JOINT APPLICATION OF BRAIN MRI AND GENE EXPRESSION ATLAS TO RECONSTRUCT NMOSD PATHOPHYSIOLOGY

Abstract Objective Brain lesions in aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) occur at areas of high AQP4 expression. However, the pathophysiological cascade requires additional factors such as complement. We sought to investigate the spatial association between brain damage and gene expression in AQP4+NMOSD. Methods In this multicenter cross-sectional study, we enrolled 90 patients and 94 age-matched healthy controls who underwent a 3.0/1.5 T brain MRI. In patients, brain damage was assessed through (i) T2-hyperintense lesion probability maps, (ii) white matter (WM) and grey matter (GM) atrophy on 3D T1-weighted sequences, and (iii) WM microstructural abnormalities on diffusion-tensor imaging. The association between imaging maps and the expression of 266 candidate genes in the Allen Human Brain Atlas was obtained and overrepresented biological processes were investigated with a functional-enrichment analysis. Results In AQP4+NMOSD, T2-hyperintense lesions were mainly located in the periventricular WM. GM and WM atrophy involved the visual pathway, while WM microstructural abnormalities were represented by a widespread increase of mean diffusivity. The expression of AQP4, C4a and C5 elements of complement resulted associated with all types of brain damage. Complement activation and the regulation and uptake of insulin-like growth factor were the most relevant enriched pathways. Non-specific pathways related to DNA synthesis and repair were associated with brain atrophy. Interpretation A joint application of quantitative MRI and gene expression atlas can identify in vivo the key elements of AQP4+NMOSD pathophysiology. This may pave the way to a novel type of imaging analysis helpful in understanding the pathophysiology of antibody-mediated autoimmune disorders.