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、语言和吞咽肌肉。半数患者在出现症状后三年内，累及支配呼吸肌的运动神经导致死亡。尽管在过去的20年里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人患有精神分裂症，还有更多的人作为他们的照顾者间接受到影响。它影响男性和女性，虽然发病率高峰在60岁出头，但年龄范围很广。人们对为什么会患上精神障碍知之甚少。虽然对大多数患者来说，没有明确的单一遗传原因导致这种疾病，但在少数患者中，由于遗传密码的单一突变或扩展，有多个家庭成员处于危险之中。这个项目将研究那些已知携带与MND发展相关的基因异常的健康志愿者，以试图捕捉神经损伤的最早迹象。这些变化可能会揭示预防性药物治疗的新目标，然后在减缓那些已经确定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强磁场（7特斯拉）核磁共振扫描仪中的一台，以检测大脑功能和结构的细微变化。核磁共振成像技术的发展意味着现在可以研究脊髓和大脑，并使用一种被称为磁共振光谱的技术来非侵入性地观察组织内的化学物质。这将与一个极其敏感的脑磁图（MEG）扫描仪相结合，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发现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目标，以及监测未来治疗药物的新方法。对全科医生来说，MND的症状最初可能并不严重。一旦转诊到医院医生那里，如果没有诊断测试，做出诊断并不总是直截了当的。目前的诊断依赖于经验丰富的神经科医生的意见和排除潜在的模拟障碍，这通常涉及漫长的调查和患者痛苦的不确定时期。精神病患者平均等待至少一年才能得到诊断。这推迟了唯一能略微减缓疾病的药物利鲁唑的早期施用，这可能是许多其他药物试验未能显示出效果的原因之一。当个人希望最大限度地提高他们剩余生活的质量时，这也是宝贵的时间。在MND中发现疾病活动的可靠标记物，称为生物标记物，可能有助于加快诊断，帮助制定护理计划，以及评估新的候选药物。牛津大学MND生物标志物研究（BioMOx）是一个由60多名所有亚型的MND患者组成的小组，他们自愿在整个疾病过程中接受跟踪，每六个月接受一次测试，以尝试识别生物标志物。先进的核磁共振脑部扫描和脊髓液和血液分析揭示了几种候选方法，并表明它们的结合提高了准确性。该项目将在那些症状可能被诊断为MND的人以及患有类似疾病的人身上进行测试，以了解哪种生物标志物表现最可靠。它还将使BioMOx能够继续定期研究MND的新病例，以便了解为什么最初孤立的症状在个体之间的传播模式和速度不同。这可能有助于更有效地组织临床试验，以及有效的护理计划。

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.