This is a revised proposal of the R21 MH072529-01 grant. All three reviewers agreed that the proposed studies are significant and innovative and may provide additional information on new mechanisms of disease but there were concerns regarding the weak clinical studies, insufficient number of HIV patients on HAART and Dr. Becker's contribution to this project. We responded to the criticisms and re-designed the clinical study (see our new Introduction). In recent years, human immunodeficiency virus (HIV) positive patients under highly active anti-retroviral therapy (HAART) regimens show a markedly improved general clinical status. It is now believed that the more aggressive antiviral therapies could have a long-term impact on the brain. We propose that increased longevity combined with a prolonged hyper-insulinemic state in long-term survivors on HAART may increase their risk of developing beta-amyloid (Abeta) deposition in the brain. In a pilot study of 162 cases, using immunocytochemistry on autopsy brain tissues, we found abundant beta-amyloid (Abeta) in the brains of HIV patients. A new positron emission tomography (PET) ligand developed at the University of Pittsburgh (PIB) can be used to test our hypothesis in vivo. SA#1: Complete a cross-sectional analysis of Abeta deposition in AIDS patients using a novel-PET ligand (PIB). Evaluate the effects of age and length of HAART on Abeta deposition. SA#2: Study the regional and cellular distribution of Abeta in autopsy brain tissues from HIV patients and controls. We propose that PET imaging may detect early signs of brain degeneration in HIV infected patients on HAART and possibly monitor the brain pathology associated with it. Since the incidence of minor cognitive impairment will probably increase, studies of Aa as a pathogenic factor will be useful in designing future NeuroAIDS studies.