Cerebral white matter free water: A sensitive biomarker of cognition and function

Objective To determine whether free water (FW) content, initially developed to correct metrics derivedfrom diffusion tensor imaging and recently found to be strongly associated with vascular risk factors, may constitute a sensitive biomarker of white matter (WM) microstructural differences associated with cognitive performance but remains unknown. Methods Five hundred thirty-six cognitively diverse individuals, aged 77 ± 8 years, received yearly comprehensive clinical evaluations and a baselineMRI examination of whom 224 underwent follow-up MRI. WM microstructural measures, including FW, fractional anisotropy, and mean diffusivity corrected for FW and WM hyperintensityburden were computed within WM voxels of each individual. Baselineand change in MRI metrics were then used as independent variables to explain baselineand change in episodic memory(EM), executive function (EF), and Clinical Dementia Rating(CDR) scores using linear, logistic, and Cox proportional-hazards regressions. Results Higher baselineFW and WM hyperintensitywere associated with lower baselineEM and EF, higher baselineCDR, accelerated EF and EM decline, and higher probability to transition to a more severe CDR stage ( p values p values Conclusions This study finds cross-sectional and longitudinal associations between FW content and trajectory of cognitive and functional performance in a large sample of cognitively diverse individuals. It supports the need to investigate the pathophysiologic process that manifests increased FW, potentially leading to more severe WM territory injury and promoting cognitive and functional decline.