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Publication Abstract Display
Type: Published Abstract
Title: Establishing a Link Between Host Genotype and HIV-related neuropathology A novel approach to understanding neuropathogenesis.
Authors: Levine A, Achim C, Singer E, Masliah E, Sinsheimer J, Soontornniyomkij V, Moore DJ
Year: 2013
Publication: Mid-Year Meeting International Neuropsychological Society
Volume: Issue: Pages:
Abstract:BACKGROUND: The prevalence of HIV-associated neurocognitive disorders (HAND) is near 50% despite the widespread use of combined antiretroviral therapy. HAND is a clinical diagnosis based on neurocognitive impairments. While the exact etiology is unclear, HAND is believed to be the end result of a sequence of physiological events that commences with HIV induced cellular changes that are modified by genetic factors. We deem quantifiable neuropathological changes that occur proximal to the beginning of this causal chain of HAND pathogenesis as neuropathological intermediate phenotypes (NIPs). Identifying the relevant neuropathological changes will help illuminate the neuropathogenesis of HAND. Here, we leverage known genetic risk factors for the clinical HAND to validate a candidate NIP. METHODS: Seven HIV-infected brains were neuropathologically characterized and genotyped. We examined synaptodendrtitic neurodegeneration as measured via quantitative imaging of both synaptophysin (SYN) and microtubule-associated protein 2 (MAP2) in the midfrontal cortex. All cases were genotyped for TNF alpha, MIP 1alpha, MCP 1, and BDNF. RESULTS: A significant difference in SYN levels was detected for the MCP 1 polymorphism (p = .04), indicating that those with the G allele at the MCP 1 promoter position 2578 site had greater synaptodendritic neurodegeneration. CONCLUSIONS: This is the first study to establish a link between host genotype and a candidate neuropathological phenotype for HAND. Through further examination of the relationship between genetic susceptibility loci and NIPs in brain tissue derived from a clinically well-characterized cohort, it will be possible to determine 1) which genetic variants are biologically relevant to HAND, 2) the pathophysiological mechanisms through which they exert their effect on the neurobehavioral phenotypes, and 3) the relative importance of NIPs as underlying causative factors of HAND.

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