Developing The Oxford Study for Biomarkers in Motor Neuron Disease (BioMOx): Capturing pre-symptomatic events and advancing clinical translation

运动神经元病（MND）是一种神经退行性疾病，其中大脑和脊髓的上下运动神经元过早死亡。也被称为肌萎缩性侧索硬化症（ALS），它会导致进行性肌肉无力和消瘦，影响手臂，腿部，言语和吞咽肌肉。供应呼吸肌的运动神经的参与导致一半患者在症状发作后三年内死亡。尽管过去20年进行了多种药物试验，但没有有效的治疗方法。在英国，大约有5000人患有MND，还有更多的人间接受到照顾者的影响。它影响男性和女性，虽然发病高峰在60岁出头，但年龄范围很广。人们对为什么会患上MND知之甚少。虽然对于大多数患者来说，发展这种疾病没有明确的单一遗传原因，但在少数患者中，由于遗传密码中的单一突变或扩增，有多个家庭成员处于危险之中。该项目将研究已知携带与MND发展相关的遗传异常的健康志愿者，以尝试捕捉神经损伤的最早迹象。这些变化可能揭示预防性药物治疗的新靶点，然后在减缓已确诊疾病的进展方面也有价值。该项目的这一部分将使用英国仅有的两台极强磁场（7特斯拉）MRI扫描仪之一，以检测大脑功能和结构的细微变化。MRI的发展意味着现在可以研究脊髓和大脑，并使用称为磁共振光谱的技术非侵入性地观察组织内的化学物质。这将被耦合到一个非常敏感的脑磁图（MEG）扫描仪，它可以实时检测大脑运动神经活动的模式。这种独特的组合有可能在症状出现之前很久就解开个体大脑和脊髓中以前未被识别的变化，目的是确定新的治疗靶点，以及监测未来治疗药物的新方法。MND的症状最初可能对GP来说并不严重。一旦转诊到医院医生，如果没有诊断测试，诊断并不总是简单的。目前的诊断取决于经验丰富的神经科医生的意见和排除潜在的模仿障碍，这往往涉及漫长的调查和一个痛苦的时期的不确定性的病人。平均而言，MND患者等待诊断至少一年。这就推迟了唯一一种轻微减缓疾病的药物利鲁唑的早期给药，这可能是许多其他药物试验未能显示出益处的原因之一。这也是人们希望最大限度地提高剩余生活质量的宝贵时间。在MND中找到可靠的疾病活动标志物，称为生物标志物，可能有助于加快诊断，帮助护理计划和评估新的候选药物。牛津MND生物标志物研究（BioMOx）是一组60多名MND患者，所有亚型，他们自愿在整个疾病期间接受随访，每六个月接受一次测试，试图识别生物标志物。先进的MRI脑部扫描和对脊髓液和血液的分析已经揭示了几个候选人，并表明它们的组合提高了准确性。该项目将在那些症状使MND成为可能诊断的人以及患有疾病模拟的人中测试这些生物标志物，以查看哪些生物标志物最可靠。它还将允许BioMOx继续定期研究新的MND病例，以了解为什么最初孤立症状的传播模式和速度在个体之间存在差异。这可能有助于更有效地组织临床试验，以及有效的护理规划。

Motor neuron disease (MND) is a neurodegenerative condition in which the upper and lower motor neurons of the brain and spinal cord die prematurely. Also known as amyotrophic lateral sclerosis (ALS), it leads to progressive muscle weakness and wasting affecting the arms, legs, and speech and swallowing muscles. Involvement of the motor nerves supplying the respiratory muscles leads to death within three years of the onset of symptoms for half of patients. There is no effective treatment despite multiple drug trials over the last 20 years. About 5000 people suffer from MND in the UK, and many more are indirectly affected as their carers. It affects men and women and, although the peak incidence is in the early 60s, there is a wide age range.Little is understood about why people develop MND. Whilst for most patients there is no clear single genetic reason for developing the disease, in a small number of patients there are multiple family members at risk due to single mutations or expansions in the genetic code. This project will study healthy volunteers who are known to carry genetic abnormalities linked to the development of MND, in order to try and capture the very earliest signs of nerve damage. Such changes might reveal new targets for preventative drug therapy, that then also have value in slowing progress in those with established disease. This part of the project will use one of only two very strong magnetic field (7 Tesla) MRI scanners in the UK in order to detect subtle changes in brain function and structure. Developments in MRI mean that it is now possible to study the spinal cord as well as the brain, and to look non-invasively at chemical substances within the tissue using a technique known as Magnetic Resonance Spectroscopy. This will be coupled to an extremely sensitive magnetoencephalography (MEG) scanner, which can detect patterns of brain motor nerve activity in real-time. This unique combination has the potential to unlock previously unrecognised changes in the brain and spinal cord of individuals long before symptoms appear, with the aim of identifying new targets for therapy, and new ways to monitor future therapeutic agents.The symptoms of MND may initially not seem serious to the GP. Once referred to a hospital physician, making a diagnosis is not always straightforward without a diagnostic test. Currently diagnosis depends upon the opinion of an experienced neurologist and the exclusion of potential mimic disorders, which often involves lengthy investigations and a distressing period of uncertainty for patients. On average MND patients wait at least one year for a diagnosis. This delays the earlier administration of the only marginally disease-slowing medication, riluzole, and might be one reason that so many other drug trials have failed to show benefit. It is also precious time when individuals wish to maximise the quality of their remaining life. Finding reliable markers of disease activity in MND, called biomarkers, might help to speed up diagnosis, aid care-planning, and the assessment of new candidate drugs.The Oxford Study for Biomarkers in MND (BioMOx) is a group of more than 60 MND patients, of all sub-types, who volunteered to be followed throughout their disease, undergoing tests every six months to try and identify biomarkers. Advanced MRI brain scans and analysis of spinal fluid and blood have revealed several candidates, and shown that their combination improves accuracy. This project will test these in people whose symptoms make MND a likely diagnosis, and in people with disease mimics, in order to see which biomarkers perform most reliably. It will also allow BioMOx to continue studying new cases of MND at regular intervals in order to understand why the pattern and speed of spread of initially isolated symptoms varies between individuals. This might help with the more efficient organisation of clinical trials, as well as effective care-planning.