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、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、轴突变性和神经元丢失。就像重新髓鞘形成一样 无论是高度可变的，还是与症状改善相关的，促进髓鞘再生的疗法都代表着 在不可逆转的损害和衰退之前进行修复的机会。鉴于髓鞘形成的重要性，磁性 磁共振成像(MRI)髓鞘完整性的生物标记物已被开发用于临床试验。 不幸的是，这些生物标记物反映了髓鞘的静态水平，不能预测脱髓鞘或重新髓鞘形成。 流程。最近的研究表明，髓鞘再生依赖于足够的组织灌注量。虽然被更改了 多发性硬化症的血流灌注已有报道，但其与髓鞘的关系尚不完全清楚。 具有活体特征的。此外，核磁共振生物标志物能否预测下游髓鞘修复 仍然是一个悬而未决的问题。这项提案旨在通过调查 核磁共振生物标记物在髓鞘脱髓鞘和髓鞘再分化中的灌注。生物标记物检测技术的发展 定量探头灌注和髓鞘含量可预测再生潜能和评估新生 促进神经保护和髓鞘再生的疗法。为了分析血流灌注的变化，多对比自旋- 而梯度回波(SAGE)MRI方法可以评估不同血管的血流动力学指标 规模(即总的血管和微血管治疗方案)。根据已知的多发性硬化症微血管成分， 能够专门量化微血管功能可能提供一个更具体的指标潜在的 病理学。髓鞘含量可以使用选择性反转恢复(SIR)方法进行分析，该方法提供了 髓鞘的定量和可靠的测量。本研究的目的是确定血管功能 是病变脱髓鞘和重新髓鞘形成的征兆。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)患者及健康体检者髓鞘与血流灌注的关系 对照；b)在健康对照中建立标准值，并在两个健康对照中建立重测重复性 和疾病稳定的PWMS；以及c)评估病变灌注是否预示脱髓鞘和重新髓鞘形成 在活动性病变的PWMS中。如果成功，这种方法将确立微血管变化作为一种 疾病的先兆和结果的预测者，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影响。强健磁共振生物标记物的研究进展 同时定量探测血流和髓鞘含量的分析方法更可靠，而且具有更高的 生物特异性，评估再生潜力和治疗反应，从而填补两个患者的关键空白 护理和临床试验，旨在评估新出现的神经保护和髓鞘再生疗法。此外， 这一方法可能提供对病变形成和消退的复杂因素的洞察。