DESCRIPTION (from applicant's abstract): Drug misuse by injecting is a global problem, which is increasing in incidence in many countries, and which is associated with increased morbidity and mortality particularly in young people. Injecting drug use is also a major risk activity for the spread for HIV infection. This project will study drug and HIV related neuropathology and Apolipoprotein E polymorphisms in a clinically well-characterized cohort of drug users in Edinburgh, Scotland, who have a high prevalence of chaotic and injecting drug use, and of HIV infection. Their lifetime drug history, and premorbid and comorbid neuropsychological and general health status is well documented. Despite early identification of the HIV epidemic in this group, and a program of methadone substitution, the mortality rate has been high, both from drug-related causes and from associated HIV and hepatitis C infections. The cohort has been characterized by a very high prevalence of HIV encephalitis [59 percent] when they progressed to AIDS. This study will include patients with pure HIV encephalitis who did, or did not, use drugs, drug users who were HIV negative and controls who were neither HIV infected nor used drugs. Histological and immunocytochemical methods will be applied to detect neurodegenerative changes particularly in the basal ganglia, central white matter and brain stem nuclei, and to quantify acute and chronic damage to the blood brain barrier. It is expected that the targets of drug and HIV related neuropathology will overlap and that the damage will be cumulative in patients who are both drug users and have HIV encephalitis. In order to explore further the question of why individuals vary in their susceptibility to the damaging effects of drugs, it is proposed to investigate Apolipoprotein E polymorphisms in the cohort since this gene exerts a major influence on other neurodegenerative and cerebrovascular diseases and has been linked to HIV related cognitive decline. Further cases will be recruiter] in order to study this possible synergy between and drug use in the more recent context of combination drug therapy. Morbidity problems associated with drug misuse are a significant drain on the health budget of many nations, quite apart from the more general impact on society. Identification of particularly hazardous patterns of illicit drug(s) use, and of possible genetic susceptibility, could lead to more focused prevention and intervention strategies in at risk cohorts and individuals.