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Abstract Details

7T MRI leptomeningeal enhancement and brain atrophy are associated with alterations in the IL-23 metabolic pathway in patients with multiple sclerosis
Multiple Sclerosis
P1 - Poster Session 1 (9:00 AM-5:00 PM)
345
To investigate the relationship between IL-23-associated metabolomics, meningeal involvement and brain atrophy in MS.

MRI leptomeningeal enhancement (LME)—a proposed marker of meningeal inflammation in multiple sclerosis (MS)—is linked to disease progression and gray matter injury though its pathogenesis is incompletely understood. IL-23 is associated with meningeal follicle formation in experimental models and IL-23 plasma levels correlate with brain atrophy in MS.
68 MS subjects [66.2% anti-CD20-treated, 33.8% untreated, age (mean±SD) 51.4±12.5 years, Expanded Disability Status Scale (EDSS) score 3.1±2.3, 64.7% relapsing-remitting (RRMS); 29.9% primary or secondary progressive (PP/SPMS); 4.4% clinically isolated syndrome], had 7T MRI and blood collection. LME was expert-quantified on post-contrast FLAIR. Normalized deep gray matter (DGM) and whole-brain parenchymal volumes were automatically quantified. Untargeted liquid chromatography-tandem mass spectrometry [hydrophilic interaction liquid chromatography and reversed-phase C18] measured several hundred identified metabolites and thousands of signals from unknowns; ~30,000 features were profiled (377 using reference standards). Spearman correlations and t-tests were corrected for multiple comparisons.
LME prevalence was 67% [PP/SPMS vs. RRMS: 80% vs. 64%; anti-CD20-treated vs. untreated: 73% vs. 55%]. LME foci number (1.9±2.0) correlated with EDSS (r=0.47) and inversely with DGM volume (r=-0.23). 383 metabolites correlated with LME, 95 surviving FDR- and 5 surviving Bonferroni-correction (p<0.05). Among untreated subjects, 41 known/identified metabolites significantly correlated with normalized thalamic volume and 14 with LME foci number, many overlapping with IL-23 signature. Untreated subjects with 0-1 vs. >1 LME focus showed 15 metabolite differences surviving FDR-correction, involving sphingomyelin, tryptophan, and bile acid metabolism. LME foci number correlated positively with pregnenolone sulfate (r=0.58), 3-guanidinoproprionic acid (r=0.63), and inversely with isolithocholate (r=-0.64). Anti-CD20 treatment altered the metabolic profile associated with LME. Gene set enrichment analysis showed trend toward IL-23 signature enrichment linked to either LME (FDR=0.13) or thalamic volume (FDR=0.05).
IL-23-associated metabolic pathways may underlie meningeal involvement and brain atrophy in MS.
Authors/Disclosures
Jonathan D. Zurawski, MD (Brigham & Women's Hospital)
PRESENTER 		The institution of Dr. Zurawski has received research support from The Race to Erase MS Foundation. The institution of Dr. Zurawski has received research support from Novartis Pharmaceuticals. The institution of Dr. Zurawski has received research support from I-Mab Biopharma . The institution of Dr. Zurawski has received research support from Elizabeth A. Kremer MS Research Foundation. The institution of Dr. Zurawski has received research support from Novartis.
Renxin Chu (Brigham & Women's Hospital) Dr. Chu has nothing to disclose.
Youmna Jalkh (Brigham and Women's Hospital) Ms. Jalkh has nothing to disclose.
Shahamat Tauhid, MD (Brigham & Women's Hospital) Dr. Tauhid has nothing to disclose.
Tanuja Chitnis, MD, FAAN (Brigham and Women's Hospital) Dr. Chitnis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Chitnis has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche-Genentech. Dr. Chitnis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave Biosciences. Dr. Chitnis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. The institution of Dr. Chitnis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Chitnis has received research support from Novartis. The institution of Dr. Chitnis has received research support from Sanofi. The institution of Dr. Chitnis has received research support from Octave. The institution of Dr. Chitnis has received research support from Genentech-Roche. The institution of Dr. Chitnis has received research support from Tiziana Life Sciences. The institution of Dr. Chitnis has received research support from Bristol-Myers Squibb. The institution of Dr. Chitnis has received research support from Wesley Clover.
Howard L. Weiner, MD (Brigham and Women'S Hospital) Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tiziana Life Sciences. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for vTv Therapeutics. Dr. Weiner has stock in vTv Therapeutics. The institution of Dr. Weiner has received research support from National Institute of Health. The institution of Dr. Weiner has received research support from National MS Society. The institution of Dr. Weiner has received research support from Genzyme Corp. The institution of Dr. Weiner has received research support from Genentech, Inc. . The institution of Dr. Weiner has received research support from Verily Life Sciences LLC. The institution of Dr. Weiner has received research support from EMD Serono, Inc..
Clary B. Clish No disclosure on file
Rohit Bakshi, MD, FAAN Dr. Bakshi has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Bakshi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. The institution of Dr. Bakshi has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Neuroimaging. The institution of Dr. Bakshi has received research support from Bristol Myers Squibb. The institution of Dr. Bakshi has received research support from EMD Serono. The institution of Dr. Bakshi has received research support from Novartis.
Chao Wang, PhD (Sunnybrook Research Institute) Prof. Wang has nothing to disclose.