Mechanisms of demyelination and neurodegeneration in the cortical grey matter in multiple sclerosis

Multiple Sclerosis (MS) is the commonest neurological disorder of young adults in the UK. The time course and severity of the disease is extremely variable and there is no way to predict whether it will follow a mild or aggressive course. Current treatments are only successful at decreasing the number of attacks but have no effect on the progression of the disease. Damage to the brain is thought to be caused by an attack by the immune system on the insulating myelin sheath that covers nerve fibres. This appears as multiple areas of inflammation in the fibre tracts. Recent research in our laboratories on post-mortem brains has identified a subgroup of MS cases (40% in the current study) in which there is also extensive damage to the surface layers of the brain. These cases are characterised by inflammation in the meninges, the tissue that forms the outside lining of the brain. We have found that antibody producing cells, B-lymphocytes, are proliferating in the meninges. This suggests that substances toxic to the cells of the brain are diffusing into the underlying layers of the cerebral cortex and causing the damage in this subset of MS cases. These cases also followed a more aggressive disease course, resulting in a shorter time to wheelchair dependence and earlier death.
This project is designed to gain an understanding of the mechanisms of damage to neurons in order to identify drug targets for the development of novel treatments. We will use two groups of MS cases for which post-mortem tissue is available, one group that has B-lymphocytes in the meninges and which followed the more aggressive disease course and a group that does not. Firstly, we will study the changes in the number of neurons in areas of tissue damage and then investigate which genes are being turned on and off by the neurons that might explain why some of them are dying. This will be achieved by studying all 30,000+ genes in these cells simultaneously using gene chips. The presence within the brain tissue of proteins known to be toxic to neurons, which may have diffused from the brain surface, will be analysed. Patient histories will be used to correlate this information with variables such as disease onset and relapse frequency. Identification of this sub-group of MS patients at high risk of a poor outcome could facilitate early treatment before extensive and irreversible damage occurs.

Multiple Sclerosis (MS) is the commonest neurological disorder affecting young adults in the UK and effective treatments that prevent the progression of neurological disability are not yet available. Although the pathological hallmarks of MS are the inflammatory demyelinated white matter plaques, cortical grey matter (GM) pathology contributes to neurological impairment. However, its pathogenesis is poorly understood. We have recently demonstrated that a subset of MS cases exhibit ectopic B-lymphocyte follicles in the meninges and are associated with greater cortical demyelination, axonal loss and a more severe disease course. The close association of ectopic B-cell follicles to cortical GM lesions implies that induction of cortical pathology could be directly or indirectly influenced by the diffusion of B-cell products from the meninges. This has significant implications for the development of immunomodulatory and neuroprotective treatments for this subset of patients. Therefore, we aim to test the hypothesis that increased cortical damage in meningeal follicle positive MS cases involves a significant loss of multiple cell populations and is linked to the increased expression of inflammatory mediators in the cortical grey matter.
The detailed cellular pathology of sub-pial GM lesions and matched areas of normal appearing grey matter from follicle positive and negative MS cases will be studied using quantitative immunohistochemistry to define the degree of neuronal loss/damage. Gene expression profiling of these well characterised sub-pial lesions will be carried out using Illumina BeadChips to determine the differential expression of inflammatory mediators and other genes and pathways of interest between the two groups. Following analysis of the gene expression data using Genespring and David Bioinformatics software, differentially expressed genes of interest will be verified using quantitative PCR analysis and immunohistochemistry. This analysis will focus on the expression of inflammatory mediators and pathways involved in the cellular reaction to those mediators, such as oxidative stress responses, DNA repair, apoptosis and cell survival. Targeted antibody arrays will then be used for a quantitative analysis of protein expression for cytotoxic mediators to determine whether a gradient of such factors exists within the cortical layers, suggesting the presence of diffusible factors from the overlying meninges. The detailed patient clinical histories will be used to assess how the molecular pathology correlates with important clinical variables, such as disease onset and relapse frequency to help define the patient sub-group. Molecular recognition of this patient sub-group at high risk of poor prognosis could facilitate early treatment before extensive and irreversible pathology occurs.