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

Abstract

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 T1-weighted, quantitative R1, R2*, and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity (MD) 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 MD of the connecting white matter tracts were related to lower thickness (β=-0.30, p-corrected<0.001), R1 (β=-0.26, p-corrected=0.001), R2* (β=-0.32, p-corrected<0.001) and susceptibility values (β=-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 (β=0.20, p-corrected=0.030), lower R1 values (β=0.20, p-corrected=0.006), lower R2* values (β=0.29, p-corrected=0.006), and lower susceptibility values (β=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.

Age-Related Differences in Human Cortical Microstructure Depend on the Distance to the Nearest Vein

“…Additional analyses of time-of-flight MRI measurements would benefit future studies. Moreover, previous studies pointed out that hypertension and alterations in brain vasculature relate to myelin loss and M1 pathology (Jacków-Nowicka et al 2021; Tsushima, et al 2003; Dobrynina et al 2018, Li et al 2023; Schreiber et al 2023). Here, 9/17 older adults showed global signs of vascular health risk (i.e., presence of hypertension and/or signs of cerebral small vessel diseases outside S1 and M1).…”

Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease

“…27 Cortical areas with a low probability of connectivity were determined using the threshold of the lowest level at 3.08 × 10 −5 percent of the total streamlines sent out from the seed masks, based on previous literature. 6,28 Cortical areas with medium and high probability (medium probability) or 25% (high probability) of the initial (low probability) surface size. 27 The cortical area connected with the WMHs was defined as the cortical region of interest (ROI).…”

“…Considering the non-uniform distribution of cortical thickness across the brain regions, it will be hard to attribute any potential corti-cal thinning in WMH-connected regions to the remote effects of WMH or the inter-regional differences in cortical thickness. 6 To minimize this effect, we split the ROIs and rROIs into six cortical regions, including frontal, temporal, parietal, occipital, cingulate, and insula cortex. The mean cortical thickness of ROI was divided by the mean cortical thickness of rROI within each region, resulting in six cortical thickness ratios of ROI to rROI.…”

“…4 WMHs are reported to contribute to the thinning of the regional cortex connected to WMHs in SVD patients. [5][6][7][8] Previous studies demonstrated that the microstructural metrics of white matter tracts passing through WMHs were related to regional cortical abnormalities in the WMH-connected cortex as measured by cortical thickness, R1, R2*, and susceptibility values, and further impaired processing speed in SVD. 6 The relationship between WMHs and cortical changes in WMHconnected cortex in AD remains unclear.…”

“…[5][6][7][8] Previous studies demonstrated that the microstructural metrics of white matter tracts passing through WMHs were related to regional cortical abnormalities in the WMH-connected cortex as measured by cortical thickness, R1, R2*, and susceptibility values, and further impaired processing speed in SVD. 6 The relationship between WMHs and cortical changes in WMHconnected cortex in AD remains unclear. In addition to the possible findings of cortical thinning, we hypothesize that WMHs may correlate with amyloid beta (Aβ) and tau deposition, as well as synaptic density change, in WMH-connected cortex.…”