Glymphatic MR Imaging and Biomarker Discovery in Aging with HIV Infection

PROJECT SUMMARY/ABSTRACT With the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus (HIV), individuals living with HIV are experiencing longer lifespans. However, they face an increased risk of cognitive decline and neurological complications compared to their age-matched peers without HIV. Understanding the neurobiological mechanisms that contribute to the variability in cognitive and functional decline in aging populations, both with and without HIV, is essential for understanding long-term health outcomes and quality of life. Among the factors thought to contribute to the heightened risk for cognitive impairment is dysfunction of the brain's waste clearance system. The so-called glymphatic system (GS) is thought to clear proteins through the flow of cerebrospinal fluid via perivascular spaces (PVS) and through the brain`s parenchyma and is augmented during sleep. For example, protein accumulation of β-amyloid (Aβ) and tau associated plaques and neurofibrillary tangles are hallmark in Alzheimer's disease (AD), α-synuclein (α-syn) with aggregates in form of Lewy bodies are hallmark biomarkers in Parkinson's disease (PD). Understanding mechanisms of proteins clearance from brain tissue is critical to developing interventions prior to onset of cognitive decline but these mechanisms remain controversial. There is some evidence that HIV infection of the CNS contributes to abnormal aging with accumulation of tau and chronic neuroinflammation. Also, longer HIV disease duration and older age have been linked to an increased prevalence of α-syn and Aβ and higher risk of cognitive impairment and neurodegenerative disease. Our preliminary MRI data show more enlarged PVS, indicative of glymphatic dysfunction, in older PLWH than controls. There are limited means of non-invasively evaluating the brain waste clearance system in vivo in human brains. Given the proximity between the brain and the eye, tear fluid recently emerged as a promising easily collectible sample matrix for biomarker analysis of Aβ peptides, tau, and α-syn. We propose using innovative diffusion MRI of free water (FW) and intra voxel incoherent motion (IVIM), as proxies of brain waste clearance, together with α-syn, Aβ, and early tau burden quantified with tear proteomics. This high-risk R21 proposal requests funding for dMRI FW/IVIM data acquisition, tear proteomic laboratory costs, and their analyses. Data available from an R01 study include clinical assessments, cognitive data, and sleep biomarkers. Leveraging the deeply phenotyped PLWH and PD participant data from the parent R01 study, we propose two Specific Aims: 1. Determine associations of PVS, FW f and flow metrics with tear α-syn, Aβ, and tau burden. 2. Determine associations among IVIM metrics, protein burden, and sleep, with cognitive outcomes in PLWH and PD. This proposal addresses a critical gap in understanding the role of microscopic FW diffusion and flow within the context of α-syn, Aβ, and tau protein accumulation, disrupted sleep-wake behavior, and cognitive worsening in people aging with HIV infection.