Spatial Association Between Gene Expression and Brain Damage in Neuromyelitis Optica Spectrum Disorders
Laura Cacciaguerra1, Loredana Storelli4, Elisabetta Pagani4, Vittorio Martinelli5, Lucia Moiola5, Massimo Filippi2, Maria Rocca3
1Neuroimaging Research Unit, Division of Neuroscience, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, 3Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientifc Institute; Vita-Salute San Raffaele University, 4Neuroimaging Research Unit, Division of Neuroscience, 5Neurology Unit, IRCCS San Raffaele Scientifc Institute
Objective:
To investigate the spatial association between brain damage and gene expression in NMOSD.
Background:
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.
Design/Methods:
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.
Results:
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.
Conclusions:
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.