The search for clues explaining phenotypic variability in multiple sclerosis

The main aim of this thesis was to identify determinants associated with phenotypic variability in multiple sclerosis (MS). We initiated a nation-wide population-based cross-sectional cohort (Project Y) in which we aimed to include all patients with MS born in the same birth year (1966) and age- and sex-matched healthy controls (HC) (1965-1967). All studies that make up this thesis involve the project Y cohort and build upon the idea that age is the most important confounder when studying phenotypic variability in MS. The total number of identified cases resulted in a prevalence of 1.89/1000 for birth year 1966 in the Netherlands, which indicates that the recently adjusted prevalence of MS (1.5/1000) in the Netherlands might still be an underestimation. We subsequently used the MS prevalence estimates in birth year 1966 to display polygenic risk of MS in relation to lifetime risk. We demonstrated that genetic factors have a profound influence on the lifetime risk of MS in men and women. We also investigated how clinical disability is related to volumetric MRI measures. In our cohort unbiased by age differences, spinal cord and deep gray matter volumes best related to physical disability, which support the use of these measures in clinical practice and trials. Furthermore, we explored the relation between several blood biomarkers (proteins, hormones and lipids) and MS disease severity. By using individuals from the same birth year, we were able to limit age variation, as all studied biomarker concentrations change with physiological aging. We reported consistent correlations of serum neurofilament light (sNflL) and serum glial fibrillary acidic protein (sGFAP) with a range of clinical and radiological metrics, especially in progressive MS. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS. Subsequently, we found associations between adipokines (hormones secreted by white adipose tissue) and clinical and radiological measures, which were independent of BMI. Also, we showed that ω-3 and ω-6 lipid mediators are associated with disability, biochemical (sNfL, GFAP) and MRI measures. Particularly in patients with progressive MS, elevated levels of specific products of the arachidonic acid (AA) pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 lipid mediators in the pathogenesis of MS. Lastly, we investigated the impact of (early life) exposure to environmental factors on MS risk and disease course. We found that being overweight or obese during childhood or adolescence was associated with MS prevalence and an earlier age of onset. Also, we found significant associations between dietary factors at childhood and developing MS, age of onset and onset type and between dietary factors at age 50 and disability and MRI-derived volumes. Combined, the findings of this thesis represents the first step in the search for determinants of phenotypic variability in people with MS from the Project Y cohort. Further integration of multi-layer data using deep phenotyping will hopefully lead to a better understanding of MS and significant advances in personalized and precision medicine.