Multimodal voxel-wise of structural and functional brain alterations across the cerebral small vessel disease spectrum.

backgroundCerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment and dementia, yet the neural structural and functional pattern of brain alterations across its clinical spectrum remains unclear. This study aimed to identify convergent and stage-specific structural and functional brain abnormalities in CSVD using a multimodal meta-analysis.

methodsFour electronic databases were searched including PubMed, Embase, Web of Science, and the Cochrane Library up to April 2025. Studies reporting whole-brain structural or functional differences comparing CSVD with normal cognition [CSVD-NC], CSVD-related mild cognitive impairment [CSVD-MCI], and CSVD-related vascular dementia [CSVD-VaD]) to healthy controls were included. Voxel-wise meta-analyses were performed using anisotropic effect-size seed-based d mapping (AES-SDM v5.15).

resultsA total of 33 datasets from 22 studies were included. CSVD-MCI patients showed increased activity in the left superior frontal gyrus, medial orbital and right lenticular nucleus, putamen, but decreased activity in the left superior medial frontal and right postcentral gyrus, alongside atrophy in the supplementary motor area and right insula. CSVD-VaD patients exhibited widespread functional and structural damage in the cingulate gyrus and corpus callosum. Multimodal analyses revealed early convergent alterations in fronto-thalamic circuits in CSVD-NC and a divergent alteration dynamic and often insidious toward callosal disruption in VaD.

conclusionOur findings map the spatial distribution of brain alterations across the clinical spectrum of CSVD, with distinct yet converging functional and structural impairments at each stage. Fronto-striatal hyperactivation and insular atrophy mark MCI, while callosal degradation characterizes VaD.