Investigations of vitamin D as a determinant of multiple sclerosis risk and of the metabolome of disease progression
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
In this project, we contributed with knowledge to our understanding of the etiology of multiple sclerosis (MS), its prodromal phase, described/quantified the burden of aging with MS, and assessed body mass index (BMI) as a predictor of MS activity and progression. EBV has long been a top suspect etiologic factor for MS, however, the proof of causality has remained elusive. The high EBV seroprevalence (~95% of adults are infected) and the fact that MS is a relatively rare disease, has been the main obstacle in demonstrating a causal link. In a collaboration with the US military, we accessed data from the unique cohort of military personnel on active duty (~10 million) with repeated blood samples collected in young adulthood (~62 million) and stored in the Department of Defense Serum Repository. By medical record review, we documented 955 individuals who developed MS during their military service. We randomly selected two controls per cases closely matched on sex, age, race/ethnicity, military branch, time of blood collection and measured EBV status in three serum samples each prior to first MS symptoms. We identified 35 individuals who were EBV negative at baseline and went on to develop MS; among the controls, 107 were EBV-negative at baseline. All but one of the MS cases seroconverted prior to developing first MS symptoms. The risk of MS was 32-fold increased with seroconversion vs. persistent seronegativity. In contrast, similar analyses revealed no association between infection with cytomegalovirus (a herpes virus with a similar mode of transmission as EBV) and MS risk. This strong link cannot be explained by other known risk factors and provides compelling evidence that EBV is the leading cause of MS. We also addressed common concerns regarding the possibility of reverse causation, i.e., that MS may increase the risk of being infected with EBV: Serum concentrations of neurofilament light chain (sNfL), a sensitive marker of neuroaxonal injury that can increase years before the first neurological symptoms and is therefore an early marker of the disease, were increased only after EBV infection. Further, the serological response to all known human pathogenic viruses as assessed by VirScan, a high throughput technology that enables a simultaneous peptide-based antibody profiling, was similar among cases and controls both pre- and post-onset, apart from the response to EBV, indicating that MS is not associated with an immune dysregulation that increases the risk of acquiring EBV and underlining the specificity of the EBV-MS link. The findings from this study, published in Science, may accelerate the development of better MS treatments and an EBV vaccine. Further, we characterized the duration of the MS prodrome using, for the first time, a biomarker. In a separate prospective nested-cases control study within the same cohort, we found that sNfL elevations preceded the clinical onset of MS by on median 6 years. The difference in sNfL between cases (n=60) and controls (n=60) increased with decreasing time to clinical MS onset. It remains challenging to identify predictors of the MS course. Among 464 participants from the BENEFIT clinical trial, recruited after a first episode suggestive of MS, we assessed the relationship of baseline BMI with MS activity and progression after 5 years. We found that obese MS patients were 39% more likely to convert to clinically definite MS and had a 59% higher relapse rate. Further, obese smokers seemed to have a larger reduction in brain volume compared to normal weight smokers. Finally, we addressed an unmet need of investigating the burden of aging with MS using data from the two large Nurses’ Health Study cohorts. We followed women with MS during their life course and compared them to women aging without MS, derived from the same study population. We used non-MS specific outcome measures, including the physical functioning scale (PF10) from the SF-36 and other indicators of general, physical, mental health, and memory repeatedly collected over 25 years. We found that women with MS scored consistently lower on the PF10 (~0.9-1.7 SDs) compared to unaffected peers during follow-up. Throughout their adult life, women with MS declined on average two times faster per additional life year (-0.8 points on PF10) than women without MS. Further, physical function declined with longer disease duration of MS compared to age-and-year matched controls, most pronounced in the first 10 years. Women with MS scored lower on the PF10 up to about 5 years prior to first symptoms. Finally, women with MS were likely to report worse health and more disability than their peers in all the other assessed domains. In summary, in this large and rigorously controlled longitudinal study, the age-related decline in physical functioning was accelerated by 15-30 years in women aging with MS compared to women aging without MS.
Publications
- Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurology. 2020 Jan 1;77(1):58-64
Bjornevik K, Munger KL, Cortese M, Barro C, Healy BC, Niebuhr DW, Scher AI, Kuhle J, Ascherio A
(See online at https://doi.org/10.1001/jamaneurol.2019.3238) - Aging with multiple sclerosis: A longitudinal study of physical function, mental health, and memory in two cohorts of US women. Multiple Sclerosis. 2022 Jan; 28(1):121-131
Cortese M, Bjornevik K, Chitnis T, Ascherio A, Munger KL
(See online at https://doi.org/10.1177/13524585211007739) - Body mass index as a predictor of MS activity and progression among participants in BENEFIT. Multiple Sclerosis. 2022 Jan 7
Escobar JM, Cortese M, Edan G, Freedman MS, Hartung H-P, Montalbán X, Sandbrink R, Radü E- W, Barkhof F, Wicklein E-M, Kappos L, Ascherio A, Munger KL
(See online at https://doi.org/10.1177/13524585211061861) - Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21
Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A
(See online at https://doi.org/10.1126/science.abj8222)
