Diffusion MRI identifies a prolonged Pre-WMH Phase in Cerebral Small Vessel Disease
TL;DR
Diffusion MRI biomarkers were abnormal at least a decade before WMH abnormality in the population, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.
Abstract
Background: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. Methods: We identified 2,077 participants from the population-based cohort study of Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 to 09/2024 with longitudinal neuroimaging. Using multi-output nonlinear mixed-effects models in those with at least two FLAIR-MRI and diffusion-MRI scans, we characterized the temporal progression of WMH, and four diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS) which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). Results: Study population had mean age of 78 years, 47% were women, 28% APOE ε4 allele carriers, 80% cognitively unimpaired with average 5.2 years (standard deviation=4.3 years) follow-up for FLAIR-MRI and 4.3 years (standard deviation=3.9 years) for diffusion MRI. ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH becomes abnormal (half-width of CI <1 year), respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities. Conclusions: Diffusion MRI biomarkers were abnormal at least a decade before WMH abnormality in the population, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.