Abstract
Cognitive impairment (CI) is a hallmark of multiple sclerosis (MS). Despite its relevance, however, knowledge of the key steps involved in its pathogenesis remains incomplete. Consequently, predictive biomarkers and actionable therapeutic options to counteract CI in MS patients are not available. To identify changes associated with CI in MS, we performed transcriptomic analyses of the prefrontal cortex (PFC), a cortical region relevant for cognition, in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our analyses highlighted the strong upregulation of inflammatory pathways in the PFC of EAE mice. Clustering of the top differentially expressed genes (DEGs) in the PFC identified a low (EAE-L) and a high (EAE-H) inflammation subgroup. Notably, enhanced inflammation in the EAE PFC caused increased changes in expression levels of MS-associated genes with relevance for CI. Cell Type-Specific Expression Analysis (CSEA) and morphological analyses indicated that, while EAE-L mice showed only microglia activation, EAEH mice also displayed the involvement of astrocytes, consistent with a more advanced stage of disease. Moreover, neuronal genes were only downregulated in the EAE-H PFC. Analysis of cognitive performance in pre-symptomatic EAE mice revealed that high expression of genes associated with the antigen presentation and the complement pathways was associated with CI. Moreover, expression of C1q complement proteins was increased in the cerebrospinal fluid of MS patients affected by CI. These findings indicate that inflammation in the PFC during EAE is associated with CI and identify a subset of inflammatory genes that may represent early markers and risk factors for functional PFC impairment and loss of cognitive performance in MS patients.