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

Pron病是一组罕见的神经退行性疾病，由蛋白质的异常折叠引起。他们目前还没有治疗或治愈的方法，但潜在的治疗方法正在开发中，在原发疾病的动物模型中的结果是有希望的。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，或者最好是在高危人群发病之前开始治疗，这将是最有效的。治疗的核心思想是在不可逆转的损害发生之前延缓病毒病的发生，或阻止核心疾病的进程。因此，我们迫切需要早期和灵敏的标记物来预测病毒疾病何时开始，使之能够在症状显现之前及早开始治疗。到目前为止，许多研究都集中在脑损伤的标志上，比如脑细胞受损时释放的蛋白质，结构扫描中的脑体积损失，或者细微的症状表达。然而，我认为，一些疾病的标志很可能比上述方法出现得更早。从逻辑上讲，大脑活动的细微变化应该在最初的症状显现之前发生，在脑细胞受到不可逆转的损害之前发生。最近开发的新技术现在可以使用脑磁图扫描仪测量大脑活动的一个细微方面(称为“回放”)。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，这使得能够直接测量大脑功能，从而能够评估与重播相关的过程是如何在普恩病毒疾病的早期出错的。因此，这项研究的目的是确定是否可以在那些没有明显的普恩病毒疾病的症状或体征，但仍有发展成普恩病毒疾病的高风险的脆弱受试者中检测到与神经重播相关的大脑活动的细微变化。与之相关的是，我们的目标是确定重播的变化是否可以预测普恩病毒疾病的症状何时开始，并使我们能够决定何时应该开始治疗，作为普恩病毒病高风险人群临床试验的一部分。参与这项研究的人将包括通过国家普恩监测队列招募的普恩疾病患者(这是一项全英国范围的研究，迄今已从1000多名患者中收集了表征普恩疾病的数据)。它还将包括那些有很高风险发展成普恩病毒疾病，但没有症状的人。健康的人，没有普恩病毒疾病，也不是发展成普恩病毒疾病的高危人群，也将被招募为对照对照组。这项研究的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，具体取决于他们是否有症状，以及他们的症状进展的速度。在评估期间，他们将接受脑磁图扫描，在此期间，他们将执行一项定制的认知任务。除了进行脑磁图扫描外，他们还将接受医生的评估，以帮助确定他们是否出现了普恩病毒疾病的症状，或者他们的疾病有多严重。这些扫描将在3年的时间内完成。通过分析普恩病毒疾病患者和有风险的患者的神经重播的强度，我们将确定神经重播是否提供了一种可以指导未来临床试验方向的定量标记物，以及了解对认知至关重要的大脑活动的特征如何在普恩疾病早期发生变化，从而提供一种新的生物标记物。

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.