Associations of Ventricular Enlargement and Extracellular Free Water With Periventricular White Matter Injury in Older Adults

Background and Objectives Ventricular enlargement and hypertension are key features of white matter injury, yet the pathways linking them to lesion development remain poorly understood. Extracellular free water (FW), a marker of fluid accumulation, may capture early periventricular alterations preceding white matter hyperintensities. We examined how hypertension, ventricular enlargement, and FW relate to white matter hyperintensity (WMH) burden and progression. Methods We analyzed participants from the University of California Davis Alzheimer's Disease Research Center, a longitudinal community-based cohort of cognitively normal individuals and participants with mild cognitive impairment or dementia. Participants with at least 1 standardized MRI examination were included. Linear mixed-effects models were used to examine associations between hypertension, ventricular volume, FW, and WMH burden and progression. To characterize periventricular spatial patterns, FW and WMH were analyzed across 2-mm white matter layers extending from 0 to 10 mm from the ventricular surface. Results Among 1,053 participants (mean age 75.3 years, 61.3% women), hypertension was associated with larger ventricular volume (β = 0.15, 95% confidence interval [CI]: [0.02; 0.28], p = 0.0203) but not with ventricular expansion over time ( p > 0.05). Larger ventricular volume was associated with higher FW at baseline FW (β = 0.12, CI: [0.09; 0.15]) and greater FW increase over time (β = 0.089, CI: [0.02; 0.15]). FW demonstrated a clear spatial gradient, with higher values near the ventricles (β = −0.24, CI: [-0.24; −0.23], p < 0.001). Higher baseline FW was associated with greater WMH burden (β = 1.73, CI: [1.61; 1.85]) and greater WMH progression (β = 0.76, CI: [0.52; 0.99]), with stronger associations closer to the ventricles. Discussion Hypertension, ventricular enlargement, extracellular FW, and periventricular WMHs were associated in a pattern consistent with altered ventricular-interstitial fluid dynamics in older adults. Because of the observational design and the nonspecific nature of FW, causal inferences and the biological origin of extracellular water cannot be established.