Our initial project aimed to 1) determine the neural correlates of attentional impairment in HIV-patients with cognitive motor complex (HIV-CMC) using functional MRI (fMRI), and 2) show that fMRI may detect abnormal brain activation in HIV patients with normal neuropsychological function. We have made significant progress despite the relocation and technical delays associated with a scanner upgrade; our work resulted in 8 papers (6 published and 2 in press), 2 manuscripts submitted, and 4 more in preparation (data collection completed and presented at recent meetings, ISMRM and HIV Workshop). We have achieved our two major aims and proven 3 of the 4 original hypotheses. Work from the initial project period provided us with significant experience and strong preliminary data for this new proposal. The new proposal has the following three aims: 1) To evaluate the possible additive or interactive effects of HIV and aging on brain metabolites using longitudinal follow-up proton magnetic resonance spectroscopy (MRS) studies. 2) To evaluate the possible additive or interactive effects of HIV and aging on brain function, especially attention and working memory, as measured by longitudinal blood-oxygenation-level-dependent functional MRI (BOLD-fMRI). 3) To determine the relationships between brain metabolite abnormalities and brain activation in the setting of HIV and aging. These relationships will provide cross-modality validation of the pathophysiological changes associated with HIV and aging. Based on our preliminary data, we hypothesize that compared to younger HIV subjects, less young (>=40 years) HIV individuals will show higher age-related increase in glial markers (choline, myoinositol) and additional decreased neuronal marker N-acetylaspartate on MRS. In addition, less young HIV patients will have more rapid age-related decline in parietal and frontal BOLD activation during attention and working memory tasks on BOLD-fMRI, over the 5-year period. We also hypothesize that the elevated glial markers and total creatine will be related to increased attentional modulation (usage of brain reserve or deactivation of adjacent or same brain regions) on brain activation. To test these hypotheses, we will enroll 75 HIV-patients and 75 seronegative controls (ages 18-80 years, 75% men, and approximately equal distribution across the decades in each group), and follow them annually over a 5-year period. This will enable us to compare the groups both cross-sectionally as well as longitudinally. The knowledge gained from this study will provide a better understanding of how HIV affects the aging brain (even at middle age), and may lead to future preventive measures (e.g. neuroprotective or anti-inflammatory treatments). [unreadable] [unreadable] [unreadable]