Tuesday, April 23, 2024
4/23/2024
PROJECT SUMMARY/ABSTRACT In the era of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders, or HAND, remains high in people with HIV (PWH); as a result, there is increasing pressure to identify neural targets for effective therapies. However, to develop effective HAND treatments, a strong need exists for the development of sensitive behavioral tests that can quickly screen and effectively identify probable neurocognitive impairment in PWH and biomarkers that can accurately determine HAND status and evaluate therapeutic effects. This 5-year prospective, controlled, cross-sectional and longitudinal observational study is theoretically driven and specifically designed to tackle these challenges. Neural injury to the frontostriatal circuits (plus hippocampus, thalamus, and other associated regions) has long been recognized as a key component in HAND; however, the association between frontostriatal injury and HAND status remains to be elucidated. Recent findings suggest that injury to different key regions in the frontostriatal circuits may play differential roles in HAND: frontal injury is more prevalent in PWH, but striatal injury better predicts HAND status. This suggests that an accurate assessment of neural injury at different frontostriatal regions (in addition to other key regions such as the hippocampus and thalamus) may have the potential to serve as a biomarker to assist with HAND diagnosis and characterization. To test this hypothesis, we will investigate frontostriatal injury in PWH using two behavioral paradigms that are known to involve distinct frontostriatal regions, along with two advanced functional MRI (fMRI) techniques: fMRI- adaptation (fMRI-A) and multivariate pattern analysis (MVPA). Compared to conventional fMRI techniques, fMRI-A and MVPA techniques can better estimate neural tuning/selectivity that can be quantitatively related to behavioral performance. Briefly, we hypothesize that frontostriatal injury – a central component in HAND – is highly prevalent in PWH and can be assessed behaviorally via two behavioral paradigms (Aim 1a), and neurally via fMRI-A & MVPA (Aim 1b). Neural injury to other regions/networks will be assessed using a multimodal MRI approach (Aim 2). The integration of behavioral & fMRI data from Aim 1 with multimodal MRI data from Aim 2 will help to assess the degree of neural injury at frontostriatal and other regions/networks, which in turn may serve as a biomarker for HAND status (Aim 3). The probable impact of common comorbidities will also be investigated. In summary, this proposal is theoretically driven and highly innovative, with a strong promise for future clinically relevant development. The feasibility of the proposed research is supported by a strong foundation in cognitive neuroscience and neuroHIV, strong preliminary data, and an established research team. The success of this proposed project may help to develop sensitive behavioral tests that can effectively detect mild neurocognitive impairment in PWH, and a biomarker that can assist in determining HAND status/severity.
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