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

使用脑磁图（MEG）测量神经重放；

• 批准号: MR/X019586/1
• 负责人: Leah Holm-Mercer
• 金额: $ 32.28万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX019586%2F1
• 关键词: Measuring; neural; replay; using; magnetoencephalography

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.

朊病毒病是一组由蛋白质异常折叠引起的罕见神经退行性疾病。他们目前没有治疗或治愈，但潜在的治疗方法正在开发中，并在动物模型的朊病毒病的结果是有希望的。也有很好的证据表明，在疾病过程中尽可能早地开始这些治疗，或者理想地在疾病发作之前，处于朊病毒疾病高风险的人将是最有效的。治疗的核心思想是延迟朊病毒疾病的发作，或在不可逆的损害发生之前阻止核心疾病的进程。因此，我们迫切需要早期和敏感的标记物，以预测朊病毒疾病何时即将开始，从而能够在症状出现之前尽早开始治疗。到目前为止，许多研究都集中在脑损伤的标志物上，例如脑细胞受损时释放的蛋白质，结构扫描时的脑容量损失，或细微的症状表达。然而，我认为，一些疾病的标志物可能比上述方法更早出现。大脑活动的微妙变化应该在最初的症状表现出来之前发生，并且在对脑细胞造成不可逆的损害之前。最近开发的新技术现在允许使用MEG扫描仪测量大脑活动的一个微妙方面（称为“重放”）。脑磁图是一种大脑成像方法，可以捕捉大脑磁场和电场的微小变化。它具有非常高的时间分辨率，可以直接测量大脑功能，允许评估与重放相关的过程如何在朊病毒疾病的早期出错。因此，本研究旨在确定与神经重放相关的大脑活动的细微变化是否可以在那些没有朊病毒疾病的明显体征或症状的脆弱受试者中检测到，但他们仍然有很高的风险患上朊病毒疾病。与此相关，我们的目标是确定重放的变化是否预测朊病毒疾病的症状何时开始，以及何时我们应该开始治疗作为朊病毒疾病高风险人群临床试验的一部分的决策。参与该研究的人员将包括通过国家朊病毒监测队列（一项英国范围内的研究，迄今为止已从1，000多名患者中收集了朊病毒疾病的特征数据）招募的朊病毒疾病患者。它还将包括那些有患朊病毒疾病高风险但没有症状的人。未患有朊病毒疾病并且不处于发展朊病毒疾病的高风险的健康个体也将被招募作为比较对照组。研究参与者将被要求进行一次或多次评估，时间间隔从六周到一年不等，这取决于他们是否有症状以及症状进展的速度。在评估期间，他们将进行MEG扫描，在此期间他们将执行定制的认知任务。除了进行MEG扫描外，他们还将接受医生的评估，以帮助确定他们是否表现出朊病毒疾病的症状，或者他们的疾病有多严重。这些扫描将在3年内完成。通过分析朊病毒病患者和有朊病毒病风险的患者的神经重放强度，我们将确定神经重放是否提供了一个定量标记，可以指导未来临床试验的方向，以及了解朊病毒病早期对认知至关重要的大脑活动特征如何变化，提供一个新的生物标志物。