Neurofunctional Mechanisms of Changes in Cognition and Motor Function in Aging with HIV and Parkinson's Disease

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PROJECT SUMMARY/ABSTRACT Since the introduction of successful treatment for human immunodeficiency virus (HIV) via antiretroviral therapy (ART), individuals infected with HIV are now living longer with estimates that in the United States over half of all HIV infected individuals and in California 67 percent of people living with HIV (PLWH) are over the age of 50. Due to this major demographic shift in the HIV-infected population in the US, and as outlined in PA-20-149, there is an urgent need to better define the underlying pathophysiology of neurological complications and neurocognitive decline in the aging HIV-infected populations. Despite ART treatment, HIV-associated neurocognitive disorders (HAND) occur with high heterogeneity in the pattern and severity of deficits, particularly in people aging on modern ART regimens. Our research points to neuroimaging biomarkers that could be of advantage for identifying diagnostic signatures and understanding the heterogeneity of CNS disease in relation to behavioral manifestations, that would need to be followed up with longitudinal research. Bradyphrenia was indicative of worse performance in other cognitive domains, mediated by basal ganglia-limbic brain pathway compromise, and related to bradykinesia, a main symptom in age-related neurodegeneration in Parkinson's disease (PD). Bradykinesia occurred in PLWH with more severe cognitive impairment and could be a sign of disease progression involving more widespread brain networks. Our novel application of fMRI-derived amplitudes of low frequency fluctuations (ALFF) indicated disrupted neurodynamics in subcortico-cortical circuits in older PLWH, with some overlap with the pathophysiology in PD8. Our research points to predictors of the interindividual variation in impairment profiles related to past HIV severity (nadir CD4, AIDS), current CD4 count, older age, alcohol and substance use, and sleep quality as a measure of resilience. Here, we extend this work in direct response to PA-20-149, aiming to longitudinally investigate the neurocognitive profile using the NIMH's Research Domain Criteria (RDoC) framework to evaluate previously identified neuroimaging biomarkers of cognitive and motor deficits in aviremic older PLWH on ART. We focus on the role of bradyphrenia and bradykinesia for the discovery of neuroimaging biomarkers for CNS disease progression by following our established study cohorts and new recruits of older PLWH, Parkinson's disease (PD), and age-matched healthy controls (HC). The specific aims of this proposal are to Aim 1: Identify neuroimaging biomarkers for worsening in cognition using a domain-based approach. Aim 2: Determine the role of subclinical parkinsonism for later impairment in PLWH, and similarities to PD. Aim 3: Seek modifiable risk factors and moderators for disease progression in PLWH.