, a potential negative effect of decreasing diastolic blood pressure level on the occurrence of severe periventricular white matter lesions should be taken into account.

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.

Background and Purpose: White matter hyperintensities (WMHs) are often observed on cerebral magnetic resonance imaging (MRI) of elderly individuals. Epidemiological studies have shown that age and hypertension are associated with WMHs, suggesting a vascular mechanism in WMH pathogenesis. In a population-based prospective study, we examined the association of carotid atherosclerosis measured at baseline and 4-year follow-up with severity of WMHs assessed at 4-year follow-up., Methods: The sample consisted of 640 healthy subjects aged 59-71 years at entry enrolled in the prospective EVA Study. Systolic and diastolic blood pressures were measured at each wave. Ultrasonographic measures of intima-media thickness (IMT) of the common carotid arteries and plaques were made at baseline and at 4-year follow-up examination. An MRI examination was performed at 4-year follow-up. The presence and severity of WMHs were evaluated by a single radiologist., Results: After adjusting for age, gender, and hypertension, the presence of carotid plaques at baseline was significantly associated with the presence of severe WMHs 4 years later [odds ratio (OR) = 1.70; 95% confidence interval (CI): 1.05-2.74]. The association was stronger in men than in women. A 0.1-mm increase of baseline IMT was associated with an increased risk of severe WMHs in both sexes (adjusted OR = 1.17; 95% CI: 0.96-1.41), but the association was not significant (p = 0.12). Cross-sectional relationships between carotid plaques and severe WMHs at 4-year follow-up showed that the risk of having severe WMHs was stronger in the group of subjects who had already plaques at study entry compared to the group of subjects whose plaques occurred during 4-year follow-up., Conclusion: This study confirmed an association between carotid atherosclerosis and WMHs independently of age and hypertension. It also suggested that the older the carotid plaques, the higher the risk of having severe WMHs., (Copyright 2002 S. Karger AG, Basel)

Objective: To investigate the relationship between baseline hypertension and severity of white matter hyperintensities (WMH) at 4-year follow-up in a sample of subjects aged 59 to 71 years old at entry., Methods: Subjects were participants in the Epidemiology of Vascular Ageing study, a longitudinal study on vascular aging and cognitive decline. At 4-year follow-up, 845 subjects had a cerebral MRI. MRI examinations were read by a single rater to determine the severity of WMH, ranging from absent to severe. Hypertension at each wave of the study was defined as systolic blood pressure > or =160 mm Hg, diastolic blood pressure > or =95 mm Hg, or use of antihypertensive medication., Results: Hypertension at baseline was significantly associated with an increased risk of having severe WMH at 4-year follow-up. When taking into account both blood pressure levels and antihypertensive drug intake, analysis showed that the risk of having severe WMH was significantly reduced in subjects with normal blood pressure taking antihypertensive medication compared with those with high blood pressure taking antihypertensive agents. Cross-sectional relationships between hypertension and WMH at 4-year follow-up showed that the frequency of severe WMH was significantly higher in people who were hypertensive at both baseline and 4-year follow-up than those who were hypertensive only at 4-year follow-up., Conclusions: Hypertension is a major risk factor for severe WMH. Subjects taking antihypertensive drugs and who have controlled blood pressure had a reduced risk of severe WMH. Longitudinal studies are needed to investigate whether reduction of the development of WMH, by treatment and prevention of hypertension, might reduce the subsequent risk of cognitive deterioration or stroke.

Cerebral blood flow velocity (CBF-V) measured by transcranial doppler was assessed in 628 elderly individuals who had cerebral magnetic resonance imaging performed as part of a population-based study on vascular aging. Cerebral white matter hyperintensities (WMHs) were associated with low CBF-V, such as the adjusted odds ratios of severe WMHs from highest (referent) to lowest quartile of mean CBF-V were 1.0, 1.7, 3.7, and 4.3 (p = 0.001). Further, CBF-V was found to be a stronger risk factor for WMHs than high blood pressure. These findings suggest that the assessment of CBF-V might be a powerful tool in future studies on WMHs.

We report a unique longitudinal epidemiological study of cognitive decline in the elderly population of the city of Cambridge, UK. A population sample of people aged 75 and over was surveyed between 1984-1996 (n = 2,616) and followed 2.4, 6, and 9 years later. CAMDEX diagnostic criteria were used for clinical assessment, and the neuropathological protocol (in 101 cases) was based on the CERAD method, with additional features to allow Braak staging of neurofibrillary pathology. The main findings are of the heterogeneity of lesions to be found in very old populations, and the existence of considerable overlap in the pathologies found in the demented and nondemented. It seems that white matter (ischemic) pallor an amyloid angiopathy, as well as neuritic plaques, neurofibrillary tangles and Lewy body formation are all lesions that increase the likelihood of dementia.