Metabolic alterations in Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is characterized by demyelination, axonal loss and inflammation in the central nervous system. Although MS is generally viewed to be an (auto-)immune mediated disease, recent studies postulate an important role for mitochondrial dysfunction and corresponding ROS production in disease progression. The goal of this thesis is to provide an overview of the metabolic alterations found with imaging techniques in MS at the different stages and lesions types of MS. Thereupon this thesis examines, to what extent these results are consistent with pathological findings and what this implies for the postulated role of metabolic alterations in MS pathogenesis. Magnetic resonance spectroscopy (MRS) imaging is a non-invasive technique, which is able to determine the concentration of a variety of metabolites in the brain. Previous MRS studies showed that the metabolites n-acetyle aspartate (NAA), lactate, glutamate and phosphocreatine (PCr) are altered in MS. In addition, other imaging techniques also detected alterations in perfusion and glucose uptake. Imaging results show that metabolic alterations are widespread in MS, where they are present throughout the white matter (WM) and gray matter (GM) in both early and chronic MS. Combined with pathological evidence, these results show that metabolism is increased in active WM lesions, which can be explained by the present inflammation. In chronic lesions, normal appearing white matter (NAWM) and GM, on the other hand, metabolism is reduced. Reduced metabolism can actively contribute to disease progression, especially in chronic lesions where there is increased energy demand. The underlying mechanism leading to reduced metabolism is not fully understood. Part of the reduction can be explained by cellular loss, but the contribution of mitochondrial dysfunction cannot be excluded in these areas. The reduced NAA and perfusion in the NAWM are of special interest, because they cannot be explained by severe inflammation or cellular loss. Altogether metabolic alterations in MS provide more insight in disease pathogenesis and can be interesting therapeutic targets. However, they require further examination.