The Metabolomics-Neurofilaments-Neurodegeneration Nexus in Multiple Sclerosis Progression
Abstract
Metabolic pathways, which supply energy and provide structural building blocks for the cell, are critically important for healthy immune and neuronal functions in the central nervous system. Dysregulated metabolic pathways may underlie neurodegeneration or brain tissue loss and disease progression in multiple sclerosis (MS) through mechanisms including deficits of molecules needed for repairing tissues areas injured by MS, lipid accumulation, and oxidative stress. This project addresses the "Biological Correlates of Disease Activity and Progression in MS" Focus Area, which "supports the identification and/or validation of biological correlates of disease activity and progression using pre-existing specimens and/or data acquired from well-characterized, adequately controlled, and sufficiently powered patient cohorts." The biological factors of interest in this project are metabolites and metabolic pathways. The goal of this project is to characterize the role of metabolites and metabolic pathways on the progression of neurodegeneration as assessed by serum neurofilament levels (a protein released from damaged nerves that reflects neurodegeneration and can be measured in blood using state-of-the-art techniques) and MRI measures of neurodegenerative injury in the brain of MS patients over 5 years. The analyses in Aim 1 and Aim 2 test the hypothesis that metabolic changes precede the changes in serum neurofilaments and MRI measures of neurodegeneration injury to the brain in multiple sclerosis patients. In Specific Aim 1, we will characterize the longitudinal changes in metabolite levels occurring over 5 years in healthy controls, relapsing remitting, and progressive MS patients using state-of-the-art approaches for simultaneously measuring many metabolites from a single sample. In Specific Aim 2, we will characterize the metabolic changes associated with the changes in serum neurofilament levels and MRI measures of neurodegeneration in MS. The Aims of this project will utilize 300 longitudinal samples and a rich body of clinical and neuroimaging data already collected at baseline and at 5 years follow-up from 70 RR-MS, 40 progressive MS, and 40 age- and sex-matched controls. All of the samples and the clinical outcomes for this study are already available and have been rigorously characterized. We also have serum neurofilament light chain levels available. The percent changes in gray matter volume and whole brain volume will be our primary and secondary measures of neurodegeneration, respectively. Metabolomics methods will be used for quantitation of numerous metabolites involved in lipid, carbohydrate, amino acid, and vitamin metabolism. The targeted metabolite analyses will use a range of cutting-edge analytical methods including automated chemistry analysis, high performance liquid chromatography, liquid chromatography-mass spectrometry, and immunoassays that are sensitive and selective for measuring biomarkers of oxidative damage and antioxidant defense. We will measure plasma fatty acid hydroperoxides as biomarkers of oxidative lipid damage. The activities of major antioxidant enzymes and levels of antioxidant vitamins and micronutrients will also be measured. Rigorous statistical methods will be used for data analysis. The project results could have potential implications for people with relapsing-remitting and progressive MS. It focuses on dysregulated metabolism, which is an important pathological mechanism that can cause irreversible loss of brain tissue and promote disease progression. The studies proposed are cutting-edge and effectively leverage a controlled, well-characterized, and statistically well-powered cohort of MS patients. The project has the potential for high short- and long-term impact on MS clinical science and on patient care and the findings can eventually be leveraged for developing diet, lifestyle, and pharmaceutical interventional strategies for preventing progression and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010551
Entities
People
- Murali Ramanathan
Organizations
- United States Army
- University at Buffalo