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

开展运动神经元疾病生物标志物牛津研究 (BioMOx)：捕获症状前事件并推进临床转化

• 批准号: MR/K01014X/1
• 负责人: Martin Turner
• 金额: $ 203.88万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01014X%2F1
• 关键词: Developing; Oxford; Study; Biomarkers; Motor

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.

运动神经元病(MND)是一种神经退行性疾病，大脑和脊髓的上、下运动神经元过早死亡。也被称为肌萎缩侧索硬化症(ALS)，它会导致进行性肌肉无力和消瘦，影响手臂、腿、语言和吞咽肌肉。供应呼吸肌的运动神经受累会导致半数患者在症状出现后三年内死亡。尽管在过去20年里进行了多次药物试验，但仍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，虽然发病高峰在60年代初，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，没有明确的单一遗传原因导致这种疾病的发生，但在少数患者中，由于遗传密码的单一突变或扩展，有多个家庭成员面临风险。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，以尝试并捕捉到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，然后在减缓既往疾病患者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非常强磁场(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。核磁共振的发展意味着现在可以研究脊髓和大脑，并使用一种名为磁共振光谱的技术非侵入性地观察组织中的化学物质。这将与一个极其灵敏的脑磁图(MEG)扫描仪相结合，该扫描仪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锁个人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。MND的症状最初在全科医生看来可能并不严重。一旦转诊给医院的医生，如果没有诊断测试，做出诊断并不总是简单的。目前的诊断取决于有经验的神经科医生的意见和排除潜在的模拟障碍，这通常涉及到漫长的调查和令人痛苦的不确定时期。平均而言，MND患者至少要等一年才能确诊。这推迟了唯一一种略微减缓疾病的药物利鲁唑的早期服用，这可能是其他许多药物试验未能显示出疗效的原因之一。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。寻找MND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，帮助护理规划和评估新的候选药物。牛津MND生物标记物研究(BioMOx)是一个由60多名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，试图识别生物标记物。先进的核磁共振脑部扫描以及对脊髓液和血液的分析已经发现了几种候选方法，并表明它们的结合可以提高准确性。该项目将在症状使MND成为可能诊断的人以及具有疾病模拟症状的人身上进行测试，以了解哪些生物标记物的表现最可靠。它还将允许BioMOx继续定期研究MND的新病例，以了解为什么最初孤立的症状的传播模式和速度在不同的人之间不同。这可能有助于更有效地组织临床试验，以及有效的护理规划。

项目成果

Amyotrophic Lateral Sclerosis and the Frontotemporal Dementias

肌萎缩侧索硬化症和额颞叶痴呆

• 发表时间: 2013
• 作者: Bowser B, Connor J, Turner MR

Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials

• DOI: 10.1136/jnnp-2013-306865
• 发表时间: 2015-01-01
• 期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
• 影响因子: 11
• 作者: Balendra, Rubika;Jones, Ashley;Al-Chalabi, Ammar
• 通讯作者: Al-Chalabi, Ammar

Defective cholesterol metabolism in amyotrophic lateral sclerosis.

• DOI: 10.1194/jlr.p071639
• 发表时间: 2017-01
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Abdel-Khalik J;Yutuc E;Crick PJ;Gustafsson JÅ;Warner M;Roman G;Talbot K;Gray E;Griffiths WJ;Turner MR;Wang Y
• 通讯作者: Wang Y

An elusive cause for a progressive neuropathy.

进行性神经病的难以捉摸的原因。

• DOI: 10.1136/practneurol-2013-000587
• 发表时间: 2014
• 期刊: Practical neurology
• 影响因子: 2.8
• 作者: Aurangzeb S

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in the older adult.

• DOI: 10.1136/practneurol-2014-000853
• 发表时间: 2014-12-01
• 期刊: Practical neurology
• 影响因子: 2.8
• 作者: Aurangzeb, Sidra;Vale, Thomas;Turner, Martin R
• 通讯作者: Turner, Martin R