The Dynamics And Clinical Relevance Of Grey Matter And Periventricular White Matter Pathology In Multiple Sclerosis

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About 130000 people in the UK have multiple sclerosis (MS) and, other than head injuries, it is the commonest cause of neurological disability in young adults, but we do not yet know its cause. The most obvious and most studied feature of MS is the presence of lesions in white matter (WM, the part of the brain that contains nerve fibres). WM lesions are seen where the covering (myelin) surrounding nerve fibres has been damaged or lost. They were the first feature of MS seen on brain scans, and it is now routine to look for WM lesions using magnetic resonance imaging (MRI) brain scans when making a diagnosis of MS. Their formation causes the episodes (termed relapses) of neurological symptoms that the majority of people with MS have initially, and we now have more than ten treatments available in the UK that can substantially reduce the risk of WM lesion formation and relapses. However, most people with MS eventually develop progressive disability without relapses, and the accumulation of WM lesions is only modestly related to this. We only have two treatments approved in the UK for progressive MS, and even these can only be given when there is MRI evidence for WM lesion activity or relapses. It is now thought that the loss of nerves cells is ultimately a more important cause of disability, but we do not know the main cause of nerve cell loss.About two decades ago it become clear that grey matter (GM; the part of the brain that contains nerve cells) is significantly involved in MS. With advances in MRI, it became possible to measure shrinkage of the brain, mainly due to loss of GM (which is itself due to nerve cell damage and loss), and it was found that this is more closely related to MS disability progression than WM lesion formation. However, other aspects of GM damage, for example GM lesions (which are usually more extensive than WM lesions) remained difficult to detect. Recognising this, in 2010 we began a study to develop new MRI methods to look for GM disease in MS. We recruited over 200 people, including people with relapsing-remitting and progressive forms of MS, and people with no known neurological disease. We developed methods to better see GM lesions, and also to detect GM abnormalities beyond lesions. We also showed that MS disease effects were greater towards the surface of the brain both in GM and WM. Importantly, we found that these abnormalities were not closely linked with WM lesions and were independently associated with disability. As such, they could represent important targets for treatments. However, with the resources available at the time, we were only able to assess about a third of people over about 18 months, and so could not robustly look for changes over time or determine if they were - in the longer-term - closely linked with brain atrophy and disability.The passage of a decade will have allowed changes in GM abnormalities to become clear, and their clinical significance to be more readily assessed, and so we now propose to follow up the people who took part in our original study. We will use updated MRI methods to look for GM and WM abnormalities, and specifically consider how WM and GM disease processes eventually lead to brain atrophy. We expect this work to provide valuable insights into the pathways leading to brain atrophy (and so nerve cell loss), and this should enable us to measure MS treatment effects on these pathways, rather than waiting for irreversible brain atrophy to occur. As we will use an MRI scanner similar to those already widely used in healthcare, we also expect this work to be quickly applicable in clinical trials (some of the methods we developed in our earlier study are already being used) and potentially in clinical practice.