Pathological and imaging exploration of progressive disability in multiple sclerosis.

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults in the UK. During early MS, patients usually experience intermittent episodes of neurological symptoms with full recovery in between. These episodes result from inflammation in the central nervous system (CNS) and can be diminished by immune-suppressing medications. Unfortunately, most patients ultimately enter a progressive phase of MS where disability accumulates irreversibly. For reasons that are unclear, the onset of progression varies considerably. We propose a study that aims to define the pathological changes that account for progressive disability in MS and understand their mechanism. To accomplish these aims we plan to (i) work with a unique magnetic resonance imaging (MRI) instrument and a highly acclaimed group of MR physicists to determine whether MRI changes seen in the brain of MS patients relate to disability, (ii) study CNS tissue derived from MS patients at autopsy to validate the same and investigate the mechanism underlying this damage. This project will occur within departments of the University of Nottingham that share distinguished research reputations. An imaging system capable of measuring a marker of progressive disability in MS could be valuably applied during trials of new treatments.

Traditionally multiple sclerosis (MS) has been regarded as an inflammatory, demyelinating disease of the white matter. Therapies diminishing inflammatory demyelination reduce the frequency of acute neurological relapses for many patients. It appears, however, that the accumulation of disability during progressive phases of MS relates more to a neurodegenerative process than it does to the collective effect of relapses and is therefore relatively resistant to existing treatments. The pathological substrates hypothesised to account for progressive motor disability in MS include neuronal or axonal loss and grey matter (GM) demyelination. The ability to validate these hypotheses has been limited so far by a lack of detailed clinical information in post-mortem pathology studies, and difficulties in demonstrating cortical lesions using conventional MRI. Additionally, the mechanism underlying neurodegeneration in MS remains uncertain as does the pathological distinction between primary progressive (PP) and secondary progressive (SP) subtypes.

We propose a project that combines a cross-sectional imaging study with a retrospective post-mortem analysis in its design and addresses the hypothesis that motor neuronal loss and cortical demyelination are primarily responsible for chronic motor disability in MS:
1. Using the only whole body 7-Tesla MRI scanner in the UK with the support of scientists at the Sir Peter Mansfield Magnetic Resonance Centre, we will develop high resolution sequences capable of visualising GM demyelination and neuronal pathology in MS patients. MR findings will be compared between disease subgroups and also validated against histopathological data in post-mortem material.
2. We will combine immunohistochemical techniques and image analysis software in human autopsy tissue, with the aim of comprehensively detailing the histopathological changes seen throughout the length of the corticospinal tract in MS. By relating findings to disease course and disease severity we aim to ascertain the pathological correlate of chronic disability in MS.
3. To characterise the mechanism of motor neuronal cell death in MS, gene array technology, quantitative PCR and immunohistochemistry will be applied to components of the motor pathway dissected from human autopsy material.

This project presents the opportunity to work with a Nobel Prize winning imaging group using a unique instrument to address a specific clinical question regarding the pathogenesis of motor disability in MS. By combining this with the use of established and contemporary pathology methods we hope to define a marker of chronic disability that is measurable in clinical settings. Results could be beneficially applied to individual patients and in large therapeutic trials.