Toward a validated in vivo imaging marker of axonal damage predictive of progressive disability in multiple sclerosis

寻找一种经过验证的轴突损伤体内成像标记物，可预测多发性硬化症进行性残疾

• 批准号: 10374144
• 负责人: Susie Yi Huang
• 金额: $ 53.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374144
• 关键词: Acute; Agreement; Appearance; Autopsy; Axon; Biological Markers; Brain; Caliber; Chronic; Clinic; Clinical; Cognition; Collaborations; Corpus Callosum; Corticospinal Tracts; Data; Demyelinations; Development; Diffusion Magnetic Resonance Imaging; Disease Progression; Dropout; Electron Microscopy; Evaluation; Evolution; Functional disorder; Goals; Histopathology; Image; Impaired cognition; Inflammatory; Investigation; Lesion; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Microscopic; Morphology; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Outcome; Pathologic; Pathology; Patient Selection; Patients; Persons; Prevalence; Publishing; Research Personnel; Research Support; Role; Sampling; Specificity; Specimen; Structure; Swelling; Techniques; Thinness; Time; Tissues; Treatment Efficacy; Virulence Factors; Work; axon injury; axonal degeneration; base; brain tissue; chronic demyelination; clinical development; clinical imaging; clinically relevant; connectome; density; disability; effective therapy; follow-up; human imaging; imaging biomarker; imaging study; improved; in vivo; in vivo imaging; insight; instrument; multiple sclerosis patient; non-invasive imaging; physically handicapped; remyelination; response; serial imaging; spatiotemporal; targeted treatment; tool; treatment response; water diffusion; white matter

SUMMARY Axonal damage occurs early in multiple sclerosis and is considered the pathologic substrate of progressive disability. The spatiotemporal dynamics of axonal loss in relation to acute and chronic demyelination are not well characterized and likely vary between patients, lesion types, and within the normal-appearing white matter (NAWM). With the emergence of promising therapies targeting remyelination, noninvasive imaging markers with greater specificity to axonal pathology are needed to improve our understanding of disease progression in MS. Histopathological analyses of MS tissue have confirmed significant reductions in axon density within lesions and NAWM accompanied by a range of morphological alterations in axonal structure, including the appearance of ovoids, swelling, thinning, and transection. We have demonstrated the imaging correlates of axonal swelling and loss in the corpus callosum of MS patients using high-gradient diffusion MRI, leveraging the 300 mT/m gradient strengths on the Connectome scanner for the in vivo microscopic assessment of axonal structure. Our goal is to validate these cross-sectional imaging findings through longitudinal investigation and systematic comparison against histopathology to gain a better understanding of the spatial and temporal evolution of axonal degeneration in MS and the pathogenic factors influencing disease progression. We hypothesize that chronic demyelination leads to axonal swelling and eventual dropout that can be detected as increased axonal size and decreased density by high-gradient diffusion MRI, and that the degree of axonal morphologic change throughout the brain reflects progressive axonal dysfunction and manifests as progressive clinical disability. We will pursue a longitudinal imaging study to determine the relationship between demyelination and progressive axonal structural pathology in MS lesions and NAWM throughout the whole brain. We will evaluate the relative influence of demyelination and axonal damage on the development of progressive physical disability and cognitive dysfunction in MS. In collaboration with investigators at the Cleveland Clinic, we will calibrate and refine diffusion MRI measures of axon diameter and density in MS lesions and NAWM against axon diameter and density measurements from histopathology in postmortem MS brain tissue. The prevalence of axonal loss in postmortem samples, and the absence of a reliable biomarker for axonal loss in living patients, reinforces the need for a validated imaging correlate of axonal degeneration that would allow us to track changes in axonal structure in real time rather than at their end stage on autopsy specimens. High-gradient dMRI techniques that map axon diameter distributions in MS patients will enable us to corroborate the changes in axon diameter observed on pathology. The data generated from this study will advance our understanding of the role of axonal damage in the pathogensis of MS and facilitate the development of clinically usable in vivo imaging markers of axonal structural pathology to aid in patient selection and assessment of treatment response in trials of neuroprotective therapies in MS.

概括 轴突损伤发生在多发性硬化症的早期，被认为是进行性硬化症的病理基础 残疾。与急性和慢性脱髓鞘相关的轴突损失的时空动态尚不清楚 其特征可能因患者、病变类型以及正常白质内的不同而不同 （NAWM）。随着针对髓鞘再生的有前途的疗法的出现，无创成像标记物 为了提高我们对多发性硬化症疾病进展的理解，需要对轴突病理学有更大的特异性。 MS 组织的组织病理学分析证实病变内轴突密度显着降低， NAWM 伴随着一系列轴突结构的形态改变，包括出现 卵圆形、肿胀、变薄和横断。我们已经证明了轴突肿胀的成像相关性 使用高梯度扩散 MRI（利用 300 mT/m 梯度）测量多发性硬化症患者胼胝体的损失 Connectome 扫描仪用于轴突结构体内微观评估的优势。 我们的目标是通过纵向调查和验证这些横截面成像结果 与组织病理学进行系统比较，以更好地了解空间和时间 MS 轴突变性的演变以及影响疾病进展的致病因素。我们 假设慢性脱髓鞘导致轴突肿胀并最终脱落，可检测为 通过高梯度扩散 MRI 发现轴突尺寸增加，密度降低，并且轴突的程度 整个大脑的形态变化反映了进行性轴突功能障碍，并表现为进行性 临床残疾。我们将进行纵向成像研究以确定之间的关系 整个大脑的 MS 病变和 NAWM 中的脱髓鞘和进行性轴突结构病理学。 我们将评估脱髓鞘和轴突损伤对进行性进展的相对影响 MS 中的身体残疾和认知功能障碍。我们与克利夫兰诊所的研究人员合作， 将校准和完善 MS 病变和 NAWM 中轴突直径和密度的扩散 MRI 测量 通过死后 MS 脑组织的组织病理学测量轴突直径和密度。 死后样本中轴突丢失的普遍性，以及缺乏可靠的轴突生物标志物 活体患者的损失，强化了对轴突变性的经过验证的成像相关性的需求 使我们能够实时跟踪轴突结构的变化，而不是在尸检标本的最终阶段。 绘制多发性硬化症患者轴突直径分布图的高梯度 dMRI 技术将使我们能够证实 病理学上观察到的轴突直径的变化。这项研究产生的数据将推动我们 了解轴突损伤在 MS 发病机制中的作用并促进临床治疗的发展 可用的轴突结构病理学体内成像标记物，以帮助患者选择和评估 多发性硬化症神经保护疗法试验中的治疗反应。