Metabolomic Profiling of Multiple Sclerosis Lesions and Periplaque White Matter Demonstrates Extensive Changes in Lipid Metabolism (P2-3.010)

Abstract

<h3>Objective:</h3> To identify whether there are differences between the brain tissue metabolome in people with multiple sclerosis (PwMS) compared to controls and between the different type of MS lesions <h3>Background:</h3> MS is characterized by immune-mediated white matter (WM) demyelination and consecutive axonal loss. Whether this process alters the metabolome in the affected brain areas is not clear. <h3>Design/Methods:</h3> Brain tissues, obtained from 5 PwMS and 12 controls, were sent for metabolomic analysis. In PwMS, tissues were extracted from the edge and core of demyelinated WM chronic active and inactive lesions, and periplaque WM, while in controls they were dissected from normal WM. Weighted gene correlation network analysis (WGCNA) were utilized to cluster highly correlated metabolites together into modules. We then applied generalized estimating equations models to compare WGCNA-module scores between different tissues, accounting for multiple metabolomic profiles contributed by some subjects. <h3>Results:</h3> MS lesions were found to have decreased concentrations of hexosylceramides (p = 0.019), glycero-phospholipids (p = 3.6E−7), nucleotide metabolites (p = 5.0E−4), and long-chain fatty acids (p = 1.6E−6) and increased concentrations of dipeptides/sugars (p = 0.0063), sphingosines (p = 0.0026), phospholipids (p = 0.0019), sphingomyelines and ceramides (p = 4.4E−10) compared to control WM. In MS periplaques there were decreased levels of glycerol-phospholipids (p = 0.017) and long-chain fatty acids (p = 0.014) and increased levels of sphingomyelines and ceramides (p = 0.0026) compared to control WM. <h3>Conclusions:</h3> Myelin lipids were significantly altered in MS with more prominent differences in lesions, and these could potentially act as biomarkers of inflammation and neurodegeneration in PwMS. <b>Disclosure:</b> Dr. Ladakis has nothing to disclose. Dr. Absinta has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Absinta has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abata Therapeutics. The institution of Dr. Absinta has received research support from International MS Alliance. The institution of Dr. Absinta has received research support from FRRB Early Career Award. The institution of Dr. Absinta has received research support from Cariplo Foundation. Dr. Reyes-Mantilla has nothing to disclose. The institution of Dr. Pardo-Villamizar has received research support from National Institutes of Health. The institution of Dr. Pardo-Villamizar has received research support from Bart McLean Fund for Neuroimmunology Research . The institution of Dr. Bhargava has received research support from EMD Serono. The institution of Dr. Bhargava has received research support from Amylyx pharmaceuticals. The institution of Dr. Bhargava has received research support from Genentech. The institution of Dr. Bhargava has received research support from GSK.