Spatial Association Between Gene Expression and Brain Damage in Neuromyelitis Optica Spectrum Disorders (S50.004)

<h3>Objective:</h3> To investigate the spatial association between brain damage and gene expression in NMOSD. <h3>Background:</h3> A former study suggested that typical brain lesions in aquaporin-4 positive Neuromyelitis Optica Spectrum Disorders (AQP4+NMOSD) occur at areas with high AQP4 expression. However, this represents a partial view of both brain damage and NMOSD pathogenesis, since the former also includes atrophy and microstructural abnormalities, and the latter involves other elements of the immune system such as complement and granulocytes. <h3>Design/Methods:</h3> 3.0 and 1.5 T brain MRI scans were acquired from 80 AQP4+NMOSD and 94 controls at two European centers. In patients, brain damage was assessed through (i) T2-hyperintense lesion probability map, (ii) white (WM) and grey matter (GM) atrophy at voxel-based morphometry on 3D T1-weighted sequences, (iii) WM microstructural abnormalities at tract-based spatial statistics on diffusion-tensor imaging. The spatial association between maps and expression of 313 genes according to the Allen Human Brain Atlas was obtained with the MENGA platform. Functional-enrichment analysis investigated the overrepresented biological processes involving the genes significantly associated with the different types of brain damage. <h3>Results:</h3> T2-hyperintense lesions were mainly located in the periventricular WM; GM atrophy was observed in the visual, prefrontal cortex, and insula, WM atrophy selectively involved the optic tracts; patients also had a widespread increase of WM mean diffusivity and no fractional anisotropy abnormalities. The expression of AQP4 and C5 were associated with all types of brain damage, IL6 family signal transducer was associated with brain atrophy only, and CD59 was protective. Interferon-gamma, interleukin-4/-13 signalling and activation of C3/C5 were associated with both lesions and microstructural abnormalities. Pathways sometimes not specific for NMOSD pathogenesis were associated with brain atrophy. <h3>Conclusions:</h3> Brain lesions and WM microstructural abnormalities are associated with biological processes specific of AQP4+NMOSD, including complement activation and eosinophils/neutrophils recruitment. More complex mechanisms contribute to atrophy. <b>Disclosure:</b> Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Celgene. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOMEDIA. Loredana Storelli has nothing to disclose. Elisabetta Pagani has nothing to disclose. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Dr. Moiola has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.