Mallik, Shahrukh; (2020) Imaging of Demyelination, Repair and Remyelination in Multiple Sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple Sclerosis (MS) is characterised pathologically by both inflammatory demyelination and neurodegenerative neuroaxonal loss, occurring in varying degrees in the white matter (WM) and in the grey matter (GM). Studies of MS commonly use imaging surrogates of inflammation (e.g. MRI lesions) and neurodegeneration (e.g. atrophy) as outcome measures to assess potential neuroprotective effects. As trials of potentially remyelinating agents become more important in the spectrum of MS research, imaging outcomes sensitive to myelin, such are magnetisation transfer ratio (MTR), are required to adequately assess any such agents. With the above in mind, for this thesis, I performed 4 studies: 1. MTR and atrophy localisation in the GM using voxel-based morphometry - MRI measures of GM MTR and volume were used to assess the regional localisation of reduced MTR (in part reflecting demyelination) and atrophy (in part reflecting neuro-axonal loss) in 98 patients with MS, as well as 29 controls. Subgroups of MS patients were compared with controls, adjusting for age and gender. Overall, whilst some regionally consistent reductions in MTR and atrophy were seen in GM, this study found that these mostly do not co-localise. The differing location and extent of regional MTR and volumetric abnormalities in MS subgroups argues against a single mechanism for demyelination and neuronal loss in the GM of MS patients. 2. MRI substudy of Dronabinol (Δ⁹-THC) vs placebo – 273 patients with secondary progressive MS (SPMS) received either Dronabinol or placebo (in a ratio of 2:1), with the aim of assessing the potential neuroprotective effects of Dronobinol. T2-weighed (T2w) and T1-weighted (T1w) lesions, and percentage brain volume change (PBVC) were assessed over 3 years. Over the course of the entire study, the occurrence of new or enlarging T2w or T1w lesions, or PBVC was not affected by Dronabinol. 3. Individual lesion area MTR analysis of autologous mesenchymal stem cells (AMSC) in patients with SPMS – A proof-of-concept individual lesion area MTR analysis pathway was developed and used post-hoc on 10 patients with SPMS and optic nerve disease from the MSCIMS study, which investigated the potential reparative effects of AMSC. For T2w lesion areas, a significant difference in rate of change of MTR was noted after infusion; this was not seen with T1w lesion areas. 4. Individual lesion MTR analysis in a crossover study of AMSC in patients with active MS – the proof-of-concept work above was refined for use in STREAMS, a crossover study of AMSC. 12 patients with active MS received either AMSC or placebo for 24 weeks, and then crossover to the other arm for a further 24 weeks. MTR was measured at week 0, 12, 24, 26, and 48 in both old and newly appearing lesions. There was not noted to be any significant effect of AMSC on the MTR of either old or newly appearing lesions.

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