Subcortical Gray Matter Loss and Ventricular Enlargement Define Specific HIV Biotypes
Devon K. Dietrich1, Cynthia McMahan1, Tianxia Wu1, Govind Bhagavatheeshwaran1, Daniel S. Reich1, Joseph Snow2, Anuradha Ganesan3, Catherine Berjohn4, Brian K. Agan3, Avindra Nath1, Bryan R. Smith1
1National Institute of Neurological Disorders and Stroke, 2National Institute of Mental Health, 3Infectious Disease Clinical Research Program, Henry M. Jackson Foundation for the Advancement of the Military Medicine, Inc., 4Infectious Disease Clinical Research Program, Naval Medical Center San Diego
Objective:
To identify and characterize neurodegenerative biotypes in people with HIV (PWH).
Background:
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.
Design/Methods:
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.
Results:
Our cohort included 209 PWH (159 male, 50 female) and 64 controls (34 male, 30 female). Subsets with the worst 20th 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).
Conclusions:
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.