7T MRI Leptomeningeal Enhancement and Brain Atrophy Are Associated with Alterations in Arginine-polyamine Metabolism in Multiple Sclerosis
Jonathan Zurawski1, Martin Profant2, Renxin Chu1, Molly Quattrucci1, Shahamat Tauhid1, Tanuja Chitnis1, Howard Weiner1, Clary B. Clish3, Rohit Bakshi1, Chao Wang2
1Brigham & Women's Hospital, 2Immunology, Sunnybrook Research Institute, 3MIT Broad Institute
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.