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

MS 中视神经、脑干、颈脊髓和胼胝体髓磷脂损伤的定量

• 批准号: 10580879
• 负责人: EUN-KEE (E.K.) JEONG
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580879
• 关键词: Affect; Age; Alzheimer' s Disease; Animal Model; Anterior; Axon; Biological Markers; Brain Stem; Central Nervous System; Central Nervous System Diseases; Cervical; Cervical spinal cord structure; Clinical; Clinical Research; Corpus Callosum; Data; Databases; Demyelinations; Detection; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Edema; Evaluation; Evolution; Exhibits; Extracellular Space; Fiber; Gender; Goals; Head and neck structure; Histology; Human; Inflammation; Injury; Investigation; Lesion; Libraries; Lysophosphatidylcholines; Magnetic Resonance Imaging; Manuscripts; Maps; Measurement; Measures; Mental Health; Methods; Minor; Modeling; Monitor; Monte Carlo Method; Multifocal Lesion; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Nerve; Nerve Degeneration; Neuromyelitis Optica; Optic Nerve; Optic Neuritis; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Performance; Radial; Rattus; Reproducibility; Sensitivity and Specificity; Signal Transduction; Spinal Cord Diseases; Spinal Cord Lesions; Spinal cord injury; Structure; Syndrome; System; Technology; Traumatic Brain Injury; Variant; Water; Water Movements; Work; age group; axon injury; cohort; data acquisition; density; disability impact; experience; imaging modality; improved; multiple sclerosis patient; myelination; neuroimaging; neuroprotection; non-invasive imaging; novel; optical imaging; physical conditioning; preclinical study; preservation; remyelination; signal processing; spinal cord white matter; treatment response; water diffusion; white matter

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.

摘要 神经影像学的一个基本目标是辨别、区分和定量：脱髓鞘， 中枢神经系统（CNS）疾病中的髓鞘再生、轴突损伤和轴突损失。比如说， 多发性硬化（MS）中的多灶性病变经常影响CNS白质（WM），表现为 脱髓鞘和轴突缺失。脱髓鞘和轴突损失导致影响身体和神经功能的残疾。 心理健康因此，定量CNS中的脱髓鞘、轴突损伤和髓鞘再生将是主要的 为早期发现、监测疾病活动以及重要的是为潜在的 神经保护和髓鞘再生疗法。尽管MRI技术取得了重大进展，但这些目标 没有完全实现。 在研究颈脊髓（CSC）WM的新兴先进MRI方法中，DTI已被 最广泛的研究。传统的DTI指标受水肿的影响程度大于受 脱髓鞘这是因为常规低b扩散方法中的信号变化是由水主导的 细胞外空间的运动。根据我们对CSC DTI的丰富经验，我们推测， 将需要改进的方法，其具有改进的定量和再现性。所以我们 开发了一种称为超高b弥散加权MRI（UHb-DWI）的新型DTI方法， 区分CNS中的脱髓鞘、炎症和轴突损伤。UHb-DWI利用已知的纤维 方向，这使得数据采集和信号处理显着简单相比， 常规DTI。 由于UHb-DWI已经成熟到可以量化CSC白质中的髓鞘形成，我们计划扩大UHb-DWI。 DWI检测CNS其他白质束的脱髓鞘、髓鞘再生和轴突损伤，包括 前视神经、脑干、颈脊髓和胼胝体。因此，本研究的目的 （a）将用UHb-DWI测量的生物标志物与动物中的脱髓鞘和轴突损失相关联 脊髓损伤模型，（B）建立八个年龄/性别组的健康人CNS数据的参考库， 和（c）获得关于具有临床孤立综合征和视神经病变的有限患者队列的探索性数据， 神经炎，以建立用于人类应用的概念验证。 在成功完成目前的工作后，我们将有一个强大的，非侵入性的成像方法， 表征患者CNS中的轴突密度和脱髓鞘。这可能会导致更早和更敏感的 检测临床上重要的脊髓病变或监测脊髓演变的能力， 治疗患有MS和其他主要CNS疾病的患者，包括视神经肌病，视神经炎， 创伤性脑损伤、阿尔茨海默病和退行性颈脊髓病。