Mapping the Association of Cerebral Small Vessel Disease, Gray Matter Integrity, and Cognitive Function

Cerebral small vessel disease (CSVD) is associated with an increased risk of cognitive impairment and dementia. While its impact on white matter is well documented, CSVD-related gray matter alterations are less understood. In this work, we aimed to investigate the association between CSVD burden, regional gray matter integrity, and cognitive function in a large population-based cohort.

We examined participants from the Hamburg City Health Study, who underwent multidomain neuropsychological testing and multimodal neuroimaging. A composite CSVD burden score was calculated by aggregating the white matter hyperintensity load, Fazekas score, perivascular space (PVS) count, and peak width of skeletonized mean diffusivity (PSMD). Advanced imaging techniques based on T1-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted MRI were leveraged to assess the integrity of cortical and subcortical gray matter, including the hippocampus. General cognitive ability (g) was derived by a principal component analysis of cognitive test scores.

Data from 2,603 participants (median age 65 years [interquartile range 14], 44.0% female) were analyzed. Higher CSVD burden was significantly associated with regionally specific gray matter abnormalities after family-wise error correction (family-wise error-corrected p value [p_FWE] < 0.05): higher mean diffusivity and free water in cingulate, insular, and temporal cortices and basal ganglia; lower tissue fractional anisotropy in the anterior cingulate, insula, caudate, and hippocampus; lower T1/FLAIR ratio in the temporal cortex and hippocampus; lower thickness in the anterior cingulate, insula, and temporal cortex; and altered subcortical/hippocampal volumes. Aggregated indices reflecting these CSVD-related gray matter abnormalities were significantly associated with lower general cognitive ability (mean diffusivity: standardized β = 0.140, 95% CI 0.09-0.19, p_FWE < 0.001; free water: standardized β = 0.183, 95% CI 0.13-0.23, p_FWE < 0.001; tissue fractional anisotropy: standardized β = -0.097, 95% CI -0.13 to -0.06, p_FWE < 0.001; T1/FLAIR: standardized β = -0.090, 95% CI -0.13 to -0.05, p_FWE < 0.001; thickness/volume: standardized β = -0.051, 95% CI -0.09 to -0.01, p_FWE = 0.026).

Complementing previous research that focuses on CSVD and white matter changes, our study highlights abnormal gray matter integrity as a possible link between small vessel pathology and cognitive disorders.