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

使用先进的扩散成像评估轴突和髓磷脂损伤：从数学模型到临床应用

• 批准号: EP/I027084/1
• 负责人: Claudia Wheeler-Kingshott
• 金额: $ 86.24万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FI027084%2F1
• 关键词: Axon; myelin; damage; assessed; using

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.

受神经系统疾病（如多发性硬化症（MS）和脊髓损伤（SCI））影响的人，通常从年轻时起就面临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。照顾者和支持网络需要维持这些生活日益受到破坏的人。医疗领域目前采用所有可用的策略来改善生活质量并实施可用的治疗策略，但是仍然迫切需要能够帮助这些患者诊断和预后的工具。在这个项目中，我们建议开发一种成像方法，导致功能受损的损伤。随着对组织水平上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，如果损伤的机制更加清晰，制药公司将能够开发针对这些机制的治疗方法。因此，如果成功的机会很大，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。该项目正在研究开发水如何在组织中移动的数学模型。通过考虑大脑和脊髓组织的结构，我们的目标是开发MR成像（MRI）方法，该方法能够从轴突的角度和从髓鞘的角度受损的组织之间拾取差异。然后，我们将在轴突和髓鞘损伤模型中测试新参数，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，以便它可以在更快的扫描时间内在临床扫描仪上运行。为了实现更快的扫描时间，我们需要对MRI扫描仪进行编程，因为我们的组织模型需要大量数据，但我们可以通过修改收集数据的方式来实现。我们还将优化影响扩散灵敏度的参数，以便我们只收集最有意义的数据。我们将通过数学建模和优化再次做到这一点。我们将不得不分别调整大脑和脊髓的MRI采集，因为对这两种结构进行成像存在不同的挑战。下一步将通过在15名健康受试者中进行研究来测试我们的测量结果的可重复性。最后，我们将在两个试点研究中获得数据：一个在MS患者中，一个在SCI患者中。还将在两种情况下研究健康对照。从这些试点研究中，我们希望测试工作流程，从联系患者到获取数据和进行数据分析。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但对髓鞘和轴突不特异的测量对病理学更敏感。最后，我们将新的参数与残疾和功能障碍的临床评分相关联，本研究的最终目的是能够提供新的工具，以更好地了解病理，并提供更准确的治疗，从而改善患者的生活质量。这些工具需要被MRI制造商和制药公司所接受，才能对医疗领域真正有用，因此对患者，他们的护理人员和社会也是如此。我们已经计划了一条通往这一长期目标的道路，首先是让行业和慈善机构参与咨询委员会，以指导我们将生产的工具的未来传播和开发。

项目成果

Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis.

• DOI: 10.3389/fneur.2018.00690
• 发表时间: 2018
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Castellazzi G;Debernard L;Melzer TR;Dalrymple-Alford JC;D'Angelo E;Miller DH;Gandini Wheeler-Kingshott CAM;Mason DF
• 通讯作者: Mason DF

Longitudinal multiple sclerosis lesion segmentation: Resource and challenge.

• DOI: 10.1016/j.neuroimage.2016.12.064
• 发表时间: 2017-03-01
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Carass A;Roy S;Jog A;Cuzzocreo JL;Magrath E;Gherman A;Button J;Nguyen J;Prados F;Sudre CH;Jorge Cardoso M;Cawley N;Ciccarelli O;Wheeler-Kingshott CAM;Ourselin S;Catanese L;Deshpande H;Maurel P;Commowick O;Barillot C;Tomas-Fernandez X;Warfield SK;Vaidya S;Chunduru A;Muthuganapathy R;Krishnamurthi G;Jesson A;Arbel T;Maier O;Handels H;Iheme LO;Unay D;Jain S;Sima DM;Smeets D;Ghafoorian M;Platel B;Birenbaum A;Greenspan H;Bazin PL;Calabresi PA;Crainiceanu CM;Ellingsen LM;Reich DS;Prince JL;Pham DL
• 通讯作者: Pham DL

Cerebellar lobules and dentate nuclei mirror cortical force-related-BOLD responses: Beyond all (linear) expectations.

• DOI: 10.1002/hbm.23541
• 发表时间: 2017-05
• 期刊: Human brain mapping
• 影响因子: 4.8
• 作者: Alahmadi AA;Pardini M;Samson RS;Friston KJ;Toosy AT;D'Angelo E;Gandini Wheeler-Kingshott CA
• 通讯作者: Gandini Wheeler-Kingshott CA

Prominent Changes in Cerebro-Cerebellar Functional Connectivity During Continuous Cognitive Processing.

• DOI: 10.3389/fncel.2018.00331
• 发表时间: 2018
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Castellazzi G;Bruno SD;Toosy AT;Casiraghi L;Palesi F;Savini G;D'Angelo E;Wheeler-Kingshott CAMG
• 通讯作者: Wheeler-Kingshott CAMG

Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

• DOI: 10.1016/j.neuroimage.2017.10.034
• 发表时间: 2018-02-01
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Alfaro-Almagro F;Jenkinson M;Bangerter NK;Andersson JLR;Griffanti L;Douaud G;Sotiropoulos SN;Jbabdi S;Hernandez-Fernandez M;Vallee E;Vidaurre D;Webster M;McCarthy P;Rorden C;Daducci A;Alexander DC;Zhang H;Dragonu I;Matthews PM;Miller KL;Smith SM
• 通讯作者: Smith SM