Cognitive impainnent is a common complication of HIV- I infection that can lead to dementia. Markers of immune activation in the central nervous system (CNS) have been shown to best correlate with the degree of cognitive impairment. Interestingly, most products of immune activation induce cytotoxicity via induction of oxidative stress. In this regard, our preliminary data indicate that levels of oxidative stress, measured by cerebrospinal fluid (CSF) induced changes in neuronal mitochondrial membrane potential and CSF levels of protein carbonyl, correlate with the severity of HIV-associated cognitive impairment. The mitochondrial membrane potential abnormalities can be reversed by drugs with antioxidant properties including selegiline (L-deprenyl). It is noteworthy that two preliminary studies suggest that selegiline may improve cognitive impairment associated with HIV infection. Based on these observations, the AIDS Clinical Trials Group (ACTG) has approved a large multicenter trial with selegiline (A5090). We hypothesize that oxidative stress is an important mechanism in the pathogenesis of HIV-associated cognitive impairment and will correlate with markers of cerebral injury as measured by magnetic resonance spectroscopy (MRS) and with established predictors of HIV-associated cognitive impairment including CSF HIV RNA (viral load) and B2 microglobulin levels. We also hypothesize that antioxidant compounds such as selegiline will improve the cognitive performance and metabolic markers of cerebral injury in HIV infected individuals and that this response will correlate with the levels of oxidative stress. We propose to further investigate the role of oxidative stress in HIV-associated cognitive impairment by addressing the following specific aims: 1) to compare markers of oxidative stress in the CSF among HIV infected subjects with and without cognitive impairment and 11W negative controls; 2) to assess the relationship between levels of oxidative stress and CSF HIV viral load and B2-microglobulin levels; 3) to assess the relationship between levels of oxidative stress and in vivo brain metabolism, as measured by MRS in HIV infected subjects with and without cognitive impairment; 4) to assess the effect of selegiline on CSF markers of oxidative stress and on in vivo brain metabolism (MRS) in subjects with 11W-associated cognitive impairment and to correlate changes in markers of oxidative stress with MRS and cognitive performance. The proposed study will take advantage of the ACTG supporting A5090 study and of the existing MRS consortium infrastructure that will allow us to perform multicenter MRS studies.
Showing the most recent 10 out of 21 publications
