Elucidating the Role of Frontostriatal Neural Circuits in HIV-Associated Neurocognitive Disorders

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PROJECT SUMMARY/ABSTRACT While combination antiretroviral therapy (cART) has significantly extended the lifespan of people with HIV (PWH), nearly half of all PWH are estimated to have HIV-associated neurocognitive disorders (HAND). Even mild forms of HAND, which are more prevalent in the cART era, significantly reduce quality of life for PWH and can result in unemployment, lack of adherence to antiretroviral therapy, and increased mortality. With a rapidly aging population, there is increased demand for improved understanding of the neural mechanisms of HAND – especially prior to the onset of clinical symptoms – as older PWH are at an increased risk of developing HAND. While dysfunction within the frontostriatal circuits has been implicated in HAND, the profile of disruption within these circuits remains elusive. The goal of this work is to determine whether functional and structural frontostriatal abnormalities present in older, virally suppressed PWH with minimal cognitive impairment. Utilizing structural and functional MRI techniques, this proposal will address the following specific aims. My dissertation research thus far (Aim 1) indicates that older, virally suppressed PWH with minimal cognitive impairment have reduced frontostriatal functional connectivity compared to controls. In addition, increased HIV disease severity and decreased neurocognitive function were associated with cortical thinning in PWH, especially in the prefrontal cortex. In the next phase of my dissertation (F99, Aim 2), I will test the hypotheses that frontostriatal white matter connections are compromised in older PWH compared to controls and that the relationship between HIV disease severity and executive function is mediated by frontostriatal white matter integrity. Results from these studies will provide critical insights into the neural mechanisms of HAND, inform the development of early diagnostic methods, and help identify potential therapeutic targets. Upon completion of my dissertation, I plan to complete a postdoctoral fellowship (K00, Aim 3) studying how comorbid conditions (e.g. depression) in people with HIV contribute to HAND development and progression.