Given the increase in drug abuse-related HIV transmission, questions arise regarding the potentially additive and/or multiplicative effects of methamphetamine (METH) dependence on neurocognitive functioning in HIV+ individuals, particularly in terms of frequency, severity, and progression of neuropsychological (NP) impairments, and possible prognostic significance of these impairments. The specific aims of this project are to 1) characterize the NP effects of co-occurring HIV infection and METH dependence; 2) correlate patterns of NP impairment with antemortem and postmortem structural brain abnormalities; and, 3) determine the clinical and/or prognostic significance of combined HIV infection and METH dependence by examining rates of NP worsening, progression to AIDS and reduced survival over a 5 year follow-up period. The following hypotheses are proposed to characterize the effects of HIV infection and METH dependence on NP functioning. First, METH dependent (METH+) HIV+ subjects are expected to show more NP impairment than non-METH abusing (METH-) HIV+ and METH+/HIV- subjects. Second, NP impairments observed in both HIV infection and METH dependence should be more frequent and severe in domains vulnerable to white matter and frontostriatal involvement (i.e., measures of abstraction, speed of information processing (SIP), attention/working memory, learning and motor functioning). Third, in HIV+ subjects, a disease stage by METH dependence interaction effect is expected, such that NP effects of METH dependence will be greater in persons who have more advanced HIV disease (AIDS). White matter abnormalities are expected to result from both METH dependence and HIV infection, and to be associated most strongly with NP deficits in SIP and learning efficiency. Reduced striatal volumes on MR morphometry are expected to relate most strongly to impaired motor skills, SIP, and learning. Also, in subjects who die during the course of the study, we predict that postmortem measures of viral burden and synaptodendritic complexity in frontostriatal circuitry will relate significantly to antemortem impairment in abstraction, verbal fluency, attention/working memory, learning, and motor functioning. We also will address the impact of METH dependence on HIV disease progression and NP functioning over time. Compared to non-drug abusing HIV+ subjects with comparable baseline NP status and CDC stage, the METH+/HIV+ subjects are expected to show higher rates of NP worsening over a 5-year period. In addition, baseline NP impairment and continuing METH abuse in HIV+ subjects are expected to predict failure to follow prescribed antiretroviral drug regimens accurately, which in turn will predict more rapid progression of immunosuppression and development of AIDS defining illnesses, as well decreased survival rates.