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: 10453345
• 负责人: Ashley M Stokes
• 金额: $ 22.35万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453345
• 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; Evaluation; Exhibits; FDA approved; Fostering; Foundations; 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; Perfusion Weighted MRI; Persons; Play; Predisposition; Process; Radiology Specialty; Recovery; Relapsing-Remitting Multiple Sclerosis; Reporting; Resolution; Role; Scanning; Specificity; Stable Disease; Symptoms; Testing; Tissues; Vascular Diseases; Veins; axon injury; axonal degeneration; base; biomarker development; hemodynamics; hypoperfusion; imaging biomarker; imaging modality; improved; in vivo; insight; magnetic resonance imaging biomarker; multiple sclerosis patient; myelination; neuroinflammation; neuron loss; neuroprotection; predictive marker; prevent; quantitative imaging; regeneration potential; regenerative therapy; remyelination; repaired; spatiotemporal; specific biomarkers; therapeutic target; therapy development; treatment response; 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.

项目摘要/摘要： 多发性硬化症是一种慢性、使人衰弱的中枢神经系统疾病，其特征是 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。由于髓鞘再生是 促进髓鞘再生的疗法具有高度可变性并且与症状改善相关 在发生不可逆转的损坏和衰退之前提供修复的机会。鉴于髓鞘形成的重要性，磁性 髓磷脂完整性的磁共振成像 (MRI) 生物标志物已开发用于临床试验。 不幸的是，这些生物标志物反映了髓磷脂的静态水平，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 灌注在 MS 中已有报道，但灌注与髓磷脂之间的关系尚未完全阐明 体内表征。此外，灌注 MRI 生物标志物是否可以预测下游髓磷脂修复 仍然是一个悬而未决的问题。该提案旨在通过调查以下角色来克服这一挑战： 使用 MRI 生物标志物进行脱髓鞘和髓鞘再生的灌注。生物标志物检测的发展 定量探测灌注和髓磷脂含量可以预测再生潜力并评估新兴的 促进神经保护和髓鞘再生的疗法。为了测定灌注变化，采用多重对比旋转 梯度回波 (SAGE) MRI 方法能够评估不同血管的血流动力学指标 尺度（即总血管和微血管状况）。鉴于 MS 的微血管成分已知， 特异性量化微血管功能的能力可以提供更具体的潜在潜在指标 病理。髓磷脂含量可以使用选择性反转恢复 (SIR) 方法进行测定，该方法提供 髓磷脂的定量和可靠测量。本研究的目的是确定血管功能是否 提示病变脱髓鞘和髓鞘再生。更具体地说，该项目旨在 a) 建立 复发缓解型多发性硬化症 (pwMS) 患者和健康人的灌注和髓磷脂之间的关系 控制； b) 建立健康对照的规范值以及健康对照的重测重复性 和疾病稳定的 pwMS； c) 评估病变灌注是否预测脱髓鞘和髓鞘再生 在具有活动性病变的 pwMS 中。如果成功，这种方法将确立微血管变化作为 疾病的前兆和结果的预测，以及提供与以下相关的潜在治疗目标 预防微血管功能障碍及其下游影响。强大的 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，并且具有更大的 生物特异性，评估再生潜力和治疗反应，从而填补了这两种患者的关键空白 旨在评估新兴神经保护和髓鞘再生疗法的护理和临床试验。而且， 这种方法可以深入了解导致病变形成和消退的复杂因素。