In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV.

PROJECT SUMMARY Older people with HIV (PWH) in the United States are a rapidly expanding group and are at increased risk for depression and cognitive impairment despite virologic suppression. While major depressive disorder is a critical contributor to reduced quality of life and currently affects 20-40% of PWH, there are no effective

diagnostics and limited therapeutics to predict disease and mitigate morbidity in PWH on antiretroviral therapy. As more providers in HIV clinics care for an aging population with HIV, we recognize the need for accessible diagnostics to assess neuropathology in clinical settings and interventional studies. We also recognize the

need to consider depression subtypes unique to older people with HIV before initiating effective antidepression therapies. Recent advances in magnetic resonance imaging (MRI) technology allow for low magnetic field strength imaging (LF-MRI) at 1/10th the cost of conventional, high-field MRI, and can be performed outside of

the controlled access environments of an MRI suite. This will enable portable LF- MRI to become part of a clinical repertoire of diagnostic tools in neurology clinics and in clinical trial design for neuropsychiatric diseases. Assessing the diagnostic performance of this point-of-care neuroimaging tool for evaluating

depression and cognitive impairment in cohorts of older PWH on antiretroviral therapy is critically important. In the parent R01 (MH131194), the PI (Dr. Shibani Mukerji) and research team detailed methods for evaluating a biological subtype of depression related to neuroactive steroids, a cholesterol-derived hormone in people with

HIV on antiretroviral therapy. The study is a randomized, placebo-controlled clinical trial of pregnenolone in people with HIV and depression (SOOTHE; NCT05570812). In this administrative supplement, the research team will focus on older PWH (age 55-years and over) with depression, leveraging the SOOTHE infrastructure

to investigate the relationship between depression and neuropathology common to older PWH (atrophy and cerebral small vessel disease) using portable LF-MRI. These neuroimaging markers are actively under investigation for age-associated dementia decline in older people without HIV presenting to memory clinics.

Data generated from this proposal will be used to expand the SOOTHE model in assessing subtypes of depression amenable to neuroactive steroids and determine the use of LF-MRI in trial design for therapeutic efficacy among people aging with HIV.