Myelin-driven structural network redundancy underlies cognition in cerebral small vessel disease

White matter hyperinxtensity (WMH) and normal-appearing white matter (NAWM) are critical markers for tracking disease progression in cerebral small vessel disease (CSVD), indicative of a spectrum of white matter injury. The core pathological alteration underlying such injury is the disruption of myelin integrity and loss of axons. We hypothesized that the myelin content in WMH and NAWM may exert distinct effects on brain networks and cognition in CSVD.

A total of 129 diagnosed CSVD patients were retrospectively enrolled. Myelin content was assessed with sub-voxel precision using iterAtive magnetic suscePtibility sources sepARaTion Quantitative Susceptibility Mapping (APART-QSM). Structural network redundancy was derived from diffusion tensor imaging (DTI). WMH and NAWM masks were generated. Associations between WMH/NAWM myelin content, structural network redundancy, and cognitive performance were examined using partial correlation and mediation analyses.

Myelin content was significantly higher in NAWM than in WMH. Decreased structural network redundancy was significantly linked to myelin loss in NAWM but not in WMH. Moreover, redundancy indirectly linked NAWM myelin to cognition, whereas no such indirect pathway was observed for WMH myelin. No direct or total effect of myelin content on cognition was observed.

These findings highlight the critical role of NAWM-related myelin integrity in preserving cognition through its association with structural network redundancy in CSVD.