Environmental risk factors and pre-diagnostic signs of multiple sclerosis
Risk factor or early sign of multiple sclerosis?
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system which affects young adults and can lead to substantial disability. This project is devoted to the investigation of newer environmental MS risk factors and susceptibility periods of known factors. It is also meant to study early signs of disease activity.
In 2016 I focused on the investigation of early signs of MS. We tried to understand whether the disease is active prior to the onset of typical neurological symptoms and if so, how long before. We investigated whether there were subtle disease activity signs beyond radiologically detectable changes in the brain. We obtained access to data of all Norwegian men born in 1950-95 who underwent the mandatory conscription examination (sesjon) at age 18-19 and linked it to the Norwegian MS-registry. We compared the cognitive test results at conscription of men who later in their lives developed MS to those who did not develop the disease. We found that men who developed first MS symptoms a few years after the cognitive tests scored significantly lower than the never-affected men, with a difference equivalent to 6 IQ points. Overall there was no difference in the cognitive performance when we compared MS patients regardless of when they showed first symptoms to the controls. This led us to interpret these findings as as sign of early pre-clinical disease activity. We further investigated MS patients in subgroups according to the MS form- the most common relapsing-remitting and the more seldom but fast advancing primary progressive form typically with an onset later in life. We found very similar results as described above when we investigated men developing relapsing-remitting MS. However, we found that men developing primary progressive MS scored significantly lower on the cognitive test compared to controls (equivalent to 4-7 IQ points) even though they developed MS up to 20 years later. A trend was perceivable and the closer the onset of symptoms occurred after conscription, the greater the difference. This is interesting because experts have long been speculating whether these two entities are the same disease, and these findings seem to support the idea that both forms of MS may start at a similar age but manifest a different clinical course, one showing attacks in the 20ies, the other accumulating disability until a threshold is crossed in the 30ies or 40ies. Understanding the natural history of a disease is crucial for the investigation of any other disease aspect. These findings will, for example, need to be considered when studying MS risk factors which should ideally be investigated before the disease starts. They may also help in understanding the more puzzling MS course, primary progressive MS, for which no treatment has yet been approved.
Risk factors and early disease signs of multiple sclerosis
Multiple sclerosis (MS) is a potentially disabling neurologic disease of young adults in which the immune-system attacks the protective sheaths around the nerve fibers in the brain or spinal cord. Our research focuses on risk factors of MS, e.g. low vitamin D and large body size, including susceptible age periods and earliest signs of MS activity.
The first article of this PhD project was published in May 2015. The aim of the first study was to investigate whether there is a specific period in life in which low vitamin D levels mattered most as risk factor of MS. We used questionnaire data from a large case-control study (EnvIMS) to assess vitamin D intake through cod liver oil use at different ages in Norwegian participants with and without MS. We found that cod liver oil use during adolescence (age 13-18) was associated with a reduced MS risk, whereas supplementation during childhood (age 0-12) or adolescence (age 19-30) did not seem to influence MS risk. The higher the cod liver oil dose during adolescence, the lower was the MS risk. The strongest effect was found for 600-800 IU daily. We concluded that adolescence may be a critical period for the action of vitamin D on MS risk. These findings have received medial attention after publication and were discussed in the 2015 Annual Report of the MS-forbundet as well as in an article for BestPractice Neurology. The second article will be submitted for publication in the beginning of 2016. The aim of the second study was to investigate potential early signs of MS and when they occurred before the first neurological symptoms of the disease became apparent to the patient and doctors. For this study, we linked the cognitive test scores at conscription at age 18 or 19 (sesjon) of all Norwegian men born in the years 1950-95 to the Norwegian MS registry and biobank to identify men who after the conscription developed MS. We compared the performance of men who later in their lives developed MS to those who did not and investigated potential differences according to the time interval between conscription and first MS symptoms. We found that men who developed their first MS symptom 1-2 year after conscription scored significantly lower during cognitive tests compared to those who did not develop the disease. The difference corresponded to 6 IQ-points on the most commonly used IQ-test (WAIS). The cognitive test scores between controls and men who later developed MS were not overall significantly different, when we analysed the cases regardless of how many years after conscription they developed first symptoms. Since there are two main forms of MS, attack-wise MS (relapsing-remitting MS, RRMS) and MS progressive from onset (primary progressive MS, PPMS), we also investigated the data in the subgroups separately. Men who later developed RRMS showed, similar to the results in the overall group, significantly lower cognitive scores compared to the controls. The risk of MS was 2.7 times higher in those with lowest scores (score > 1 SD below the mean score among controls) in the 2 years following conscription compared to those scoring higher. Men who later developed PPMS scored instead significantly lower than controls even if first progressive symptoms appeared up to 20 years later. The risk of MS was significantly higher during 2 decades following the conscription in men scoring lowest compared to the rest. These findings are of great importance because they imply that MS starts with subtle symptoms years before the first symptoms occur. PPMS symptom onset is usually later in life than RRMS onset. These findings suggest, however, that PPMS may have a long subclinical phase before we perceive first progressive symptoms and that both subtypes of MS may begin at a similar age. These findings challenge traditional thinking about MS.
Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.
Ann Neurol 2016 Oct;80(4):616-24.
PMID: 27554176 - Inngår i doktorgradsavhandlingen
Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study.
Mult Scler 2016 Sep 23. Epub 2016 sep 23
Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study.
Mult Scler 2015 Dec;21(14):1856-64. Epub 2015 mai 6
PMID: 25948625 - Inngår i doktorgradsavhandlingen