White matter microstructure fingerprint of cerebral small vessel disease.

White matter hyperintensities (WMHs) are the imaging hallmark of cerebral small vessel disease (SVD), yet their microstructural composition, spatial heterogeneity, and relationship to diffuse normal-appearing white matter (NAWM) damage and cardiovascular risk remain incompletely defined. In 363 community-dwelling adults from the BrainLaus cohort (mean age 55.5 years; range 19.8-89.4; 48.8% male), we combined quantitative relaxometry (MTsat, R1, R2*) and diffusion-derived metrics (FA, MD, NODDI, g-ratio). WMHs were automatically segmented on FLAIR and microstructure was quantified across lobes, white matter compartments, and geodesic layers extending from the WMH core into surrounding NAWM. Multivariate organisation was assessed using principal component analysis, and associations with cardiovascular risk factors were tested using partial least squares. Our analysis revealed demyelination, axonal loss, and extracellular fluid accumulation, particularly in periventricular regions. Layer-specific profiles showed a centrifugal gradient, with myelin loss and oedema at the core and axonal alteration in surrounding tissue. These signatures were associated with age-related cardiovascular risk factors, including higher blood pressure, bioimpedance, and lower haemoglobin levels. WMHs index the endpoint of a broader, spatially structured white matter injury process that extends into NAWM, is regionally concentrated in periventricular tissue, and covaries with systemic vascular/metabolic factors. These findings support sustained vascular risk management to mitigate CSVD-related white matter degeneration.