Joint application of brain mri and gene expression atlas to reconstruct nmosd pathophysiology

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Supported in part by the Ministry of Science, Republic of Serbia (project no. 175031) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval was received from the ethical standards committee of IRCCS Ospedale San Raffaele, Milan, Italy and of the University Clinical Centre of Serbia, Belgrade, Serbia I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes