Role of evolving white matter damage in neurocognitive effects of HIV and HCV

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DESCRIPTION (provided by applicant): An existing NIH-funded contract (CHARTER) supports a multi-site longitudinal study of CNS alterations in a sample of 600 HIV-infected (HIV+) individuals. This sample is representative of infected groups in the communities where they are recruited: most are treated with combination ARVs and a significant proportion are co-infected with HCV. In addition to comprehensive neuromedical and neurobehavioral assessments this study involves annual neuroimaging examinations for assessment of structural brain abnormalities using MR morphometry techniques. Within 149 participants examined in this contract at baseline, the degree of damage in cerebral white matter is associated with disease factors such as CDC classification and the presence of HCV antibodies in serum. The neurocognitive impairment measured in these participants is associated with both increased white matter damage and volume loss in cerebral cortex, and the two factors, which show only modest correlation, appears to contribute independently to severity of neurocognitive impairment. The pattern of the results suggests that damage to the cerebral white matter is an important mediator of HIV-related neurocognitive impairment and may also mediate increases in impairment associated with co-infection with HCV. Multiple lines of evidence suggest that white matter damage and cortical degeneration to some extent reflect distinct pathogenetic mechanisms. The proposed study would take advantage of the existence of the CHARTER longitudinal study to identify 20 individuals at the UCSD site in whom there is evidence of evolving white matter damage (and 10 apparently unaffected individuals with comparable disease characteristics). These targeted individuals would then be studied semiannually with an extended high field (3T) neuroimaging investigation which would include multispectral sMRI, computational morphometry, diffusion tensor imaging (DTI), and chemical shift imaging (CSI). These additional neuroimaging data would be used to address questions about the evolution of white matter damage over time; about the relationship between the white matter damage and the damage to cerebral cortex; and about the role of immune activation and viral levels in mediating this damage.