Investigating the role of cerebral perfusion in demyelination and repair in multiple sclerosis with MRI

用 MRI 研究脑灌注在多发性硬化症脱髓鞘和修复中的作用

• 批准号: 10623344
• 负责人: Ashley M Stokes
• 金额: $ 19.85万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623344
• 关键词: Acute; Advanced Development; Biological Assay; Biological Markers; Blood Vessels; Blood Volume; Brain; Central Nervous System Diseases; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Complex; Data; Demyelinations; Development; Disease; Disease Progression; Disease remission; Evaluation; Exhibits; FDA approved; Fostering; Future; Gliosis; Goals; Healthcare; Immune; Inflammation; Inflammatory; Ischemia; Lesion; Magnetic Resonance Imaging; Measures; Metabolic dysfunction; Methods; Microvascular Dysfunction; Multiple Sclerosis; Myelin; Outcome; Pathology; Patient Care; Patients; Perfusion; Persons; Play; Predisposition; Process; Radiology Specialty; Recovery; Relapse; Relapsing-Remitting Multiple Sclerosis; Reporting; Resolution; Role; Scanning; Specificity; Stable Disease; Testing; Tissues; Vascular Diseases; Veins; axon injury; axonal degeneration; biomarker development; hemodynamics; hypoperfusion; imaging biomarker; improved; in vivo; insight; magnetic resonance imaging biomarker; multiple sclerosis patient; myelination; neuroinflammation; neuron loss; neuropathology; neuroprotection; predictive marker; prevent; quantitative imaging; regeneration potential; regenerative therapy; remyelination; repaired; spatiotemporal; specific biomarkers; symptomatic improvement; therapeutic target; therapy development; treatment response; vascular factor; white matter

PROJECT SUMMARY / ABSTRACT: Multiple sclerosis is a chronic, debilitating disease of the central nervous system characterized by neuroinflammation, focal demyelination, gliosis, axonal degeneration, and neuronal loss. As remyelination is both highly variable and associated with improvement of symptoms, therapies that foster remyelination represent an opportunity for repair prior to irreversible damage and decline. Given the importance of myelination, magnetic resonance imaging (MRI) biomarkers of myelin integrity have been developed for use in clinical trials. Unfortunately, these biomarkers reflect static levels of myelin and cannot predict demyelination or remyelination processes. Recent studies have suggested that remyelination relies on adequate tissue perfusion. While altered perfusion has been reported in MS, the relationship between perfusion and myelin has not been fully characterized in vivo. Furthermore, whether perfusion MRI biomarkers can predict downstream myelin repair remains an outstanding question. This proposal aims to overcome this challenge by investigating the role of perfusion in demyelination and remyelination using MRI biomarkers. The development of biomarker assays to quantitatively probe both perfusion and myelin content may predict regenerative potential and evaluate emerging therapies that promote neuroprotection and remyelination. To assay perfusion changes, a multi-contrast spin- and gradient-echo (SAGE) MRI method enables evaluation of hemodynamic measures at distinct vascular scales (i.e., total vascular and microvascular regimes). Given the known microvascular component of MS, the ability to specifically quantify microvascular function may provide a more specific indicator of underlying pathology. Myelin content can be assayed using a selective inversion recovery (SIR) method that provides quantitative and reliable measures of myelin. The objective of this study is to determine whether vascular function is indicative of lesion demyelination and remyelination. More specifically, this project aims to a) establish the relationship between perfusion and myelin in persons with relapsing-remitting MS (pwMS) and in healthy controls; b) establish normative values in healthy controls and test-retest repeatability in both healthy controls and pwMS with stable disease; and c) assess whether lesion perfusion predicts demyelination and remyelination in pwMS with active lesions. If successful, this approach will establish the role of microvascular changes as a precursor of disease and prognosticator of outcomes, as well as provide potential treatment targets related to preventing microvascular dysfunction and its downstream effects. The development of robust MRI biomarker assays that quantitatively probe both perfusion and myelin content could more reliably, and with greater biospecificity, assess regenerative potential and therapeutic response, thus filling a critical gap in both patient care and clinical trials designed to evaluate emerging neuroprotective and remyelinating therapies. Moreover, this approach may provide insight into the complex factors that contribute to both lesion formation and resolution.

项目总结/摘要： 多发性硬化症是一种中枢神经系统的慢性衰弱性疾病，其特征在于 神经炎症、局灶性脱髓鞘、神经胶质增生、轴突变性和神经元损失。就像髓鞘再生 两者都是高度可变的，并且与症状的改善相关，促进髓鞘再生的疗法代表了 在不可逆转的损害和衰退之前进行修复的机会。考虑到髓鞘形成的重要性， 已经开发了髓磷脂完整性的共振成像（MRI）生物标志物用于临床试验。 不幸的是，这些生物标志物反映了髓鞘的静态水平，不能预测脱髓鞘或髓鞘再生 流程.最近的研究表明，髓鞘再生依赖于足够的组织灌注。虽然改变了 尽管在MS中已经报道了灌注，但是灌注和髓鞘之间的关系还没有完全被证实。 在体内表征。此外，灌注MRI生物标志物是否可以预测下游髓鞘修复， 仍然是一个悬而未决的问题。本提案旨在通过调查以下方面的作用来克服这一挑战 使用MRI生物标志物的脱髓鞘和髓鞘再生的灌注。生物标志物测定的发展， 定量探测灌注和髓鞘含量可以预测再生潜力， 促进神经保护和髓鞘再生的疗法。为了分析灌注变化，使用多对比旋转- 和梯度回波（SAGE）MRI方法能够评价不同血管的血流动力学指标 刻度（即，总血管和微血管状态）。鉴于MS的已知微血管成分， 特异性量化微血管功能的能力可以提供更特异性的基础指标， 病理可以使用选择性反转恢复（SIR）方法测定髓鞘含量，所述方法提供 定量和可靠的测量髓鞘。本研究的目的是确定血管功能是否 表明损伤脱髓鞘和髓鞘再生。更具体地说，该项目旨在a）建立 复发-缓解型MS患者和健康人的灌注和髓鞘之间的关系 对照; B）建立健康对照的标准值和两种健康对照的重复性 以及c）评估病变灌注是否预测脱髓鞘和髓鞘再生 活动性病变的多发性硬化症。如果成功的话，这种方法将确立微血管变化作为一种 疾病的前兆和结果的预测因素，以及提供与以下方面相关的潜在治疗目标： 预防微血管功能障碍及其下游效应。稳健的MRI生物标志物的开发 定量探测灌注和髓磷脂含量的测定可以更可靠， 生物特异性，评估再生潜力和治疗反应，从而填补了两个患者的关键空白 护理和临床试验，旨在评估新兴的神经保护和髓鞘再生疗法。此外，委员会认为， 这种方法可以提供对有助于损伤形成和消退的复杂因素的深入了解。