Toward a Validated in Vivo Imaging Marker of Axonal Damage Predictive of Progressive Disability in Multiple Sclerosis

建立可预测多发性硬化症进行性残疾的轴突损伤体内成像标记物

• 批准号: 10598014
• 负责人: Susie Yi Huang
• 金额: $ 57.35万
• 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/10598014
• 关键词: Acute; Agreement; Appearance; Autopsy; Axon; Biological Markers; Brain; Calibration; Chronic; Clinic; Clinical; Cognition; Collaborations; Corpus Callosum; Corticospinal Tracts; Data; Dedications; Demyelinations; Development; Diameter; Diffusion Magnetic Resonance Imaging; Disease Progression; Dropout; Educational process of instructing; 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; brain tissue; chronic demyelination; clinical development; clinical imaging; clinically relevant; comparison control; connectome; density; disability; effective therapy; follow-up; human imaging; imaging biomarker; imaging study; improved; in vivo; in vivo imaging; insight; instrument; multiple sclerosis patient; neuropathology; neuroprotection; non-invasive imaging; pathogen; physically handicapped; remyelination; response; serial imaging; spatiotemporal; targeted treatment; tool; treatment response; usability; 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中，被认为是进行性的病理底物 残疾。与急性和慢性脱髓鞘有关的轴突损失的时空动力学不好 患者，病变类型和正常表现的白质的表征和可能有所不同 （nawm）。随着有前途的靶向再生疗法的出现，具有无创成像标记 需要对轴突病理学的更特异性来提高我们对MS疾病进展的理解。 MS组织的组织病理学分析已证实病变内轴突密度显着降低 NAWM伴随着轴突结构的一系列形态变化，包括出现 卵形，肿胀，变薄和横切。我们已经证明了轴突肿胀和 使用高梯度扩散MRI的MS患者call体的损失，利用300 mt/m梯度 轴突结构体内微观评估的连接组扫描仪的强度。 我们的目标是通过纵向研究来验证这些横截面成像发现和 与组织病理学的系统比较，以更好地了解空间和时间 MS中轴突变性的演变以及影响疾病进展的致病因素。我们 假设慢性脱髓鞘会导致轴突肿胀和最终的辍学，可以检测到 通过高梯度扩散MRI和轴突的程度增加了轴突尺寸和密度降低 整个大脑的形态变化反映了渐进的轴突功能障碍，并且表现为渐进式 临床残疾。我们将进行一项纵向成像研究，以确定 在整个大脑中，MS病变和NAWM中的脱髓鞘和进行性轴突结构病理。 我们将评估脱髓鞘和轴突损伤对渐进发展的相对影响 MS的身体残疾和认知功能障碍。与克利夫兰诊所的调查员合作，我们 将校准和完善MS病变中轴突直径和密度的扩散MRI测量 轴突直径和密度测量来自事后MS脑组织的组织病理学。 死后样品中轴突损失的患病率，以及没有可靠的生物标志物的轴突 活着的患者的损失，加强了对轴突变性的经过验证的成像相关的需求 允许我们实时跟踪轴突结构的变化，而不是在尸检标本的末端阶段。 MS患者中映射轴突直径分布的高梯度DMRI技术将使我们能够证实 在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的 了解轴突损伤在MS病原体中的作用，并促进临床的发展 可用的轴突结构病理学的体内成像标记，以帮助患者选择和评估 MS神经保护疗法试验中的治疗反应。