This is a revised R03 application for a pilot study to examine genetic influences on brain plasticity and repair using an existing neuroimaging dataset in 200 patients with MS. This R03 requests funds for genotyping, processing of archived image data, and computational genetics. Genes related to brain plasticity and repair may modify the impact of MS and help account for its heterogeneity in terms of symptomatology, progression, and neuroimaging profile. APOE genotype, an important predictor of brain response to injury, has been found to relate to clinical disability and progression in some but not all MS studies. However, presence of the E4 allele consistently predicts brain imaging findings in MS, including brain atrophy and T1 hypointense lesions. This suggests the potential of imaging to serve as a sensitive and useful endophenotype of brain structural abnormalities in this disease. Other genes involved in brain plasticity and repair have received less empirical attention in MS despite the strong likelihood that multiple genes act in concert to modify disease impact. Research on disease-modifying genes in relation to neuroimaging in MS is important given the potential to help inform development of novel therapeutic approaches and effective monitoring and prognostic strategies. We propose to examine a targeted panel of genetic polymorphisms involved in brain plasticity and repair as predictors of neural integrity on structural neuroimaging in MS. We hypothesize that the presence and number of alleles reducing capacity for plasticity/repair will be directly related to lesion volume and brain atrophy in MS. Novel aspects of this proposal include the examination of polymorphisms related to hypothesized neurotrophins and growth factors in a large dataset of lesion and atrophy data, and the use of computational genetic techniques recently developed at Dartmouth to examine combinatorial genetic models in relation to continuous neuroimaging variables. The proposed study leverages existing data, tools and expertise. We have acquired and archived imaging, neurological, and clinical data in a sample of 1400 patients with MS, of whom we will include 200 patients with mild to moderate relapsing-remitting disease in this initial pilot study. As part of the R03 study, patients will undergo blood draw for genotyping. In addition, lesion volume, brain parenchymal fraction, and regional gray matter density will be quantified. We will employ the custom microarray we have developed that incorporates a panel of target genes related to brain plasticity and repair. This pilot study will provide a test bed for our approach and hypotheses, and data to demonstrate feasibility to support larger grant applications incorporating a larger and more diverse sample of MS patients, additional genes of interest, further structural, neurochemical and functional imaging modalities, and longitudinal follow-up data. Multiple sclerosis is the leading cause of chronic neurologic disability in young adults, affecting 1 in 750 people in the United States. The health care costs associated with MS are 2 to 3 times those of healthy adults per year. Advances in neuroimaging have revolutionized the process of diagnosing and monitoring MS, facilitating earlier detection and earlier treatment and thereby effecting an overall reduction in disease burden and health care costs. Combining genetics and advanced neuroimaging, as proposed in the present application, should ultimately further enhance disease detection, prognostic accuracy, and early intervention and treatment monitoring. ? ? ?
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