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.

项目摘要和摘要 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 以急性免疫介导的炎症和阴险的反复发作为特征 中枢神经系统的神经变性。 MRI是诊断最重要的工具 并评估MS，允许将标志性病理可视化为T2-Hyperintens 炎症病变。急性阶段后，大多数MS病变迅速变得静止。 但是，在大约40％的患者中，有些患者仍保持长期活跃。这些“闷烧”的病变 可以通过其顺磁性边缘在易感性敏感性MRI上识别， 在组织病理学上显示的，由富含铁的促炎性小胶质细胞和 巨噬细胞；假设这些活化的神经胶质细胞加速和永久 炎症过程最终导致神经退行性。但是，确定的 这些“顺磁性边缘病变”（PRL）的识别和临床后果仍然存在 未知。此外，使用当代疾病 - 修改疗法（DMT）是一个重要的临床问题。 该项目旨在首先确定这些病变在临床上可用的 在回顾性纵向中，使用敏感性T2-Star相序列的3T MRI MS患者队列。将检查PRL的存在与其他关联 神经退行性的已知标记物，包括缓慢的病变扩展，新出现 皮质病变和整个大脑萎缩率。 DMT的影响也将通过 检查与PRL有关的单个治疗历史的细节。接下来，在潜在的 纵向队列我们旨在使用称为定量易感性的先进MRI技术 映射以确定定量PRL铁浓度作为炎症的相关性 严重程度，并观察到不同DMT的MS患者铁变化的客观率。 候选人计划将自己的职业生涯用于神经退行性的调查和 它与神经炎症的联系。职业目标包括创建，验证和翻译 MRI生物标志物使用新序列。作为该项目的一部分，候选人将接受培训 易感性协议多模式结构MRI的开发和使用以及 学习处理复杂所必需的高级统计建模工具 - 通常 不完整的纵向临床数据集。总的来说，这个项目涉及一种新颖的翻译 探索将闷烧感染与病理生理相关的假设的方法 我们认为是照顾MS患者的临床医生的神经变性的表现。