Bridging structure and function: triple network remodeling driven by white matter hyperintensities in vascular...

Cerebral small vessel disease-induced vascular cognitive impairment (VCI) is a major contributor to the pathogenesis of dementia. Accumulating evidence suggests that VCI disrupts large-scale brain networks, but how it selectively impairs inter-network connectivity and contributes to specific cognitive deficits remains unclear. This case-control study included 132 participants (74 VCI patients, 58 healthy controls) who underwent neuropsychological assessments and multimodal MRI. To investigate changes in core networks supporting higher-order cognition, we analyzed intra- and inter-network functional connectivity of the default mode network (DMN), salience network (SN), and frontoparietal network (FPN) using independent component analysis (ICA) and dynamic functional network connectivity (dFNC). Structural alterations were assessed using voxel-based morphometry and tract-based spatial statistics. Mediation analysis evaluated whether white matter hyperintensities (WMH) affected cognition through altered network connectivity. VCI participants showed gray matter atrophy within cognitive networks, including the hippocampus, orbitofrontal cortex, and middle frontal gyrus. White matter integrity was also compromised, with reduced fractional anisotropy in the SN and FPN. Functional connectivity analysis revealed decreased intra-network connectivity in the precuneus (DMN), supramarginal gyrus (SN), and inferior parietal lobule (FPN). dFNC analysis indicated less time spent in a state of strong left FPN-SN connectivity. Mediation analysis revealed a hierarchical pattern of network interactions. SN connectivity partially mediated the relationship between the DMN and FPN, while DMN-right FPN connectivity fully mediated the association between WMH burden and memory impairment. This study shows that VCI involves structural and functional network disruption. Inter-network dysfunction links vascular burden to memory impairment. These findings may inform early detection and network-based interventions for vascular cognitive impairment.