MRI paramagnetic rim lesions as biomarkers and agents of neurodegeneration in multiple sclerosis

MRI 顺磁边缘病变作为多发性硬化症神经变性的生物标志物和代理

• 批准号: 10595617
• 负责人: Christopher C. Hemond
• 金额: $ 19.11万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595617
• 关键词: Acceleration; Acute; Acute Disease; Affect; Age; American; Antioxidants; Appearance; Area; Biological Markers; Brain; Caring; Cells; Central Nervous System; Chronic; Cladribine; Clinical; Clinical Data; Complex; Data; Data Set; Databases; Demyelinations; Development; Diagnosis; Disease; Enrollment; Fumarates; Goals; Histologic; Histopathology; Image; Immune; Individual; Inflammation; Inflammatory; Investigation; Iron; K-Series Research Career Programs; Learning; Lesion; Link; Longitudinal cohort; Macrophage; Magnetic Resonance Imaging; Maps; Mediating; Mentorship; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Nerve Degeneration; Neuroglia; Outcome; Pathology; Patients; Phase; Phenotype; Predisposition; Prevalence; Process; Property; Protocols documentation; Recording of previous events; Records; Recurrence; Research; Resolution; Role; Severities; Severity of illness; Signal Transduction; Spinal Cord; Statistical Data Interpretation; Statistical Models; Techniques; Time; Training; Translations; Treatment Efficacy; Validation; Visualization; alemtuzumab; career; cerebral atrophy; clinically relevant; cohort; disability; follow-up; healing; immune reconstitution; improved; in vivo; insight; magnetic field; magnetic resonance imaging biomarker; multimodality; multiple sclerosis patient; nervous system disorder; neuroinflammation; novel; oxidative damage; personalized predictions; pharmacologic; potential biomarker; predictive modeling; prevent; prospective; success; tool; translational approach

PROJECT ABSTRACT AND SUMMARY Multiple Sclerosis (MS) is a devastating and incurable neurological disease characterized by recurrent bouts of acute immune-mediated inflammation as well as insidious neurodegeneration of the central nervous system. MRI is the most important tool to diagnose and assess MS, allowing visualization of the hallmark pathology as T2-hyperintense inflammatory lesions. After an acute phase, most MS lesions quickly become quiescent; however in about 40% of patients, some remain chronically active. These “smoldering” lesions can be identified on susceptibility-sensitive MRI by their paramagnetic rim, which has been shown on histopathology to be composed of iron-enriched, pro-inflammatory microglia and macrophages; these activated glial cells are hypothesized to accelerate and perpetuate the inflammatory processes ultimately causing neurodegeneration. However, the definitive identification and clinical consequences of these “paramagnetic rim lesions” (PRL) remains unknown. Additionally, the possibility of treating these PRLs using contemporary disease- modifying therapies (DMT) is an important clinical question. This project aims to first determine the presence of these lesions on clinically-available 3T MRI using a susceptibility-sensitive T2-star phase sequence, in a retrospective longitudinal cohort of MS patients. The presence of PRLs will be examined for associations with other known markers of neurodegeneration including slow lesion expansion, the appearance of new cortical lesions, and the whole brain atrophy rate. The effects of DMT will also be assessed by examining the details of individual treatment histories in relation to PRLs. Next, in a prospective longitudinal cohort we aim to use an advanced MRI technique called quantitative susceptibility mapping to determine the quantitative PRL iron concentration as a correlate of inflammatory severity, and observe the objective rates of iron change in MS patients on different DMTs. The candidate plans to devote his career to the investigation of neurodegeneration and its links to neuroinflammation. Career goals include the creation, validation, and translation of MRI biomarkers using novel sequences. As part of this project, the candidate will be training in the development and use of susceptibility-protocol multimodal structural MRI, as well as learning advanced statistical modeling tools necessary to handle complex -and often incomplete- longitudinal clinical datasets. Overall this project involves a novel translational approach to explore hypotheses connecting smoldering inflammation to pathophysiological manifestations of neurodegeneration that we see as clinicians caring for our patients with MS.

项目摘要和总结 多发性硬化症 (MS) 是一种毁灭性且无法治愈的神经系统疾病 其特点是反复发作的急性免疫介导的炎症以及隐匿性的 MRI 是诊断中枢神经系统神经退行性疾病的最重要工具。 并评估 MS，允许将标志性病理可视化为 T2 高信号 急性期后，大多数多发性硬化症病变很快就会静止； 然而，在约 40% 的患者中，有些患者的这些“闷烧”病变仍处于长期活动状态。 可以在磁化率敏感 MRI 上通过其顺磁性边缘进行识别，该边缘已被 组织病理学显示由富铁、促炎性小胶质细胞和 巨噬细胞；这些活化的神经胶质细胞被重新捕获以加速和延续 然而，炎症过程最终会导致神经变性。 这些“顺磁边缘病变”（PRL）的识别和临床后果仍然存在 此外，使用现代疾病治疗这些 PRL 的可能性尚不清楚。 改良疗法（DMT）是一个重要的临床问题。 该项目旨在首先确定临床可用的这些病变的存在 使用磁化率敏感的 T2 星相序列进行 3T MRI 回顾性纵向研究 将检查多发性硬化症患者队列中 PRL 的存在是否与其他患者相关。 已知的神经变性标志物，包括病变缓慢扩张、新病变的出现 皮质病变和全脑萎缩率也将通过 DMT 进行评估。 接下来，前瞻性地检查与 PRL 相关的个体治疗史的细节。 纵向队列我们的目标是使用一种称为定量磁化率的先进 MRI 技术 绘图以确定定量 PRL 铁浓度作为炎症的相关性 严重程度，并观察不同 DMT 下 MS 患者铁变化的客观率。 该候选人计划将自己的职业生涯奉献给神经退行性疾病的研究和 它与神经炎症的联系包括创建、验证和翻译。 使用新序列的 MRI 生物标记作为该项目的一部分，候选人将接受以下培训： 磁敏度协议多模式结构 MRI 的开发和使用，以及 学习处理复杂且经常需要的高级统计建模工具 总体而言，该项目涉及一种新颖的转化临床数据集。 探索将闷烧炎症与病理生理学联系起来的假设的方法 我们将神经退行性变的表现视为对多发性硬化症患者的关怀。