Williams, Thomas; (2022) The Application of Novel and Evolving Biomarkers to patients with Multiple Sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis reports on the application of biomarkers to cohorts of patients with MS, with the aim of improving our understanding of disease and therapeutic mechanisms. In chapter 3 we demonstrate that the mechanism of action of simvastatin on brain atrophy in SPMS is largely independent of the main determinants of sNfL and sNfH concentrations. Our secondary analyses, however, found considerable evidence to support an association between sNfL and current or futures measures of MS severity. This therefore suggests that both simvastatin treatment, and sNfL concentrations, are relevant to the pathophysiology of SPMS, but via largely independent mechanisms. I then applied sNfL quantification to a longitudinal cohort study of patients with a clinically isolated syndrome. Our results suggest that persistent elevations in sNfL are of prognostic importance. In Chapter 5, I describe my work as the lead clinical research fellow for the phase 3 MS-STAT2 trial. I provide analysis of the recruitment process, trial baseline data, and an analysis of the relationships between cardiovascular risk and MS severity. Greater premature cardiovascular risk was associated with more severe brain atrophy and poorer episodic memory performance. The latter appears to be particularly driven by abnormal lipid profiles, which is of particular interest given the established role of simvastatin in lipid modification. Chapter 6 presents quantitative susceptibility mapping data as a biomarker of iron accumulation. We find thalamic susceptibility is significantly lower in people with SPMS compared to controls, and strongly associated with other clinical and imaging measures of MS severity. Finally, in chapter 7, I present data from a pilot case-control study using a unique time-domain near-infrared spectroscopy (tdNIRS) system to assess cortical oxygenation. Building upon pre- clinical data from the laboratory of Prof. Ken Smith within our department, we find preliminary evidence for cortical hypoxia in pwSPMS compared to controls.

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