Establishment and applications of a multiple sclerosis biobank : Analysis of biomarkers and therapeutic complications in MS

Sammanfattning: Biomarkers for disease activity and prognosis in multiple sclerosis (MS) are lacking. We established a MS biobank consisting of paired cerebrospinal fluid samples (CSF) and peripheral blood samples from MS patients and controls. A standardized procedure for sampling and data collection was developed when forming the European network for MS biomarker research (BioMS) and applied when processing samples and data. The MS biobank was then used for the following studies: In paper I, we analyzed the basal viral load of JC virus (JCV) DNA in untreated MS patients and controls in aspects of PML risk. In our system, a low JCV DNA replication could occasionally be found in CSF or plasma in MS patients and controls without clinical signs of PML. We concluded that JCV analysis, in untreated MS patients, is not useful for identification of patients with higher risk of PML. In paper II a comparison of N-acetylaspartate (NAA) and neurofilament subunits in CSF as biomarkers for axonal damage in MS was performed. We observed that CSFNAA might serve as a biomarker for axonal damage during later stages of disease. Increased levels of CSF neurofilament light chain (NfL) correlated to acute axonal damage associated with inflammation whereas high levels of CSF neurofilament heavy chain (NfH) was indicative of irreversible axonal damage. The combined analysis of all biomarkers identified a higher number of MS patients with an abnormal biomarker panel compared to analysis of a single biomarker. In paper III we used a new assay for detection of anti-myelin antibodies in CSF and report that approximately 50% of the MS patients had increased anti-myelin antibodyreactivity in CSF and that their levels correlated to the number of MRI lesions in MS patients. In paper IV, we analyzed the levels of vascular endothelial growth factor A (VEGFA) in CSF cells and peripheral blood mononuclear cells (PBMCs) from MS patients and controls and demonstrated that both relapsing-remitting MS patients (RRMS) and secondary progressive MS patients (SPMS) had decreased levels of VEGF-A in CSF. In addition, SPMS also displayed a significant decrease of VEGF-A in PBMCs which was associated with an altered peripheral blood monocyte phenotype. We conclude that decreased PBMCs VEGF-A may be a new biomarker for SPMS. In paper V we performed a large genetic association study in MS patients and controls and demonstrated that IL7R gene variants influence the risk of MS. Functional analysis showed that MS patients had an increase of IL7R and IL7 mRNA expression in CSF cells compared to controls. These findings suggest that IL7-IL7R signaling might be involved in the dysregulated immune response in MS. In summary, we present an example of a genetic biomarker for risk of disease. We related different markers for neurodegeneration to disease stage, explored two possible immune related markers, and analyzed a treatment related complication in MS. The papers included in this thesis are examples of the value of quality biobanking for clinical research.