Subcortical Gray Matter Loss and Ventricular Enlargement Define Specific HIV Biotypes (S25.008) (2023)

<h3>Objective:</h3> To identify and characterize neurodegenerative biotypes in people with HIV (PWH). <h3>Background:</h3> PWH may develop brain atrophy and neurocognitive dysfunction despite suppressive antiretroviral therapy. Distinguishing biotypes within this population is critical since they may represent unique underlying pathophysiological mechanisms and require different therapeutic approaches. <h3>Design/Methods:</h3> Participants in a longitudinal natural history study of a large, well-characterized, diverse cohort of PWH and matched controls underwent deep phenotyping including MRI and neuropsychological testing. Subcortical gray matter (SGM) and ventricular volumetrics were derived from FreeSurfer, then transformed into percentiles adjusted for age, sex, skull size, and MRI scanner. Correlation coefficients between percentile and clinical variables were calculated. Logistic regression assessed effects of continuous clinical variables on binary percentiles. <h3>Results:</h3> Our cohort included 209 PWH (159 male, 50 female) and 64 controls (34 male, 30 female). Subsets with the worst 20<sup>th</sup> percentile of SGM atrophy (n=51) or ventricular enlargement (n=77) were identified. In PWH with SGM atrophy (n=43), analyses controlled for age, sex, and IQ showed positive associations with overall T-score (r=0.41, p=0.008); executive (r=0.43, p=0.004), learning (r=0.37, p=0.015), memory (r=0.38, p=0.014), and motor (r=0.36, p=0.021) domains; and global deficit score (GDS) (r=−0.37, p=0.015). Interestingly, SGM percentile also negatively correlated with total cholesterol (r=−0.44, p=0.014). Ventricular enlargement was associated with lower overall T-score in both HIV+ males (OR=0.92, CI=0.87–0.98, p=0.011) and HIV+ females (OR=0.89, CI=0.80–0.98, p=0.032). In HIV+ males, ventricular enlargement was associated with reduced verbal (OR=0.94, CI=0.89–0.98, p=0.010), speed of information processing (OR=0.96, CI=0.91–1.00, p=0.037), and motor (OR=0.94, CI=0.89–0.98, p=0.004) performance. In HIV+ females, it was associated with increased GDS (OR=8.20, CI=1.43–81.56, p=0.042) and systolic blood pressure (OR=1.04, CI=1.00–1.09, p=0.038). <h3>Conclusions:</h3> PWH with neurodegeneration can be grouped into SGM atrophy or ventricular enlargement biotypes. These subsets associate with distinct neurocognitive deficits and clinical risk factors, suggesting disparate underlying pathophysiological mechanisms. <b>Disclosure:</b> Ms. Dietrich has nothing to disclose. Ms. McMahan has nothing to disclose. Tianxia Wu has nothing to disclose. Mr. Bhagavatheeshwaran has received research support from National Institutes of Health. Dr. Reich has received research support from NIH. The institution of Dr. Reich has received research support from Vertex Pharmaceuticals. The institution of Dr. Reich has received research support from Adelson Medical Research Foundation. The institution of Dr. Reich has received research support from Myelin Repair Foundation. The institution of Dr. Reich has received research support from Sanofi-Genzyme. The institution of Dr. Reich has received research support from Abata Therapeutics. The institution of Dr. Reich has received research support from National Multiple Sclerosis Society. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with PeerView. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with AcademicCME. Dr. Reich has a non-compensated relationship as a Advisor with Sanofi-Genzyme that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Board of Directors with ACTRIMS that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Abata Therapeutics that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Roche that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with American Brain Foundation that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with University of Basel RC2NB that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Multiple Sclerosis Society of Canada that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Tuscan Doctorate in Neuroscience that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Editorial Board with Multiple Sclerosis Journal that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Glaxo-Smith-Kline that is relevant to AAN interests or activities. Dr. Snow has received research support from NIH/NIMH. The institution of Anuradha Ganesan has received research support from NIAID. Dr. Berjohn has received personal compensation in the range of $100,000-$499,999 for serving as a Active Duty Physician salary with US Navy. Brian K. Agan has received personal compensation for serving as an employee of Henry M. Jackson Foundation for the Advancement of Military Medicine. Dr. Nath has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Nath has received research support from National Institutes of Health. The institution of Dr. Nath has received research support from ALS Association. Dr. Smith has nothing to disclose.