Sources of Active Brain White Matter Injury in Virally Suppressed HIV Infection Revealed Through Fixel-Based Analysis

Background: To better understand HIV and cardiovascular disease (CVD) effects on brain white matter during HIV infection, advanced diffusion imaging and comprehensive predictor analyses are essential. Setting: Prospective observational cohort study Method: 84 virally suppressed people with HIV infection (PWH) and 48 uninfected controls underwent T1-weighted, FLAIR, and diffusion MRI at baseline and 24 months later (75 PWH and 40 controls). White Matter Hyperintensity (WMH) volumes were derived from structural scans. Fixel-based analysis tract-based metrics included fibre density (FD), fibre cross-section (FC) and fibre density and cross-section (FDC). Results: Relative to controls, mixed models showed significant reductions (p<.05 - p<.01) of FC, and lower FDC to a lesser extent, in multiple long cortical association tracts, and within striatal- and thalamic-frontoparietal connections in PWH at both time points. Higher CVD risk was associated with reduced FC in the arcuate fasciculus and FDC in the cingulate gyrus (p<.05). In PWH, more severe cognitive impairment and longer duration of HIV disease was associated with worse FDC across multiple tracts (p<.03 – p<.001). Lower baseline CD4 counts was associated with lower FD in the frontal association tracts (p<.05 – p<.005). Higher WMH volume was associated with higher CVD risk (periventricular p<.001, deep p<.03), but not HIV status. Conclusions: Major brain white matter tracts are impacted by HIV status, HIV duration, cognitive impairment, baseline CD4, and CVD risk to a lesser extent, despite equal WMH burden between infection groups. Our study provides further evidence of active immuno-vascular underpinning of HIV neuropathogenesis on fine white matter structure despite controlled HIV.