Resting-state fMRI-based perfusion-timing analysis in cerebral small vessel disease: biomarker potential and...

Cerebral small vessel disease (CSVD) is an important contributor to stroke and dementia, yet the role of venous dysfunction in its pathophysiology remains poorly understood. Resting-state fMRI captures spontaneous low-frequency oscillations (sLFOs), reflecting cerebral blood flow dynamics primarily in the venous system. We applied sLFO lag-time mapping to investigate venous perfusion alterations in covert CSVD. We stratified 572 community-dwelling individuals into controls and CSVD subtypes based on MRI markers, and compared voxel-wise lag-time-derived perfusion indices-mean positive lag-time, mean negative lag-time, and spatial lag-time distribution-between groups. Participants with ischemic CSVD exhibited significantly prolonged positive lag times, indicating altered perfusion timing in regions corresponding to the superficial venous drainage system. Voxel-wise analyses revealed heterogeneous alterations in perfusion timing and spatial distribution across CSVD subtypes, with both delayed and advanced venous timing observed in distinct regions of the superficial and deep venous systems. Hierarchical clustering analyses identified a distinct perfusion pattern in the strictly-lobar cerebral microbleeds subgroup, suggestive of cerebral amyloid angiopathy. These results suggest that altered venous perfusion timing is an early hallmark of CSVD, and that rs-fMRI lag-time mapping may serve as a non-invasive biomarker to detect early perfusion changes and distinguish between different CSVD pathophysiological processes.