Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis.

The image contains two neurons, one with intact myelin sheath along its axon (bottom) and one with demyelination occurring (top)

Virupakshaiah A, Ladakis DC, Nourbakhsh B, Bhargava P, Dilwali S, Schoeps V, Borkowski K, Newman JW, and Waubant E. (2023) Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis. Multiple Sclerosis Journal

Multiple sclerosis is the most common demyelinating disease within the central nervous system (CNS). The cause of MS is not known but it is considered an autoimmune disease because the body’s immune system attacks its myelin sheath, a membrane that surrounds the axons of neurons and helps with the transmission of nerve signals and prevents interference from other signals. This demyelination results in numbness, muscle weakness, paralysis, dizziness, muscle spasticity, incoordination of muscles, slurred speech, and fatigue. Myelin is primarily composed of lipids and a large proportion of these are plasmalogens, a class of lipid that contain a vinyl-ether bond at the sn-1 position causing a more compact conformation. Because of this, changes to lipids and their metabolites is an area of interest in MS research. It is known that the lipidome is different when comparing healthy controls and either adults or children with MS, but whether these changes cause MS or are a result of the disease is not well understood. Virupakshaiah et al wanted to investigate if changes to lipid metabolites have a role in the risk of relapse and disability in children with MS.

To determine the relationship between lipid metabolites and risk of MS relapse and the association between the two were calculated. Each metabolite was assessed for its impact on relapse incidence rate ratio (IRR) and the Expanded Disability Status Scale (EDSS) was used to evaluate disability. A normalized enrichment score (NES) was calculated and classified as a positive enrichment score, which indicates a positive association with the outcome, or as a negative enrichment score, indicating a negative association with the outcome. Ether lipids such as plasmalogens and phosphatidylethanolamines and primary bile acids were associated with a lower risk of relapse and lower baseline EDSS scores, with IRR NES scores ranging -2.0 to -2.5 and EDSS NES scores from -1.9 to -2.1. In contrast, acylcarnitines and poly-unsaturated fatty acids were associated with an increased risk for relapse and worse baseline EDSS scores with IRR NES scores of 1.6 and 2.1, respectively, and EDSS NES scores of 1.7 and 1.9, respectively. Other lipids that were associated with a lower risk of relapse were phosphatidylcholines. The lipids that were associated with worse EDSS scores were ceramides, sphingolipid metabolites, monoacylglycerols, and diacylglycerols while monohydroxy fatty acids and dicarboxylate fatty acids were associated with an increased risk of relapse, however the latter were also associated with lower baseline EDSS scores.

Virupakshaiah et al wanted to further our understanding of how lipid changes that occur in MS affect the risk of disease relapse and severity of disease, which can result in disability children with MS. It is well documented that there are significant lipidome differences between people with MS and healthy controls, but the consequence of these changes was not well understood. The outcomes of relapse rate and EDSS were chosen because relapse frequency echoes MS activity and reflects severity of immune-mediated demyelination, while EDSS provides a value for the severity of the disease and the success of the repair and compensatory mechanisms between disease states. The authors found that certain lipids are associated with reduced risk of relapse and severity of disease, such as plasmalogens, while other lipids and their metabolites are associated with increased risk of either or both. Plasmalogens are essential components of myelin therefore when they are present in normal levels it reasons that the risk of relapse or disease severity would be lower than for a person with reduced plasmalogen levels. Similarly, the association with lipid metabolites and increased risk could signify an increase in demyelination or axonal injury. An example Virupakshaiah et al give is of the relationship between ceramide levels and oligodendrocyte injury and cell death. Ceramide levels have also been shown to be different in blood and white blood cells of people with MS and healthy controls, therefore this could explain their relationship with increased relapse and disease severity. The more we are able to learn about alterations to the lipidome and how these changes impact the mechanisms of disease onset and progression, the better we will be able to develop biomarkers of MS and potential therapeutic targets.