Age-related dementia disrupts normal functioning of afflicted individuals and their families, imposing significant social, economic, and public health burdens in both developed and developing countries, including Venezuela. Yet many of the underlying causes for dementia remain to be identified and understood. Ischemic small vessel disease (SVD) is a leading cause of vascular dementia and a major contributor to Alzheimer's disease. It has been shown that white matter hyperintensities (WMH) from neuroimaging can be used to evaluate subclinical and clinical SVD. The WMH phenotype is complex, and its causes are not well known. WMH is highly heritable (55-83%);yet, previous studies have not been able to identify genes that contribute to the WMH phenotype, probably because WMH is affected by multiple genetic variants with small effect sizes;by multiple environmental risk factors;or their interactions. To circumvent some of the aforementioned problems, we propose to study one highly inbred, extended family, residing in Lake Maracaibo, Venezuela. In this uniquely homogenous population, genetic and environmental heterogeneity will be minimized, and thus the complexity reduced. Using this cohort, we will obtain a comprehensive set of phenotype and risk factor data, including neuroimaging to characterize subclinical and clinical SVD;cardiovascular and demographic risk factors to understand how these factors may influence WMH;and neuropsychology battery to assess cognitive performance (Aim 1). Subsequently, we will estimate heritability. For the highly heritable traits, we will perform genome wide linkage study and family based genome wide association study using a high density 2.5M SNP chips to identify genetic variants that may contribute to the WMH phenotype (Aim 2). The top SNPs from this gene mapping experiments will be replicated in an independent, nearby community-dwelling elderly in Santa Lucia, who have been studied for the past decade by the PI, using the same clinical and imaging protocols. To accomplish these goals, we have build a team of scientists with extensive experience in genomics, neuroimaging, and Venezuelan populations. In addition to the scientific aims, we will enhance the local research capacity along with the ability to recognize and provide care for a rapidly growing population of elderly (Aim 3). This project will contribute fundamentally to the understanding of the mechanisms responsible for SVD, and in turn, identify new means to predict, prevent and effectively treat age-related dementia.
Ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke and Alzheimer's disease. We propose to study a uniquely homogeneous population of Lake Maracaibo, Venezuela, applying the novel genomic technologies along with high resolution neuroimaging techniques to identify gene variants that contribute specifically to SVD. Pinpointing specific causes of SVD will facilitate improved efforts to predict, prevent, and effectively treat age-related dementia.
|Gu, Yu-Mei; Thijs, Lutgarde; Li, Yan et al. (2014) Outcome-driven thresholds for ambulatory pulse pressure in 9938 participants recruited from 11 populations. Hypertension 63:229-37|
|Janicki, S C; Park, N; Cheng, R et al. (2014) Estrogen receptor ? variants affect age at onset of Alzheimer's disease in a multiethnic female cohort. Dement Geriatr Cogn Disord 38:200-13|
|Gertz, Edward Michael; Hiekkalinna, Tero; Digabel, Sébastien Le et al. (2014) PSEUDOMARKER 2.0: efficient computation of likelihoods using NOMAD. BMC Bioinformatics 15:47|
|Li, Yan; Wei, Fang-Fei; Thijs, Lutgarde et al. (2014) Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations. Circulation 130:466-74|
|Conen, David; Aeschbacher, Stefanie; Thijs, Lutgarde et al. (2014) Age-specific differences between conventional and ambulatory daytime blood pressure values. Hypertension 64:1073-9|
|Mena, Luis J; Maestre, Gladys E; Hansen, Tine W et al. (2014) How many measurements are needed to estimate blood pressure variability without loss of prognostic information? Am J Hypertens 27:46-55|
|Asayama, Kei; Thijs, Lutgarde; Li, Yan et al. (2014) Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population. Hypertension 64:935-42|
|Janicki, S C; Park, N; Cheng, R et al. (2013) Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort. Dement Geriatr Cogn Disord 35:340-6|
|Mena, Luis J; Felix, Vanessa G; Ostos, Rodolfo et al. (2013) Mobile personal health system for ambulatory blood pressure monitoring. Comput Math Methods Med 2013:598196|