Novel Methods to Access Brain Function in HIV-1

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Since the availability of potent antiretroviral therapy, the incidence of opportunistic infections and neoplasms in HIV-1-infected individuals in the developed world has dramatically declined. In contrast, the incidence of dementia has declined less. The reason for this difference is not known, but it may be due to the inability of some antiretroviral agents to penetrate the central nervous system (CNS). Data from our preliminary clinical studies and from studies of other groups suggest that treatment and prevention of HIV-1-associated cognitive impairment will require control of both peripheral and central HIV-1 infection throughout the course of disease. The primary goal of this R21 application is to generate preliminary data on functional magnetic resonance imaging (fMRI) and functional magnetic resonance spectroscopy (fMRS). These data will be used to support a trial that assesses the efficacy of antiretroviral therapy in the CNS using functional neuroimaging. This application is written in response to NIMH PA-99-134, "Exploratory/Developmental Grants for MH Intervention Research". As suggested in the Program Announcement (PA), we will pilot test an intervention (fMRI and fMRS) that identifies early signs of a disorder (brain dysfunction due to HIV-1 infection) in a high-risk group (subjects with advanced HIV-1-associated disease). We will address stage 2 and stage 3 of intervention development as outlined in the PA. In stage 2, we will develop fMRI and fMRS as diagnostic tests of brain function in HIV-1-uninfected and HIV-1-infected subjects. In stage 3, we will perform a pilot study of changes in these functional neuroimaging measures in response to potent antiretroviral therapy. Specifically, the aims of this project are: 1) Optimize the fMRI and fMRS method, including correction for brain perfusion, and estimate variability of these measures of brain activation over time in HIV-1-uninfected subjects; 2) Estimate differences in brain activation as measured by fMRI and fMRS between HIV-1-uninfected and HIV-1-infected individuals; 3) Perform a pilot study to estimate the magnitude of changes in brain activation as measured by fMRI and fMRS and by neuropsychological test performance in response to potent antiretroviral therapy in HIV-1- infected individuals. The studies proposed in this application may ultimately lead to better means of assessing the efficacy of therapy in the CNS compartment and thus to an improvement in our ability to prevent and treat HIV-1 -associated dementia.