Clinical Relevance of Spatial Correspondence Between Regional Gene Expression and Gray Matter Atrophy in Multiple Sclerosis
Paolo Preziosa1, Loredana Storelli3, Nicolò Tedone3, Monica Margoni4, Carmen Vizzino3, Damiano Mistri3, Mor Gueye4, Massimo Filippi2, Maria Rocca1
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience, 4Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, IRCCS San Raffaele Scientific Institute
Objective:
To investigate the spatial associations between regional gray matter (GM) atrophy and gene expression in multiple sclerosis (MS).
Background:
Heterogeneous pathological processes, possibly influenced by specific regional gene expression differences, may contribute to a non-random and clinically-relevant GM atrophy progression in MS.
Design/Methods:
Brain 3T MRI, neurological evaluation and neuropsychological assessment were obtained from 286 MS patients and 172 healthy controls (HC). Patterns of regional GM atrophy in MS patients compared to HC and according to clinical disability and cognitive status were investigated using voxel-based morphometry (VBM) (p<0.05, family-wise error-corrected). Genes associated with MS were identified from Open Target Platform (n=2710). The spatial cross-correlations between VBM-derived GM maps and gene expressions provided by Allen Human Brain Atlas were explored using the MENGA platform. Using ToppGene Suite, enrichment analyses were performed to explore over-represented molecular functions and cellular components involving gene expressions significantly associated with VBM-derived GM maps (p<0.05, Bonferroni-corrected).
Results:
Compared to HC, MS patients showed widespread GM atrophy being significantly associated with the regional expression of 74 genes, involved in synaptic GABA receptor functions and mitochondrial oxidoreductase activities. Lower volume in bilateral deep GM nuclei and cerebellum, and left insula was significantly associated with a higher Expanded Disability Status Scale score and with the expression of 44 genes being enriched in the mitochondrial and cellular nucleoids. Cognitively-impaired (n=113) vs cognitively-preserved (n=173) MS patients had distributed GM atrophy being significantly associated with the expression of 64 genes involved in protein heterodimerization and oxidoreductase activities of mitochondrial and organelle membranes/envelopes.
Conclusions:
Different regional expressions of genes involved in synaptic GABA receptor activities and mitochondrial oxidoreductase functions are associated with a clinically-relevant regional GM atrophy in MS. Specific differences in gene expressions may influence regional susceptibility to MS-related excitatory/inhibitory imbalance and oxidative stress, and GM atrophy development.