Novel MRI Biomarkers in Neuromuscular Disease

每年有2000多人死于运动神经元疾病（MND）。在这种不断恶化的情况下，控制肌肉的运动神经纤维死亡，导致虚弱，最终瘫痪。早期诊断使患者能够接受延长生命的治疗，但目前的临床试验只对疾病的晚期阶段敏感，到那时这些治疗可能已经太晚了。我们最近开发了一种全新的方法来检测MND患者肌肉的早期变化。这种方法使用一种核磁共振成像扫描，可以检测到神经纤维死亡前肌肉微小区域的特征性抽搐（称为束动）。这些区域被称为运动单元。我们能够展示我们的新技术，我们称之为运动单元核磁共振成像（MUMRI），在MND患者的腿部肌肉中检测到数百种肌束，但在健康受试者中却没有。这是非常令人兴奋的，因为这是第一次使用核磁共振成像检测到束控，它有可能提供一种敏感、快速、完全无痛的方法来诊断和监测MND和其他疾病的患者。该项目的目的是：利用这些有希望的早期结果，并将其发展成可用于重复研究同一肌肉区域的工具；然后用精细的技术来回答关于疾病如何发展的基本问题；并生产一种“全身”版本，可用于临床研究患者。我们将要求MND患者在两年的时间里接受多次扫描。除了拍摄MUMRI图像，我们还将进行目前常用的测试，如肌肉MRI、超声波和肌肉电测试。这将使我们能够看到在MUMRI上看到的变化首次出现的时间，这些变化是否比目前可用的测试更早出现在疾病中，以及随着疾病的进展，这些变化是如何发展的。MUMRI的一大优点是它能检测到单个运动神经纤维的活动。这在人类身上是不可能的，它让我们可以回答一些关于MND是如何发展的基本问题。例如，我们不知道开始表现出束状的运动单元是否即将死亡，或者实际上这些是健康的单元在尽最大努力补偿周围发生的损害。我们也不知道这种疾病是开始于整个肌肉，还是开始于几个运动单元，然后才扩散。由于我们可以用MUMRI反复成像相同的运动单元，我们可以开始回答这些问题，进而更多地了解这种疾病本身。最后，我们将开发在腿部以外的肌肉中使用MUMRI的新方法。这一点很重要，因为MND可以影响身体的任何部位，这是将MUMRI用于临床的重要一步。这也将使我们能够研究在MND中肌束是如何在全身扩散的，这是对早期了解该疾病起源的工作的补充。我们的团队包括研究物理学家、神经生理学家、放射科医生和神经科医生。这使我们能够汇集广泛的技术来研究MND。它还帮助我们与广泛的利益相关者接触，从参与基础科学的人到新的成像技术，应用这些技术来诊断和治疗患者的临床医生，以及患者自己。这给了我们最好的机会将这项有前途的新技术转化为临床，同时确保我们的结果是相关的和可接受的。

More than 2,000 people a year die of motor neuron disease (MND). In this relentlessly progressive condition, the motor nerve fibres that control the muscles die off, resulting in weakness and eventually paralysis. Early diagnosis allows patients to receive life-prolonging treatment, but current clinical tests are only sensitive to the later stages of the disease by which time it may be too late for these to work.We have recently developed an entirely new way to detect early changes in the muscles of patients with MND. This uses a type of MRI scanning that can detect characteristic twitches in tiny regions of the muscles (called fasciculation) that occur before the nerve fibres have died. These regions are called motor units. We were able to show that our new technique, which we call Motor Unit MRI (MUMRI), detected hundreds of fasciculations in the leg muscles of patients with MND but not in healthy subjects. This is very exciting as it is the first time that fasciculation has been detected using MRI, and it potentially offers a sensitive, quick, and entirely pain-free way to diagnose and monitor patients with MND and other diseases.The aims of this project are: to take these promising early results and develop them into a tool that can be used to study the same muscle region repeatedly; to then use the refined technique to answer fundamental questions about how the disease develops; and to produce a 'whole-body' version that can be used to study patients in the clinic.We will ask patients with MND to undergo several scans over a two-year period. As well as taking the MUMRI images, we will also perform currently used tests such as muscle MRI, ultrasound, and electrical muscle tests. This will allow us to see when the changes seen on MUMRI first appear, whether these occur earlier in the disease than currently available tests, and how the changes develop as the disease progresses.A great strength of MUMRI is that it detects activity at the level of individual motor nerve fibres. This has never before been possible in humans, and it allows us to answer some fundamental questions about how MND develops. For example, we do not know if motor units that start to show fasciculation are about to die, or whether in fact these are the healthy ones doing their best to compensate for the damage occuring around them. We also do not know if the disease starts throughout the muscle, or start in just a few motor units before spreading. Since we can repeatedly image the same motor units with MUMRI we can begin to answer these questions, and in turn learn more about the disease itself.Finally, we will develop new ways to use MUMRI in muscles other than the legs. This is important since MND can affect anywhere in the body, and this is an essential step to MUMRI being used in the clinical setting. It will also allow us to study how fasciculation spreads throughout the body in MND, complimenting the earlier work on understanding how the disease originates.Our team includes research physicists, neurophysiologists, radiologists and neurologists. This gives us the ability to bring together a broad range of techniques to study MND. It also helps us to engage with a wide range of stakeholders from people involved in basic science into new imaging techniques, clinicians who apply these to diagnose and treat patients, and patients themselves. This gives us the best opportunity to translate this promising new technique into the clinic, whilst ensuring that our results are relevant and acceptable.