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

项目摘要和总结 多发性硬化症(MS)是一种毁灭性的不可治愈的神经系统疾病 以反复发作的急性免疫介导性炎症为特征，以及潜伏的 中枢神经系统的神经变性。核磁共振是诊断疾病最重要的工具 评估MS，允许将标志性病理可视化为T2-高信号 炎症性病变。在急性期之后，大多数MS病变很快就会变得静止； 然而，在大约40%的患者中，一些人仍然长期活跃。这些“阴燃”的损伤 可以通过他们的顺磁边缘在敏感性敏感的MRI上识别出来，这已经被 组织病理学显示由富含铁的促炎小胶质细胞和 巨噬细胞；这些被激活的神经胶质细胞被假设为加速并使 炎症过程最终导致神经退化。然而，最终的 这些“顺磁边缘病变”(PRL)残留物的鉴定和临床后果 未知。此外，使用当代疾病治疗这些PRL的可能性- 改良疗法(DMT)是一个重要的临床问题。 这个项目的目的是首先确定这些病变在临床上的存在。 3T磁共振使用敏感性T2-STAR相序列，纵向回溯 多发性硬化症患者队列。将检查PRL的存在是否与其他 已知的神经退行性变的标志包括缓慢的病变扩张，新的 皮质损害，以及全脑萎缩率。DMT的效果也将通过以下方式进行评估 检查与催乳素相关的个体治疗史的细节。接下来，在未来 纵向队列我们的目标是使用一种先进的磁共振成像技术，称为定量敏感性 确定定量催乳素铁浓度作为炎症相关性的作图 并观察不同DMT治疗的MS患者铁的客观变化率。 候选人计划将他的职业生涯献给神经退行性疾病的研究和 它与神经炎症有关。职业目标包括创建、验证和翻译 使用新序列的核磁共振生物标记物。作为该项目的一部分，应聘者将在 磁化率多模式结构磁共振成像的发展和应用 学习处理复杂问题所需的高级统计建模工具--通常 不完整的纵向临床数据集。总体而言，该项目涉及一种新颖的翻译 探索阴燃炎症与病理生理联系的假说的方法 神经退行性变的表现，我们认为是临床医生在照顾我们的MS患者。

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.