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）是一种毁灭性的和不可治愈的神经系统疾病 其特征是反复发作的急性免疫介导的炎症以及潜伏的 中枢神经系统的神经变性。磁共振成像是最重要的诊断工具 并评估MS，允许将标志性病理可视化为T2高信号 炎性病变在急性期之后，大多数MS病变迅速变得静止; 然而，在大约40%的患者中，一些患者仍然长期活跃。这些“阴燃”损伤 可以通过它们的顺磁边缘在磁敏MRI上识别， 在组织病理学上显示由富含铁的促炎性小胶质细胞组成， 巨噬细胞;这些活化的神经胶质细胞被假设为加速和延续 炎症过程最终导致神经变性。然而，最终 这些“顺磁边缘病变”（PRL）的识别和临床后果仍然是 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。 该项目旨在首先确定这些病变的存在， 在回顾性纵向研究中，使用磁敏T2-星星相位序列的3 T MRI MS患者的队列。PRL的存在将被检查与其他 已知的神经退行性变的标志物，包括缓慢的病变扩展，新的 皮质病变和全脑萎缩率。DMT的影响也将通过以下方式进行评估： 检查与PRL相关的个体治疗史的细节。接下来，在一个前瞻性 纵向队列，我们的目标是使用一种先进的MRI技术，称为定量磁化率 映射以确定定量PRL铁浓度作为炎症相关性， 严重程度，并观察不同DMT的MS患者的铁变化的客观率。 这位候选人计划将自己的职业生涯投入到神经退行性疾病的研究中， 与神经炎症的联系职业目标包括创建、验证和翻译 使用新序列的MRI生物标志物。作为该项目的一部分，候选人将接受以下培训： 开发和使用可行性协议多模态结构MRI，以及 学习必要的高级统计建模工具，以处理复杂的，经常 不完全纵向临床数据集。总的来说，这个项目涉及一个新的翻译 探索阴燃性炎症与病理生理学联系的假说的方法 神经退行性变的临床表现，我们看到临床医生照顾我们的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.