Specific genetic and biological patterns underlying cortical morphological alterations in vascular cognitive impairment

The pathogenic mechanisms of vascular cognitive impairment (VCI) are complicated, involving brain atrophy, parenchymal damage, and functional dysconnectivity associated with vascular risk factors, cerebrovascular diseases, and mixed pathologies. The alterations of the cortical structural similarity in VCI and their relationships with specific gene expression patterns and neurobiological characteristics have not been fully investigated. Individual Morphometric INverse Divergence (MIND) networks were constructed from structural MRI data from all participants. General linear model (GLM) and partial least squares (PLS) analysis were utilized to assess the alterations in MIND and the spatial associations of MIND differences with brain-wide transcriptional patterns. Finally, enrichment analysis of PLS weighted genes, along with cell-type-specific genes, and correlation analysis of MIND changes and neurotransmitter receptors, as well as mitochondrial metrics, were conducted to examine the neurobiological foundations of cortical morphometric similarity changes. A total of 245 individuals were enrolled, including 100 cognitively unimpaired (CU) individuals and 145 VCI patients. Compared with the CU subjects, individuals with VCI showed reduced MIND in the frontal, parietal, and cingulate lobes. The PLS2− weighted genes correlated with MIND changes in VCI overlapped with genes related to oligodendrocytes and neurons. They were also substantially enriched in neuronal system activities and the RHO GTPase cycle associated with signal transduction and cytoskeleton regulation. The differences in MIND between the two groups were spatially associated with the levels of multiple neurobiological features. Our results improved the understanding of the transcriptional patterns and molecular features at the micro level that contribute to macroscale changes in morphological resemblance among individuals with VCI, offering potential clues for future diagnostic and therapeutic studies.