The Dynamics And Clinical Relevance Of Grey Matter And Periventricular White Matter Pathology In Multiple Sclerosis

在英国大约有13万人患有多发性硬化症（MS），除了头部受伤，它是年轻人神经系统残疾的最常见原因，但我们还不知道其原因。MS最明显和研究最多的特征是在白色物质（WM，包含神经纤维的大脑部分）中存在病变。WM病变可见于神经纤维周围的覆盖物（髓鞘）受损或丢失。它们是MS在脑部扫描上看到的第一个特征，现在在诊断MS时，使用磁共振成像（MRI）脑部扫描寻找WM病变已成为常规。（称为复发）的神经症状，大多数人与MS最初，我们现在在英国有超过10种治疗方法，可以大大降低WM损伤形成和复发的风险。然而，大多数MS患者最终会发展为进行性残疾而不会复发，WM病变的积累与此仅适度相关。在英国，我们只有两种治疗方法被批准用于进行性MS，即使是这些治疗方法也只能在有WM病变活动或复发的MRI证据时使用。现在人们认为神经细胞的丧失最终是残疾的一个更重要的原因，但我们不知道神经细胞丧失的主要原因。（全球机制;大脑中包含神经细胞的部分）与MS密切相关。随着MRI的进步，测量大脑的收缩成为可能，这主要是由于GM的损失（其本身是由于神经细胞损伤和损失），并且发现这与MS残疾进展比WM损伤形成更密切相关。然而，GM损伤的其他方面，例如GM病变（通常比WM病变更广泛）仍然难以检测。认识到这一点，我们在2010年开始了一项研究，开发新的MRI方法来寻找MS中的GM疾病。我们招募了200多人，包括复发缓解型和进行性MS患者，以及没有已知神经系统疾病的患者。我们开发了更好地观察GM病变的方法，并检测病变以外的GM异常。我们还表明，MS疾病的影响是更大的对大脑的表面在GM和WM。重要的是，我们发现这些异常与WM病变没有密切联系，并且与残疾独立相关。因此，它们可能是治疗的重要靶点。然而，当时的资源有限，我们只能在18个月内对三分之一的人进行评估，因此无法有力地寻找随着时间的推移而发生的变化，也无法确定这些变化是否与脑萎缩和残疾密切相关。十年的过去将使GM异常的变化变得清晰，其临床意义也将更容易评估。因此，我们现在建议对参与我们最初研究的人进行随访。我们将使用最新的MRI方法来寻找GM和WM异常，并特别考虑WM和GM疾病过程最终如何导致脑萎缩。我们希望这项工作能够为导致脑萎缩（以及神经细胞损失）的途径提供有价值的见解，这应该使我们能够测量MS对这些途径的治疗效果，而不是等待不可逆的脑萎缩发生。由于我们将使用与医疗保健中广泛使用的MRI扫描仪类似的MRI扫描仪，我们还希望这项工作能够快速应用于临床试验（我们在早期研究中开发的一些方法已经在使用）并可能用于临床实践。

About 130000 people in the UK have multiple sclerosis (MS) and, other than head injuries, it is the commonest cause of neurological disability in young adults, but we do not yet know its cause. The most obvious and most studied feature of MS is the presence of lesions in white matter (WM, the part of the brain that contains nerve fibres). WM lesions are seen where the covering (myelin) surrounding nerve fibres has been damaged or lost. They were the first feature of MS seen on brain scans, and it is now routine to look for WM lesions using magnetic resonance imaging (MRI) brain scans when making a diagnosis of MS. Their formation causes the episodes (termed relapses) of neurological symptoms that the majority of people with MS have initially, and we now have more than ten treatments available in the UK that can substantially reduce the risk of WM lesion formation and relapses. However, most people with MS eventually develop progressive disability without relapses, and the accumulation of WM lesions is only modestly related to this. We only have two treatments approved in the UK for progressive MS, and even these can only be given when there is MRI evidence for WM lesion activity or relapses. It is now thought that the loss of nerves cells is ultimately a more important cause of disability, but we do not know the main cause of nerve cell loss.About two decades ago it become clear that grey matter (GM; the part of the brain that contains nerve cells) is significantly involved in MS. With advances in MRI, it became possible to measure shrinkage of the brain, mainly due to loss of GM (which is itself due to nerve cell damage and loss), and it was found that this is more closely related to MS disability progression than WM lesion formation. However, other aspects of GM damage, for example GM lesions (which are usually more extensive than WM lesions) remained difficult to detect. Recognising this, in 2010 we began a study to develop new MRI methods to look for GM disease in MS. We recruited over 200 people, including people with relapsing-remitting and progressive forms of MS, and people with no known neurological disease. We developed methods to better see GM lesions, and also to detect GM abnormalities beyond lesions. We also showed that MS disease effects were greater towards the surface of the brain both in GM and WM. Importantly, we found that these abnormalities were not closely linked with WM lesions and were independently associated with disability. As such, they could represent important targets for treatments. However, with the resources available at the time, we were only able to assess about a third of people over about 18 months, and so could not robustly look for changes over time or determine if they were - in the longer-term - closely linked with brain atrophy and disability.The passage of a decade will have allowed changes in GM abnormalities to become clear, and their clinical significance to be more readily assessed, and so we now propose to follow up the people who took part in our original study. We will use updated MRI methods to look for GM and WM abnormalities, and specifically consider how WM and GM disease processes eventually lead to brain atrophy. We expect this work to provide valuable insights into the pathways leading to brain atrophy (and so nerve cell loss), and this should enable us to measure MS treatment effects on these pathways, rather than waiting for irreversible brain atrophy to occur. As we will use an MRI scanner similar to those already widely used in healthcare, we also expect this work to be quickly applicable in clinical trials (some of the methods we developed in our earlier study are already being used) and potentially in clinical practice.