Measuring neural replay using magnetoencephalography (MEG); use as a biomarker in human prion disease

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Prion diseases are a group of rare neurodegenerative diseases which are caused by abnormally folded proteins. They currently have no treatment or cure, but potential treatments are being developed, and results in animal models of priondiseases are promising. There is also good evidence that starting these treatments as early in the disease course as possible, or ideally before disease onset in people who are at high risk of developing prion diseases, would bemost effective. The core idea of treatments is to delay onset of prion diseases, or to arrest the core disease process before irreversible damage has occurred.Therefore, we urgently need early and sensitive markers that predict when prion diseases are about to start, enabling early commencement of treatments even before symptoms manifest. Up to now much research has focused on markers of brain damage, such as proteins that are released when brain cells are damaged, brain volume loss on structural scans, or subtle symptom expression. However, I believe that it is likely that some markers of disease may appear even earlier than the above approaches. Subtle changes in brain activity should logically happen before initial symptoms are manifest, and before irreversible damage to brain cells.New techniques, recently developed, now allow measurement of a subtle aspect of brain activity (termed 'replay') using MEG scanners. MEG is a brain imaging method that can capture tiny changes in the brain's magnetic andelectrical fields. It has very high temporal resolution, that enables direct measurements of brain function, allowing assessment of how processes related to replay go awry early in prion diseases.Therefore, this study aims to determine whether subtle changes in brain activity, related to neural replay, can be detected in those vulnerable subjects who have no overt signs or symptoms of prion disease, but who nevertheless are at high risk of developing prion diseases. Relatedly, we aim to ascertain whether changes in replay predict when symptoms of prion diseases are about to start, as well as enable decision making as to when we should start treatments as part of clinical trials in people at high risk for prion disease. People involved in the study will include patients with prion diseases who are recruited via the National Prion Monitoring Cohort (a UK wide study that has so far collected data characterising prion diseases from over 1,000 patients). It will also include people who are at high risk of developing prion diseases but who do not have symptoms. Healthy individuals, who do not have prion diseases, and are not at high risk of developing prion diseases, will also be recruited as a comparison control group. Participants in the study will be asked to have one or more assessments, at time intervals ranging from six weeks to one year, depending on whether they have symptoms, and how quickly their symptoms are progressing. During assessments they will have a MEG scan, during which they will perform a bespoke cognitive task. As well as having a MEG scan they will also have an assessment by a doctor to help decide if they are showing symptoms of prion diseases, or how advanced their disease is. These scans will be done over the course of 3 years.By analysing the strength of neural replay in patients with, and at risk of prion diseases, we will determine whether neural replay provides for a quantitative marker that can guide the direction of future clinical trials, as well asunderstanding how a signature of brain activity crucial to cognition changes early on in prion disease, providing a novel biomarker.