A longitudinal study of biomarkers in primary progressive multiple sclerosis

Abstract

This thesis describes the work performed using conventional (whole and regional brain volume) and non-conventional magnetic resonance imaging (MRI) which measures diffusion tensor imaging, magnetization transfer imaging and magnetic resonance spectroscopy, to arrive at the most sensitive way of detecting neurodegenerative change in patients with primary progressive multiple sclerosis (PPMS). The experiments described aim to identify the most useful surrogate marker or combination of such markers that could be used to power trials of neuroprotective agents in PPMS. First, we compared within-patient variability using the same primary progressive MS cohort and a small number of healthy controls of a number of different MR outcome measures. We outlined efforts made to reduce this measurement related variability. We then demonstrated significant longitudinal change over one year in most MR measures in our PPMS cohort compared to healthy controls. We also compared these values to the measured change over time and the across group standard deviation which are necessary values required to power studies. Next we explored the value of non-conventional MRI metrics at baseline and time to get to a baseline value (disease duration) to predict brain atrophy longitudinally over one year. We demonstrated that baseline corpus callosum volume predicted percentage brain volume change over the 6 subsequent year and this correlation between the two became stronger when the annual baseline loss in corpus callosum volume (CCV) was considered. Finally, we showed that the grey matter volume when incorporated into the power calculation for a longitudinal study was the single measure that reduced the sample size required by the most. The combination of volumetric measures (Thalamic Volume+GM Volume) was the most powerful combination, interestingly more powerful than combinations involving PBVC which is the current gold standard. Sample sizes were halved by combining two measures and reduced even futhur by using three measures in combination compared to using a single MR measure.EThOS - Electronic Theses Online ServiceGBUnited Kingdo