? ? Highly active antiretroviral therapy (HAART) has resulted in a marked rise in survival among HIV-infected persons. To what extent the brain compartment truly benefits from such treatment, particularly in the setting of advanced, even stable disease, remains unclear. The frequency, spectrum and extent of neurological injury, its relationship to cognitive functioning and responsiveness to antiretroviral therapies thus remain important yet unresolved issues. The HIV MRS consortium has identified regional and cellular abnormalities specific to different stages of HIV-associated cognitive impairment (AIDS dementia complex, ADC) as well as an in vivo model of brain injury that suggests basal ganglia and neuronal events are critical to the development of ADC. It has also identified potential host(plasma MCP-1, CSF IP-10) and viral factors (SCF HIV RNA) at baseline that may increase the risk for cognitive impairment or further decline. This application proposes a longitudinal multicenter study to examine the pattern and dynamics of regional injury by MRS and Morphometry among neurologically asymptomatic (NA) and ADC subjects with advanced disease (nadir CD4<50/ml) in relationship to cognitive performance and to identify virological and immunological events in the CSF and peripheral compartments that may contribute to neurological impairment in the setting of HAART. We will accrue 180-200 subjects (125-135 NA subjects and 55-65 ADC subjects) from two cohorts: 120-140 subjects from ACTG 362 (85-95 NA and 35-45 ADC subjects), previously immune reconstituted on HAART, and 60 subjects from the UCLA NNAB and UCSD CNTC (40 NA subjects and 20 ADC subjects) divided into virologically suppressed and not suppressed groups. The primary aims are: 1) to identify NA subjects at risk for brain injury as measured by MRS, and examine host and viral factors at baseline that may increase the risk for subsequent neurological injury; 2) to determine whether the emergence of basal ganglia and neuronal factors over time is a predictor of cognitive impairment; 3) to examine the impact of changing virologic and immunologic factors in addition to the effects of hepatitis C exposure and aging on CNS function; and 4) to determine the brain morphometric signatures (caudate, white matter and whole brain) associated with each stage of cognitive impairment and the relationship between changes in regional volumes to MRS patterns of brain injury and indices of disease activity . Longitudinal and regression statistical models will be used to study the neurological effects of HIV-infection brain as a dynamic system of interrelated factors. At a mechanistic level, the study aims to elucidate in vivo the development of brain injury and identify host and viral factors that may contribute to its risk. Detection of brain injury among NA subjects on HAART and at risk for ADC will have critical ramifications for overall health outcome and early therapeutic intervention. ? ? ?
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