White matter hyperintensities drive propagating grey matter atrophy in cerebral small vessel disease

WMH, a neuroimaging marker of cerebral small vessel disease, is closely associated with cognitive decline and structural brain changes. However, the precise mechanisms through which WMH-associated GMV changes ultimately translate to cognitive decline remain unclear, particularly regarding propagation patterns and causal interactions within affected neural circuits. To investigate the progressive structural changes in WMH patients based on disease severity, we recruited 185 patients with cerebral small vessel disease and 40 healthy controls, who underwent magnetic resonance imaging scans. First, voxel-based morphometry analysis was performed to compare GMV differences between WMH patients and healthy controls, followed by subgroup analyses across different disease stages to identify key regions with significant morphological changes. Subsequently, causal structural covariance network analysis, modularity analysis and functional decoding were employed to map the causal relationships of GMV changes, the hierarchical topography and functional characteristics of the structural network throughout the WMH progression. Finally, mediation analysis was conducted to explore the relationships between WMH volume, GMV, and cognition, providing insights into the underlying causal pathways. The results revealed that GMV reductions originated in the right insula and progressively extended to cortical and subcortical regions with increasing disease severity. Causal structural covariance network analysis identified the right insula as a central hub, exerting causal effects on GMV reductions in regions associated with executive function and attention. Modularity analysis and functional decoding further highlighted key pathways linking the right insula to cortico-subcortical networks involved in cognitive regulation and motor coordination. Additionally, compensatory GMV increases were observed in specific regions, suggesting neuroplastic responses to WMH-related damage. Mediation analysis demonstrated that GMV reductions significantly mediated the relationship between WMH volume and cognitive impairments, particularly in executive function and processing speed. Overall, the right insula acts as a critical hub driving hierarchical GMV atrophy and network disruption in WMH. Its early involvement and causal influence highlight its importance as a potential target for interventions to mitigate cognitive decline.