Spatial gene expression and functional network abnormalities in multiple sclerosis: exploring biological influence on brain functional reorganization

In multiple sclerosis (MS), functional network abnormalities arise as structural damage accumulates. However their biological basis and spatial distribution remain unclear. This study investigated the associations between MS-related functional network abnormalities and physiological gene expression using the Allen Human Brain Atlas (AHBA). Five-hundred fifty-eight MS patients and 214 healthy controls (HC) underwent neurological assessment and 3 T MRI; 491 patients also completed a neuropsychological evaluation. Resting-state functional MRI was used to generate degree centrality maps to identify network topography alterations. Spatial correlations between centrality abnormalities (p < 0.01 uncorrected) and the expression of 3634 MS-related genes was evaluated using AHBA and the Multimodal Environment for Neuroimaging and Genomic Analysis. Genes showing significant associations (p < 0.001, R² ≥ 0.15) underwent pathway enrichment analysis (p < 0.05, Bonferroni-corrected). Compared to HC, MS patients showed higher centrality mainly in the default-mode network (DMN), linked to genes regulating inflammation resolution and immune functions, and lower centrality in regions mostly located in the salience network and cerebellum, associated with genes implicated in cytokine response. Compared to HC and relapsing-remitting MS, progressive MS patients showed higher centrality in DMN and cerebellar regions, correlating with genes related to epigenetic and mitochondrial functions. Of the MS cohort, 144 (29.3%) patients were cognitively impaired. Compared to cognitively preserved MS and HC, they showed higher centrality in DMN and mesial temporal lobe regions, negatively correlated with expression of DNASE1, regulating DNA degradation, and CP, encoding ceruloplasmin, involved in iron homeostasis and potentially iron-driven neurodegeneration. Physiological regional gene expression spatially correlates with MS-related functional network alterations. Biological factors may shape regional vulnerability or resilience to MS pathology, influencing functional reorganization.