Use of brain MRI and gene expression atlases to reconstruct the pathophysiology of autoimmune neurological disorders: The proof-of-concept of NMOSD

Abstract

Background: The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements. Objective: As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD). Methods: In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes. Results: In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy. Conclusions: Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders. © The Author(s), 2024.