Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e. processing speed, executive function and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T-1-weighted, quantitative R1, R2* and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity of the connecting white matter tracts. We found that cortical thickness, R1, R2* and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all P-corrected < 0.001). Linear regression analyses showed that higher mean diffusivity of the connecting white matter tracts were related to lower thickness (beta = -0.30, P-corrected < 0.001), lower R1 (beta = -0.26, P-corrected = 0.001), lower R2* (beta = -0.32, P-corrected < 0.001) and lower susceptibility values (beta = -0.39, P-corrected < 0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (beta = 0.20, P-corrected = 0.030), lower R1 values (beta = 0.20, P-corrected = 0.006), lower R2* values (beta = 0.29, P-corrected = 0.006) and lower susceptibility values (beta = 0.19, P-corrected = 0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary degeneration.