@article {660, title = {Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {32}, year = {2001}, month = {2001 Sep}, pages = {1939-46}, abstract = {

BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings.

METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics.

RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007).

CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.

}, keywords = {Aged, Aging, Alcohol Drinking, Atrophy, Brain, Brain Diseases, Cerebral Infarction, Comorbidity, Demography, Female, Health Surveys, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Odds Ratio, Prospective Studies, Sensitivity and Specificity, United States}, issn = {1524-4628}, doi = {10.1161/hs0901.095723}, author = {Mukamal, K J and Longstreth, W T and Mittleman, M A and Crum, R M and Siscovick, D S} } @article {838, title = {Determinants of vascular dementia in the Cardiovascular Health Cognition Study.}, journal = {Neurology}, volume = {64}, year = {2005}, month = {2005 May 10}, pages = {1548-52}, abstract = {

OBJECTIVE: The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.

METHODS: Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

RESULTS: Approximately 44\% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.

CONCLUSIONS: Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer{\textquoteright}s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cardiovascular Diseases, Cerebral Arteries, Cerebral Infarction, Cohort Studies, Comorbidity, Continental Population Groups, Dementia, Vascular, Female, Humans, Lateral Ventricles, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Neuropsychological Tests, Risk Factors, Sex Factors}, issn = {1526-632X}, doi = {10.1212/01.WNL.0000160115.55756.DE}, author = {Kuller, L H and Lopez, O L and Jagust, W J and Becker, J T and DeKosky, S T and Lyketsos, C and Kawas, C and Breitner, J C S and Fitzpatrick, A and Dulberg, C} } @article {1120, title = {Brain structure and obesity.}, journal = {Hum Brain Mapp}, volume = {31}, year = {2010}, month = {2010 Mar}, pages = {353-64}, abstract = {

Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5\%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.

}, keywords = {Age Factors, Aged, Analysis of Variance, Body Mass Index, Brain, Continental Population Groups, Diabetes Mellitus, Type 2, Fasting, Female, Humans, Insulin, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Nerve Fibers, Unmyelinated, Obesity, Organ Size, Regression Analysis, Sex Factors}, issn = {1097-0193}, doi = {10.1002/hbm.20870}, author = {Raji, Cyrus A and Ho, April J and Parikshak, Neelroop N and Becker, James T and Lopez, Oscar L and Kuller, Lewis H and Hua, Xue and Leow, Alex D and Toga, Arthur W and Thompson, Paul M} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {1269, title = {Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 Mar 01}, pages = {858-65}, abstract = {

BACKGROUND: Our objective was to investigate the association between hypertension and concurrent impairments in mobility, cognition, and mood; the role of brain white matter hyperintensities in mediating this association; and the impact of these impairments on disability and mortality in elderly hypertensive individuals.

METHODS AND RESULTS: -Blood pressure, gait speed, digit symbol substitution test, and the Center for Epidemiological Studies Depression Scale were measured yearly (1992-1999) on 4700 participants in the Cardiovascular Health Study (age: 74.7, 58\% women, 17\% blacks, 68\% hypertension, 3600 had brain magnetic resonance imaging in 1992-1993, survival data 1992-2005). Using latent profile analysis at baseline, we found that 498 (11\%) subjects had concurrent impairments and 3086 (66\%) were intact on all 3 measures. Between 1992 and 1999, 651 (21\%) became impaired in all 3 domains. Hypertensive individuals were more likely to be impaired at baseline (odds ratio 1.23, 95\% confidence interval 1.04 to 1.42, P=0.01) and become impaired during the follow-up (hazard ratio=1.3, 95\% confidence interval 1.02 to 1.66, P=0.037). A greater degree of white matter hyperintensities was associated with impairments in the 3 domains (P=0.007) and mediated the association with hypertension (P=0.19 for hypertension after adjusting for white matter hyperintensities in the model, 21\% hazard ratio change). Impairments in the 3 domains increased subsequent disability with hypertension (P<0.0001). Hypertension mortality also was increased in those impaired (compared with unimpaired hypertensive individuals: HR=1.10, 95\% confidence interval 1.04 to 1.17, P=0.004).

CONCLUSIONS: Hypertension increases the risk of concurrent impairments in mobility, cognition, and mood, which increases disability and mortality. This association is mediated in part by microvascular brain injury.

}, keywords = {Aged, Aged, 80 and over, Brain, Cognition Disorders, Female, Humans, Hypertension, Kaplan-Meier Estimate, Longitudinal Studies, Magnetic Resonance Imaging, Male, Microcirculation, Mobility Limitation, Mood Disorders, Nerve Fibers, Myelinated, Retrospective Studies, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.978114}, author = {Hajjar, Ihab and Quach, Lien and Yang, Frances and Chaves, Paulo H M and Newman, Anne B and Mukamal, Kenneth and Longstreth, Will and Inzitari, Marco and Lipsitz, Lewis A} } @article {1310, title = {Progression of magnetic resonance imaging-defined brain vascular disease predicts vascular events in elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Oct}, pages = {2970-2}, abstract = {

BACKGROUND AND PURPOSE: To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly.

METHODS: The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans≈5 years apart and have been followed for ≈9 years since the follow-up scan for incident vascular events.

RESULTS: Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95\% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95\% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95\% confidence interval, 1.28-2.24), and cardiovascular death (hazard ratio, 1.97; 95\% confidence interval, 1.24-3.14).

CONCLUSIONS: Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown.

}, keywords = {Aged, Brain, Disease Progression, Female, Follow-Up Studies, Heart Failure, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Predictive Value of Tests, Prognosis, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.622977}, author = {Longstreth, W T and Arnold, Alice M and Kuller, Lewis H and Bernick, Charles and Lefkowitz, David S and Beauchamp, Norman J and Manolio, Teri A} }