Aging with multiple sclerosis: A longitudinal study of physical function, mental health, and memory in two cohorts of US women.

BACKGROUND: It is unknown how individuals with multiple sclerosis (MS) age compared to unaffected peers. OBJECTIVES: The objective of the study is to describe the impact of MS on health and functioning in aging women. METHODS: We used 10-item Physical Functioning Scale (PF10) scores (from the Short Form-36 (SF-36)) and other indicators of general, physical, mental health, and memory collected repeatedly over 25 years with self-administered questionnaires among participants in the Nurses' Health Study (n = 121,700 recruited at ages 30-55) and Nurses' Health Study II (n = 116,429 recruited at ages 25-42) to compare women with MS (n = 733) to unaffected peers in their health and disability, and describe/quantify the burden of aging with MS. RESULTS: Women with MS had a consistently lower PF10 by 0.9-1.7 standard deviations with greater overall variability than unaffected women. PF10-scores gradually decreased with increasing age in both groups, but MS cases declined 3-4 times faster in midlife, while decline was similar in old age. The physical function score of 45-year-old women with MS was comparable to that of 75-year-old unaffected women; 70-year-old women with MS scored similarly to 85-year-old unaffected women. MS cases also reported worse health/more disability throughout adulthood on the other indicators. CONCLUSION: The age-related decline in physical health is accelerated by 15-30 years in MS patients compared to unaffected peers.

Body mass index as a predictor of MS activity and progression among participants in BENEFIT.

BACKGROUND: There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. METHODS: Body mass index (BMI) at baseline was available for 464 patients with CIS in BENEFIT. Obesity was defined as BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. Patients were followed up for 5 years clinically and by magnetic resonance imaging. Hazard of conversion to clinically definite (CDMS) or to 2001 McDonald criteria (MDMS) MS, annual rate of relapse, sustained progression on Expanded Disability Status Scale (EDSS), change in brain and lesion volume, and development of new brain lesions were evaluated. RESULTS: Obese individuals were 39% more likely to convert to MDMS (95% CI: 1.02-1.91, p = 0.04) and had a 59% (95% CI: 1.01-2.31, p = 0.03) higher rate of relapse than individuals with normal weight. No associations were observed between obesity and conversion to CDMS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes, except for a larger reduction of brain volume in obese smokers as compared to normal weight smokers (-0.82%; 95% CI: -1.51 to -0.12, p = 0.02). CONCLUSION: Obesity was associated with faster conversion to MS (MDMS) and a higher relapse rate.

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study.

BACKGROUND: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). OBJECTIVES: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. METHODS: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. RESULTS: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35-3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49-2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78-2.54), n = 11). CONCLUSION: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

Maternal prepregnancy BMI and physical activity and type 1 diabetes in the offspring.

BACKGROUND: Previous studies showed conflicting results on the association between maternal prepregnancy body mass index (BMI) and type 1 diabetes in the offspring, and the role of maternal prepregnancy physical activity is unclear. We aimed to assess whether maternal prepregnancy BMI and physical activity predict type 1 diabetes in their offspring. METHODS: Prospective study including women participating in the Nurses' Health Study II with follow-up from 1989 to 2011. Women repeatedly reported their BMI and physical activity, from which prepregnancy exposures were derived; and retrospectively reported their BMI at age 18 and physical activity at ages 18-22, considered early adulthood exposure. We estimated risk ratios (RR) and 95% confidence intervals (95%CI) using generalized estimating equations, adjusted for covariates. Findings at p < 0.05 were considered statistically significant. RESULTS: We identified 276 cases of type 1 diabetes among offspring (n = 70,168) with maternal prepregnancy information and 448 cases among offspring (n = 111,692) with maternal early adulthood information. Prepregnancy and early adulthood maternal BMI and physical activity were not associated with offspring type 1 diabetes. The RR comparing overweight to normal weight mothers was 1.08 (95%CI: 0.73-1.59) and comparing obese to normal weight was 0.94 (95%CI: 0.49-1.79, p-trend: 0.98). Comparing highest to lowest quartile of maternal physical activity the RR was 0.90 (95%CI: 0.61-1.32; p-trend: 0.73). Maternal type 2 diabetes was associated with an increased risk of type 1 diabetes in the offspring (RR = 1.87; 95%CI: 1.25-2.80). CONCLUSIONS: Our findings do not support a relationship between maternal prepregnancy BMI or physical activity and the risk of type 1 diabetes in the offspring.

Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.

OBJECTIVE: To determine whether maternal Epstein-Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring. METHODS: We conducted a prospective nested case-control study in the Finnish Maternity Cohort (FMC) with serum samples from >800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n = 326) on region and dates of birth, sample collection, and mother's birth. We used conditional logistic regression to estimate relative risks (RRs) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25-hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC. RESULTS: Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RRtop vs bottom quintile = 2.44, 95% confidence interval [CI] = 1.20-5.00, p trend = 0.004); no associations were found between maternal EBV nuclear antigen 1 (EBNA-1), diffuse early antigen, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA-1 IgG levels had a 3-fold higher risk of MS (RR = 3.21, 95% CI = 2.37-4.35, p trend <1.11e-16). These associations were not confounded or modified by 25-hydroxyvitamin D. INTERPRETATION: Offspring of mothers with high viral capsid antigen IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated prediagnostic EBNA-1 IgG levels is consistent with previous results. ANN NEUROL 2019;86:436-442.

Diet quality and risk of multiple sclerosis in two cohorts of US women.

OBJECTIVE: To determine the association between measures of overall diet quality (dietary indices/patterns) and risk of multiple sclerosis (MS). METHODS: Over 185,000 women in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) completed semiquantitative food frequency questionnaires every 4 years. There were 480 MS incident cases. Diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED) index, and Dietary Approaches to Stop Hypertension (DASH) index. Principal component analysis was used to determine major dietary patterns. We calculated the hazard ratio (HR) of MS with Cox multivariate models adjusted for age, latitude of residence at age 15, body mass index at age 18, supplemental vitamin D intake, and cigarette smoking. RESULTS: None of the dietary indices, AHEI-2010, aMED, or DASH, at baseline was statistically significantly related to the risk of MS. The principal component analysis identified "Western" and "prudent" dietary patterns, neither of which was associated with MS risk (HR, top vs bottom quintile: Western, 0.81 (p = 0.31) and prudent, 0.96 (p = 0.94)). When the analysis was repeated using cumulative average dietary pattern scores, the results were unchanged. CONCLUSION: There was no evidence of an association between overall diet quality and risk of developing MS among women.

Rotating night shift work and risk of multiple sclerosis in the Nurses' Health Studies.

OBJECTIVES: Night shift work has been suggested as a possible risk factor for multiple sclerosis (MS). The objective of the present analysis was to prospectively evaluate the association of rotating night shift work history and MS risk in two female cohorts, the Nurses' Health Study (NHS) and NHSII. METHODS: A total of 83 992 (NHS) and 114 427 (NHSII) women were included in this analysis. We documented 579 (109 in NHS and 470 in NHSII) incident physician-confirmed MS cases (moderate and definite diagnosis), including 407 definite MS cases. The history (cumulative years) of rotating night shifts (≥3 nights/month) was assessed at baseline and updated throughout follow-up. Cox proportional hazards models were used to estimate HRs and 95% CIs for the association between rotating night shift work and MS risk adjusting for potential confounders. RESULTS: We observed no association between history of rotating night shift work and MS risk in NHS (1-9 years: HR 1.03, 95% CI 0.69 to 1.54; 10+ years: 1.15, 0.62 to 2.15) and NHSII (1-9 years: HR 0.90, 95% CI 0.74 to 1.09; 10+ years: 1.03, 0.72 to 1.49). In NHSII, rotating night shift work history of 20+ years was significantly associated with MS risk, when restricting to definite MS cases (1-9 years: HR 0.88, 95% CI 0.70 to 1.11; 10-19 years: 0.98, 0.62 to 1.55; 20+ years: 2.62, 1.06 to 6.46). CONCLUSIONS: Overall, we found no association between rotating night shift work history and MS risk in these two large cohorts of nurses. In NHSII, shift work history of 20 or more years was associated with an increased risk of definite MS diagnosis.

Sodium intake and multiple sclerosis activity and progression in BENEFIT.

OBJECTIVE: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. METHODS: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. RESULTS: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS: -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles. INTERPRETATION: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20-29.

Polyunsaturated fatty acids and the risk of multiple sclerosis.

BACKGROUND: Results from previous studies on polyunsaturated fatty acid (PUFA) intake and multiple sclerosis (MS) risk are conflicting. OBJECTIVE: To prospectively investigate the association between dietary intake of PUFA and MS risk. METHODS: We followed 80,920 women from Nurses' Health Study (1984-2004) and 94,511 women from Nurses' Health Study II (1991-2009) who reported on diet using a validated food frequency questionnaire every 4 years and identified 479 incident MS cases during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for the effect of PUFA intake on MS risk adjusting for age, latitude of residence at age 15, ancestry, cigarette smoking, supplemental vitamin D intake, body mass index, and total energy intake. RESULTS: Higher intake of total PUFA at baseline was associated with a lower risk of MS (HR top vs bottom quintile: 0.67, 95% CI: 0.49-0.90, p trend = 0.01). Among the specific types of PUFA, only α-linolenic acid (ALA) was inversely associated with MS risk (HR top vs bottom quintile: 0.61, 95% CI: 0.45-0.83, p trend = 0.001). The long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with MS risk. CONCLUSION: Low dietary PUFA intake may be another modifiable risk factor for MS.

Weighing Evidence from Mendelian Randomization-Early-Life Obesity as a Causal Factor in Multiple Sclerosis?

In this Perspective, Alberto Ascherio and Kassandra Munger discuss the implications of Richards and colleagues' study exploring the role of early-life obesity in risk of multiple sclerosis.

EBV and Autoimmunity.

Although a role of EBV in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been possible only for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE), whereas evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify the conclusion that EBV is a component cause of MS and SLE and possible mechanisms underlying these effects.

Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses' Health Study.

OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) to identifying the role of lifestyle, diet, and genetic or biological factors in several neurodegenerative diseases, including cognitive decline, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. METHODS: We completed a narrative review of the publications of the NHS and NHS II between 1976 and 2016. RESULTS: In primary findings for cognitive function, higher intake of nuts, moderate alcohol consumption, and higher physical activity levels were associated with better cognitive function. Flavonoids, physical activity, and postmenopausal hormone therapy were related to cognitive decline over 2 to 6 years. The NHS also has been integral in establishing Epstein-Barr virus infection, inadequate vitamin D nutrition, cigarette smoking, and obesity as risk factors for multiple sclerosis and inverse associations between cigarette smoking and caffeine and risk of Parkinson's disease. Increased risk of amyotrophic lateral sclerosis has been associated with cigarette smoking and decreased risk associated with obesity. CONCLUSIONS: The NHS has provided invaluable resources on neurodegenerative diseases and contributed to their etiological understanding. We anticipate that the NHS cohorts will continue to make important contributions to the field of neurodegenerative diseases.

Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update.

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, obesity in early life, infection with the Epstein-Barr virus, and cigarette smoking are the most consistent environmental predictors of MS risk. The authors review the epidemiological data, critically discuss the evidence for causality of these and other associations, and briefly review the possibility of interventions to reduce MS risk.

Smoking and multiple sclerosis risk in black people: A nested case-control study.

BACKGROUND: Smoking is a well-established risk factor for MS; however, it is not known whether its effect on disease risk varies by race/ethnicity. METHODS: We conducted a nested case-control study among US military personnel who have serum samples stored at the Department of Defense Serum Repository. We measured serum cotinine levels, a marker of tobacco smoke exposure, in 157 Black and 23 White individuals who developed MS during follow-up. Controls were randomly selected and matched to each case by age, sex, race/ethnicity, dates of sample collection, and branch of military service. RESULTS: Smoking was not associated with an increased risk of MS in Black people (RR: 1.08, 95 % CI: 0.63-1.85). The results remained similar in analyses restricted to smoking status at baseline, to samples collected 5 years before symptom onset, and using different cut-off levels in cotinine to define smoking status. Smoking was not statistically significantly associated with MS risk in White people, but the point estimate was similar to what has previously been reported in other studies (RR: 1.85, 95 % CI: 0.56-6.16). CONCLUSIONS: Smoking was not associated with MS risk in Black people. Given the consistent association between smoking and MS risk in predominantly White populations, this may suggest that the association between smoking and MS varies by race/ethnicity.

Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.

Importance: It remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are. Objective: To assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response. Design, Setting, and Participants: In this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023. Exposure: Antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing). Main Outcome and Measure: Rate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored. Results: A total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted. Conclusion and Relevance: These findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel.

To determine whether serum levels of 25-hydroxyvitamin D (25(OH)D) in young adults are associated with risk of type 1 diabetes mellitus (T1D), we conducted a prospective, nested case-control study among US active-duty military personnel with serum in the US Department of Defense Serum Repository, identifying 310 T1D cases diagnosed between 1997 and 2009 with at least 2 serum samples collected before disease onset and 613 controls matched to cases on age, sex, race/ethnicity, branch of military service, and dates of serum collection. Conditional logistic regression was used to estimate rate ratios and 95% confidence intervals. Among non-Hispanic whites, those with average 25(OH)D levels of ≥ 100 nmol/L had a 44% lower risk of developing T1D than those with average 25(OH)D levels < 75 nmol/L (rate ratio = 0.56, 95% confidence interval: 0.35, 0.90, P for trend = 0.03) over an average follow-up of 5.4 years. In quintile analyses, T1D risk was highest among individuals whose 25(OH)D levels were in the lowest 20% of those measured. There was no association between 25(OH)D levels and risk of T1D among non-Hispanic blacks or Hispanics. Low 25(OH)D levels may predispose healthy, young, non-Hispanic white adults to the development of T1D.

Maternal dietary fat intake in association with autism spectrum disorders.

Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991-2007). Dietary information was collected prospectively through a validated food frequency questionnaire. Binomial regression was used to estimate crude and adjusted risk ratios. Maternal intake of linoleic acid was significantly inversely associated with ASD risk in offspring, corresponding to a 34% reduction in risk in the highest versus lowest quartiles of intake. Mothers in the lowest 5% of ω-3 fatty acid intake had a significant increase in offspring ASD risk as compared with the remaining distribution (risk ratio = 1.53, 95% confidence interval: 1.00, 2.32); this association was also seen in the subgroup of women (86 cases and 5,798 noncases) for whom dietary information during pregnancy was available (risk ratio = 2.42, 95% confidence interval: 1.19, 4.91). Thus, variations in intake of polyunsaturated fats within the range commonly observed among US women could affect fetal brain development and ASD risk. Because the number of women with diet assessed during pregnancy was small, however, these results should be interpreted cautiously.

Childhood body mass index and multiple sclerosis risk: a long-term cohort study.

BACKGROUND: Obesity in late adolescence has been associated with an increased risk of multiple sclerosis (MS); however, it is not known if body size in childhood is associated with MS risk. METHODS: Using a prospective design we examined whether body mass index (BMI) at ages 7-13 years was associated with MS risk among 302,043 individuals in the Copenhagen School Health Records Register (CSHRR). Linking the CSHRR with the Danish MS registry yielded 774 MS cases (501 girls, 273 boys). We used Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among girls, at each age 7-13 years, a one-unit increase in BMI z-score was associated with an increased risk of MS (HR(age 7)=1.20, 95% CI: 1.10-1.30; HR(age 13)=1.18, 95% CI: 1.08-1.28). Girls who were ≥95(th) percentile for BMI had a 1.61-1.95-fold increased risk of MS as compared to girls <85(th) percentile. The associations were attenuated in boys. The pooled HR for a one-unit increase in BMI z-score at age 7 years was 1.17 (95% CI: 1.09-1.26) and at age 13 years was 1.15 (95% CI: 1.07-1.24). CONCLUSION: Having a high BMI in early life is a risk factor for MS, but the mechanisms underlying the association remain to be elucidated.

Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics.

PURPOSE OF REVIEW: This review provides a brief update of new research findings on the role of vitamin D in multiple sclerosis (MS). RECENT FINDINGS: Evidence continues to accumulate supporting a protective role for vitamin D in MS risk and progression. Notable recent findings are that high 25-hydroxyvitamin D [25(OH)D] at the time of a first demyelinating event predicts a lower MS risk and a decreased risk of MS among offspring whose mothers had high predicted 25(OH)D levels. While a small vitamin D intervention study did not find an association between vitamin D and MS progression, this study had little statistical power, and larger trials will be needed to assess the therapeutic potential of vitamin D. Recent immunological studies also show modulation of the immune system by vitamin D that may be favorable for preventing or slowing the progression of MS. The demonstration that rare variants in CYP27B1, which encodes the enzyme that converts vitamin D to its active form, are strongly associated with MS risk supports a causal role of vitamin D deficiency as a risk factor for MS. SUMMARY: Research on the nature of the association between vitamin D and MS risk and progression continues to progress; however, additional research on the timing and dose-response relationship will be crucial for designing future prevention and treatment trials.