- The stress-axis in multiple sclerosis: Clinical, cellular and molecular aspects
- Award date
- 2 April 2014
- Number of pages
- 's-Hertogenbosch: Boxpress
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Multiple sclerose (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which autoimmune demyelination leads to severe and progressive neurologic decline. A hallmark of MS is its clinical and pathological heterogeneity. This is most evident in the highly variable and unpredictable disease course: some MS patients may remain relatively asymptomatic for decades, whereas others may progress to a state of severe disability and death within years or in cases with fulminant disease even within months after onset.
Strongly implicated in the heterogeneity of MS are inter-individual differences in cortisol production by the hypothalamus-pituitary-adrenal (HPA)-axis. In most MS patients, the HPA-axis is strongly activated. However, we and others identified an association between low HPA-axis activity and more severe MS. Therefore, this thesis aimed to provide a better understanding of the relation between activity and regulation of the HPA-axis and various aspects of MS: clinical course, neurodegeneration, lesion pathology, glucocorticoid receptor (GR) polymorphisms, and molecular as well as cellular characteristics of normal-appearing white matter (NAWM).
On the whole, this thesis supports the conclusion that high stress-axis activity substantially contributes to suppression of MS disease activity, as the presented evidence strongly suggests that it impacts on clinical course, lesion pathology as well as cellular and molecular mechanisms in the NAWM. Finding ways to evaluate and possibly modify stress-axis responsiveness to inflammation might therefore improve the clinical care of MS patients. In addition, identifying mechanisms to modulate microglia and glucocorticoid-related molecular pathways in the NAWM may represent a valuable therapeutic strategy for preventing lesion formation and disease progression in MS.
- Research conducted at: Universiteit van Amsterdam