Axon and myelin damage assessed using advanced diffusion imaging: from mathematical models to clinical applications

患有多发性硬化症（MS）和脊髓损伤（SCI）等神经系统疾病的人，往往从年轻时起就面临着多年的生活质量低下的斗争，这可能导致工作生涯缩短甚至中断。护理人员和支持网络需要支持这些生活日益遭受破坏的人。医疗领域目前采用了所有可用的策略来改善生活质量并实施现有的治疗策略，但仍然迫切需要能够帮助诊断和预测这些患者的工具。在这个项目中，我们建议开发一种成像方法，以阐明导致功能受损的损伤机制。随着对组织层面发生的事情的了解的提高，医生可以了解个体患者的需求，从而可以对他们的社会和工作生活做出明智的决定。特别是，如果损伤的机制更清楚，制药公司将能够开发针对这些机制的治疗方法。因此，如果有很高的成功机会，患者将能够进入临床试验。反过来，这将更快地将药物推向市场，医生将能够为正确的患者开出正确的治疗方案。这个项目着眼于开发水在组织中如何运动的数学模型。考虑到大脑和脊髓组织的结构，我们的目标是开发磁共振成像（MRI）方法，能够从轴突的角度区分受损组织和髓鞘的角度区分受损组织。然后，我们将在轴突和髓鞘损伤模型中测试新的参数，以确保我们的组织模型能够很好地描述微观水平上真正发生的事情。然后，我们将调整MRI协议，使其能够在临床扫描仪上以更快的扫描时间运行。为了实现更快的扫描时间，我们需要对核磁共振扫描仪进行编程，因为我们的组织模型需要大量的数据，但我们可以通过修改收集数据的方式来实现。我们还将优化影响我们对扩散敏感性的参数，以便我们能够只收集最有意义的数据。我们将通过数学建模和优化再做一次。我们将不得不分别调整我们对大脑和脊髓的核磁共振成像采集因为对这两个结构成像有不同的挑战。下一步将是通过在15名健康受试者中进行研究来测试我们的方法的可重复性。最后，我们将获得两个试点研究的数据：一个在MS患者中，一个在SCI患者中。在这两种情况下，还将研究健康对照。从这些试点研究中，我们希望测试从联系患者到获取数据和执行数据分析的工作流程。我们还想测试我们的新参数是否比目前可用的对组织变化敏感的方法对病理更敏感，但对髓磷脂和轴突不是特异性的。最后，我们将把新的参数与残疾和功能障碍的临床评分联系起来。这项研究的最终目的是能够为更好地理解病理和提供更准确的治疗提供新的工具，从而改善患者的生活质量。这些工具需要被核磁共振成像制造商和制药公司接受，才能真正对医疗领域有用，从而对病人、他们的护理人员和社会有用。我们已经规划了一条途径来引导我们实现这一长期目标，首先是让行业和慈善机构参与一个顾问委员会，以指导我们将生产的工具的未来传播和开发。

People affected by neurological conditions, such as multiple sclerosis (MS) and spinal cord injury (SCI), face many years of struggle with a poor quality of life, often since a young age, that can lead to a shortened or even interrupted work career. Carers and support networks need to sustain these people whose life is increasingly devastated.The medical field currently employs all the strategies available to improve quality of life and to administer treatment strategies that are available, but there is still an urgent need for tools that could assist in the diagnosis and prognosis of these patients.In this project we are proposing to develop an imaging method that will clarify the mechanism of the damage that causes impaired function. With an improved knowledge on what is happening at a tissue level, doctors can understand the needs of individual patients who can, therefore, make informed decisions about their social and work life.In particular, if the mechanisms of damage are clearer, drug companies will be able to develop treatments that are specific to these mechanisms. Therefore, patients will be able to enter clinical trials if there is a high chance of success. This, in turn, will deliver drugs to the market quicker and doctors will be able to prescribe the right treatment to the right patient.This project is looking at developing mathematical models of how the water moves in the tissue. By taking into consideration the structure of the brain and spinal cord tissue, we aim at developing MR imaging (MRI) methods able to pick up differences between tissue that is damaged from the axon point of view from tissue that is damaged from the myelin sheath point of view. We will then test the new parameters in models of axon and myelin damage to make sure that our tissue model is a good description of what is really happening at microscopic level. Then, we will adjust the MRI protocol so that it can be run on clinical scanners in much quicker scan times. For achieving quicker scan times, we will need to programme the MRI scanner because our tissue model will require a lot of data, but we can do it by modifying the way we collect the data. We will also optimise the parameters that influence our sensitivity to diffusion so that we can collect only the most meaningful data. We will do this again through mathematical modelling and optimisation. We will have to adjust our MRI acquisition for the brain and the spinal cord separately because there are different challenges with imaging these two structures.The next step will be to test how reproducible our measures are by studying them in a group of 15 healthy subjects. Finally, we will acquire data in two pilot studies: one in patients with MS and one in patients with SCI. Healthy controls will also be studied in both cases. From these pilot studies we wish to test the workflow, from contacting the patient, to acquiring the data and performing the data analysis. We also want to test whether our new parameters are more sensitive to pathology than currently available measures sensitive to tissue changes, but which are not specific to myelin and axons. Finally, we will correlate the new parameters with clinical scores of disability and functional impairment.The ultimate aim of this study is to be able to provide new tools for a better understanding of pathology and providing more accurate treatment with a consequent improvement on the patients' quality of life. These tools will need to be embraced by MRI manufacturers and drug companies to become really useful for the medical field, and therefore for patients, their carers and society. We have planned a pathway to lead us to this long-term goal, starting by involving industry and charities in an advisory board to steer the future dissemination and development of what the tools that we will produce.