White Matter Microstructure Fingerprint of Cerebral Small Vessel Disease

There is much controversy about the spatial heterogeneity and microstructural characterisation of white matter hyperintensities (WMHs), the neuroimaging hallmark of cerebral small vessel disease. To address this knowledge gap, we analysed relaxometry and diffusion-weighted magnetic resonance imaging (MRI) together with cardiovascular risk data in a community-dwelling adult cohort (202 participants, mean age: 69.2 years, range: 53.3-85.4 years, 110 females). Following automated WMH detection, we compared MRI-derived metrics of tissue myelination, iron content, axonal density, and extracellular water, between WMH and normal-appearing white matter (NAWM). Principal component analysis demonstrated a pattern of demyelination, axonal loss, and extracellular fluid accumulation, particularly pronounced in periventricular regions. The layer-specific profiles of theWMHs revealed a centrifugal gradient of white matter vulnerability, with myelin loss and extracellular water accumulation, interpreted as oedema, at the core, and ongoing axonal reorganization and demyelination in the surrounding tissue. The obtained signatures of white matter pathology were intimately linked to the aging-related increase in cardiovascular risk. High blood pressure and impaired glucose regulation, together with reduced cholesterol and hemoglobin levels, emerged as key contributors. Our findings suggest that WMHs represent the radiologically visible endpoint of a more widespread white matter damage in cerebral small vessel disease. This underscores the pressing need for early detection and consequent treatment of cardiovascular risk factors.