Abstract Details

Title 7T MRI Leptomeningeal Enhancement and Brain Atrophy Are Associated with Alterations in Arginine-polyamine Metabolism in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P11 - Poster Session 11 (5:30 PM-6:30 PM)

Poster/Presentation
Number 6-007

Objective To investigate the relationship between meningeal involvement, brain atrophy, and polyamine metabolism in MS.

Background MRI leptomeningeal enhancement (LME), a proposed marker of meningeal inflammation in multiple sclerosis (MS), is linked to disease progression and atrophy though its pathogenesis is incompletely understood. Polyamine metabolism has been implicated in immune disorders but potential role in MS is unknown.

Design/Methods 67 MS subjects [67.2% anti-CD20-treated, 32.8% untreated, age (mean±SD) 51.4±12.5 years, Expanded Disability Status Scale (EDSS) score 3.1±2.3, 65.7% relapsing-remitting MS (RRMS); 29.9% primary or secondary progressive (PP/SPMS); 4.4% clinically isolated syndrome], had 7T brain MRI and blood collection. LME was expert-quantified on post-contrast 3D-FLAIR. MP2RAGE images were segmented to assess brain volumes. From plasma, untargeted liquid chromatography-tandem mass spectrometry measured several hundred identified metabolites and thousands of signals from unknowns; ~30,000 features were profiled (376 using reference standards). An animal model of MS (experimental autoimmune encephalitis, EAE) investigated associations between metabolites of interest, meningeal inflammation, brain volumes, and clinical status. Spearman correlations and t-tests were corrected for multiple comparisons.

Results LME prevalence was 66% [PP/SPMS vs. RRMS: 80% vs. 64%; anti-CD20-treated vs. untreated: 73% vs. 55%]. LME foci number (1.9±2.0) correlated positively with EDSS (r=0.47, p<0.05) and inversely with deep gray matter volume (r=-0.23, p<0.05). MS patient serum identified several metabolites of the arginine-polyamine pathway that were significantly associated with higher LME burden (p<0.05). In the EAE model, increased hippocampal polyamine levels were associated with reduced hippocampal volume and demyelination. Pharmacological inhibition of polyamine biosynthesis after EAE onset decreased meningeal inflammation, restricting the frequencies of follicular helper T-cells, and preventing hippocampal demyelination and volume loss (p<0.05). Genetic perturbation of polyamine biosynthesis in T-cells partially recapitulated the effects of pharmacological inhibition on meningeal inflammation.

Conclusions

In MS patients and the EAE model, dysregulation of arginine-polyamine metabolism may play a role in meningeal involvement and brain atrophy.

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.
Martin Profant (Sunnybrook Research Institute)	No disclosure on file
Renxin Chu (Brigham & Women's Hospital)	Dr. Chu has nothing to disclose.
Molly Quattrucci (Brigham & Women's Hospital)	Molly Quattrucci 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.

��ɫ��

��ɫ��