Quantitation of myelin damage in optic nerve, brainstem, cervical spinal cord, and corpus-callosum in MS

摘要 神经成像的一个基本目标是辨别、区分和量化：脱髓鞘， 中枢神经系统(CNS)疾病中的重新髓鞘形成、轴突损伤和轴突丢失。例如, 多发性硬化症(MS)中经常影响中枢神经系统白质(WM)的多灶性病变，既表现为 脱髓鞘和轴突丢失。脱髓鞘和轴突丢失导致残疾，影响身体和 心理健康。因此，量化中枢神经系统中的脱髓鞘、轴突损伤和重新髓鞘形成将是一个主要的研究方向。 向前迈进一步，以便及早发现和监测疾病活动，并对潜在的临床研究具有重要意义 神经保护和髓鞘再生疗法。尽管核磁共振技术取得了重大进步，但这些目标 没有完全实现。 在新兴的研究颈脊髓(CSC)WMS的先进MRI方法中，DTI已被 研究最广泛的。传统的DTI指标受水肿的影响程度大于 脱髓鞘。这是因为在常规的低b扩散方法中，信号的变化是由水主导的。 细胞外空间的运动。根据我们在CSC DTI方面的丰富经验，我们推测 需要改进方法，改进量化和重现性。因此，我们有 开发了一种名为超高b扩散加权磁共振(UHB-DWI)的新DTI方法，有望 区分中枢神经系统脱髓鞘、炎症和轴突损伤。UHB-DWI利用已知光纤 方向，这使得数据采集和信号处理与 传统的DTI。 随着UHB-DWI在CSC白质髓鞘定量方面的成熟，我们计划扩大UHB-DWI- DWI检测中枢其他白质束脱髓鞘、重新髓鞘形成和轴突损伤，包括 前视神经、脑干、颈髓和胼胝体。因此，这项研究的目标是 目的是：(A)将UHB-DWI测量的生物标记物与动物脱髓鞘和轴突丢失相关联 建立脊髓损伤模型，(B)建立8个年龄/性别组健康人体中枢神经系统数据参考库， 以及(C)获得临床孤立综合征和视神经疾病患者有限队列的探索性数据 神经炎为人类应用建立概念证明。 在成功完成当前工作后，我们将拥有一种强大的、非侵入性的成像方法来 确定患者中枢神经系统轴突密度和脱髓鞘的特征。这可能导致更早和更敏感的 检测临床上重要的脊髓损伤或监测脊髓在 治疗MS和其他主要中枢神经系统疾病，包括视神经脊髓炎，视神经炎， 创伤性脑损伤、阿尔茨海默病和退行性颈椎病。

ABSTRACT A fundamental goal of neuroimaging is to discern, differentiate and quantitate: demyelination, remyelination, axonal injury and axonal loss in the central nervous system (CNS) disorders. For instance, multifocal lesions in Multiple Sclerosis (MS) that frequently effect CNS white-matter (WM), exhibit both demyelination and axonal loss. Demyelination and axonal loss result in disability impacting physical and mental health. Thus, quantification of demyelination, axonal injury and remyelination in the CNS will be a major step forward for early detection, monitoring of disease activity and importantly for clinical studies of potential neuroprotective and remyelinating therapies. Despite significant advances in MRI technology, these goals have not been fully achieved. Among the emerging advanced MRI methods for studying cervical spinal cord (CSC) WMs, DTI has been the most extensively studied. The conventional DTI metrics are affected to a greater degree by edema than by demyelination. This is because the signal change in routine low-b diffusion methods is dominated by water movement in extra-cellular space. From our extensive experience with DTI of CSC, we surmised that a modified approach with improved quantitation and reproducibility would be required. Therefore, we have developed a novel DTI method called ultrahigh-b Diffusion-Weighted MRI (UHb-DWI) that promises to distinguish demyelination, inflammation, and axonal injury in CNS. UHb-DWI takes advantage of known fiber direction, which makes data acquisition and signal processing significantly simple compared with the conventional DTI. As the UHb-DWI is matured to quantification of myelination in CSC white-matters, we plan to expand UHb- DWI to detect demyelination, remyelination, and axonal injury in other white-matter tracts in CNS, including anterior optic nerves, brainstem, cervical spinal cord, and corpus callosum. Therefore, the goals of this study are to: (a) correlate biomarkers measured with UHb-DWI with demyelination and axonal loss in an animal model of cord injury, (b) establish a reference library of healthy human CNS data in eight age/gender groups, and (c) acquire exploratory data on limited cohorts of patients with clinically isolated syndrome and optic neuritis to establish proof of concept for human applications. Upon successful completion of current work, we will have a powerful, non-invasive imaging method to characterize axonal density and demyelination in patients’ CNS. This may lead to earlier and more sensitive detection of clinically important spinal cord lesions or the ability to monitor the evolution of the cord during the treatment of patients with MS and other major CNS diseases including Neuromyelitis Optica, Optic Neuritis, Traumatic Brain Injury, Alzheimer’s Disease, and degenerative cervical myelopathy.