Abstract Details

Title Clinical Relevance of Spatial Correspondence Between Regional Gene Expression and Gray Matter Atrophy in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S27 - MS Neuroimaging (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

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.

Objective

To investigate the spatial associations between regional gray matter (GM) atrophy and gene expression in multiple sclerosis (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.

Authors/Disclosures
Paolo Preziosa (Ospedale San Raffaele) PRESENTER	Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.
Loredana Storelli	Loredana Storelli has nothing to disclose.
Nicolò Tedone (San Raffaele hospital)	No disclosure on file
Monica Margoni	Monica Margoni has received research support from MAGNIMS. Monica Margoni has received research support from Merck-Serono. Monica Margoni has received research support from Sanofi-Genzyme.
Carmen Vizzino	No disclosure on file
Damiano Mistri, MSC (Università Vita-Salute San Raffaele)	Mr. Mistri has nothing to disclose.
Mor Gueye	No disclosure on file
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi;. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi- Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. 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, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Maria A. Rocca (Neuroimaging Research Unit)	Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. The institution of Maria Assunta Rocca has received research support from MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.