Diffusion MRI Identifies a Prolonged Pre-WMH Phase in Cerebral Small Vessel Disease

Area of Science:

• Neurology
• Radiology
• Biomarkers

Background:

• White matter hyperintensities (WMH) indicate late-stage cerebral small vessel disease (SVD).
• Diffusion MRI biomarkers may detect earlier microstructural damage from SVD.
• The progression of diffusion MRI biomarkers relative to WMH and associated risk factors are not well understood.

Purpose of the Study:

• To investigate the temporal progression of diffusion MRI biomarkers in relation to WMH.
• To identify risk factors associated with the progression of these biomarkers.
• To explore the potential of diffusion MRI for early SVD detection.

Main Methods:

• Utilized longitudinal neuroimaging data from 2077 participants (aged 50-101) in the Mayo Clinic Study of Aging.
• Employed multioutput nonlinear mixed-effects models to analyze WMH and four diffusion MRI biomarkers (fractional anisotropy, peak width of skeletonized mean diffusivity, free water, Arteriolosclerosis-score).
• Incorporated participant-specific time shifts, biomarker correlations, and risk factors (sex, education, APOE ε4, cardiometabolic conditions).

Main Results:

• Diffusion MRI biomarkers showed abnormalities significantly earlier than WMH, with Arteriolosclerosis-score abnormal 16 years prior, followed by fractional anisotropy (12 years), free water (10 years), and peak width of skeletonized mean diffusivity (7 years).
• Global markers were correlated, suggesting shared injury mechanisms.
• Cardiometabolic conditions accelerated the worsening of all biomarkers; sex influenced the timing of specific biomarker abnormalities.

Conclusions:

• Diffusion MRI biomarkers precede WMH by over a decade, indicating a prolonged early SVD phase.
• These findings underscore the potential of diffusion MRI for SVD prevention strategies.
• Early detection of SVD through diffusion MRI could enable timely interventions.