The timing of environmental risk factors and prodromal signs of multiple sclerosis

Abstract

Background: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that can lead to severe disability. It is a complex disease likely caused by genetic and environmental factors combined. Epstein-Barr virus (EBV) infection, low vitamin D, smoking, and being overweight are the environmental factors, which have most consistently been associated with an increased MS risk. However, detailed aspects of their involvement are not entirely resolved. Timing of exposure appears to be important, but whether the effect of vitamin D on susceptibility varies by age is unclear. Further, while a link between being overweight and MS risk has consistently been reported among women, it is less clear among men. Still, as the cause of MS is ultimately unknown, research on new potential etiologic factors is also warranted. One attractive candidate is physical exercise, as it is modifiable and could prevent disease if proven effective. Etiologic research can be facilitated if the natural history of MS is well characterized and understood. However, the nature and timing of prodromal MS, i.e. subclinical disease activity before the onset of classic neurologic symptoms, is largely unknown, and is thus a challenge to studies of risk factors and relevant timing. Objectives: The main objectives in this thesis were to gain knowledge on susceptibility periods and prodromal MS and advance research on established and putative new environmental risk factors. In detail, we intended to 1) investigate the association between postnatal timing of cod liver oil use, an important oral vitamin D source in Norway, and MS risk, 2) compare cognitive performance of men who later in their life developed MS to those who did not, to capture potential differences indicative of disease processes prior to first symptom and therefore prodromal MS, and 3) examine the association between being overweight and MS risk in men and whether fitness, as a proxy of exercise, is independently related to disease risk. Methods: For the first objective, we used the Norwegian data of the multi-national population-based case-control study Environmental Factors in Multiple Sclerosis (EnvIMS). We included, in total, 953 MS cases with neurologist-verified diagnosis recruited from the Norwegian MS registry and with disease duration of maximally 10 years, and 1,717 controls randomly selected from a population registry, frequencymatched on sex and age. Participants reported their cod liver oil use from childhood to adulthood and other relevant age-specific information using a validated questionnaire (EnvIMS-Q). The association between exposure to vitamin D through cod liver oil use at different ages and MS risk was estimated as odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. Apart from age and sex, we adjusted the analyses for outdoor activity during the summer, a proxy of sun exposure, dietary intake of vitamin D-rich fatty fish, history of mononucleosis, smoking, body size during adolescence, education, and MS family history. For the second and third objectives, we conducted population-based nested case-control studies within the historical cohort of all men born in 1950-1995 who underwent the mandatory Norwegian conscription examination at age 18-19 (about 90% of all Norwegian men). We identified men who went on to develop MS later in life through linkage of the Conscript Service Database to the Norwegian MS registry and selected controls randomly from the same database frequency-matched on year of birth to all the cases in the MS registry. For article 2, we included 924 men who later developed MS and 19,530 controls with information on cognitive performance at conscription. We compared their cognitive scores (standard nine scale, mean=5, standard deviation (SD)=2), standardized on 5-year birth cohorts, overall and according to initial disease course, relapsing-remitting (RRMS) and primary progressive MS (PPMS), using Student’s t-test. We also assessed the risk of MS in the years following conscription among men who scored lowest (>1 SD below the controls’ mean) compared to the rest using Cox regression to estimate relative risk (RR) and 95% CI. For article 3, we included 854 men who later developed MS and 14,563 controls, all born in 1950- 1975, with information on a) weight and height, from which we determined body mass index (BMI), and on b) physical fitness test result (score on standard nine scale). We estimated the independent effect of BMI, as a measure of body size, and fitness, as a measure of regular vigorous exercise, at age 19 and MS risk later in life using Cox regression and reported RR and 95% CI. Results: In article 1, we found that cod liver oil use during adolescence was significantly associated with a decreased MS risk compared to no supplementation during adolescence (OR=0.67, 95% CI: 0.52-0.86), whereas there was no association between use reported during childhood or adulthood. The estimates were mutually adjusted for each other and did not materially change after adjustment for other potential confounders. A dose-response relationship was suggested between higher cod liver oil doses during adolescence and lower MS risk peaking at 600-800 international units/ day of vitamin D consumed through cod liver oil (OR=0.46, 95% CI: 0.31-0.70, p trend=0.001). In article 2, we found that only men who developed MS within 2 years after conscription scored cognitively significantly lower at age 18- 19 than controls, equivalent to 6 IQ-points. There was, however, no overall difference in cognitive scores between the comparison groups. Results were similar when we assessed men who went on to develop RRMS, while men who went on to develop PPMS scored significantly lower than controls at that age, by an equivalent of 4.6-6.9 IQ-points, although they would not develop first symptoms up to 20 years later. Men who scored lowest had an increased RRMS risk within 2 years from conscription (RR=2.69, 95% CI: 1.41-5.16), and an increased PPMS risk within 20 years. Finally, in article 3, we found that higher BMI (≥25kg/m2) was associated with higher MS risk (RR=1.36, 95% CI: 1.05-1.76) compared to normal BMI, and that higher aerobic fitness was independently associated with lower MS risk (RR=0.69, 95% CI: 0.55- 0.88, p trend=0.003). Conclusions: The findings of this thesis add to the evidence linking low vitamin D to MS risk and further point to adolescence as the crucial postnatal period, in which adequate levels should be ensured. Further, these findings suggest that MS has a prodromal phase with subtle but detectable signs. RRMS could start years prior to first relapse, while PPMS could potentially start decades prior to onset of progressive symptoms. Lastly, these findings add weight to evidence linking being overweight to MS risk among men and suggest, further, that vigorous exercise or a factor strongly associated with high cardiorespiratory fitness may be an additional modifiable protective factor for MS that warrants further investigations.