Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

• 批准号: 9157557
• 负责人: Daniel Reich
• 金额: $ 215.53万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9157557
• 关键词: 3-Dimensional; 3D Print; Acute; Address; Algorithms; Animal Model; Animals; Area; Astrocytes; Autopsy; Blood - brain barrier anatomy; Boxing; Brain; CNS degeneration; Callithrix; Central Vein; Cerebral cortex; Chronic; Clinical; Clinical Trials; Collaborations; Correlation Studies; Data; Demyelinations; Development; Diagnosis; Diagnostic; Disease; Educational workshop; Environment; Event; Evolution; Experimental Autoimmune Encephalomyelitis; Extramural Activities; First Degree Relative; Formalin; Gadolinium; Genes; Goals; Heavy Metals; Hospitals; Hour; Human; Image; Individual; Inflammation; Inflammatory; Inherited; International; Investigation; Lead; Leptomeninges; Lesion; Location; Longitudinal Studies; Lymphocyte; MRI Scans; Magnetic Resonance Imaging; Methodology; Methods; Microglia; Modeling; Monkeys; Mononuclear; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; National Institute of Neurological Disorders and Stroke; Natural History; Neuraxis; New Agents; Onset of illness; Participant; Patients; Pattern; Permeability; Pharmaceutical Preparations; Phase; Primates; Process; Publishing; Relative (related person); Research; Resolution; Risk; Scanning; Selection for Treatments; Serum; Staging; Statistical Models; System; Systems Analysis; Techniques; Testing; Tissues; United States National Institutes of Health; Universities; Vascular Permeabilities; Veins; Woman; Work; axon injury; base; brain tissue; design; efficacy testing; gadolinium oxide; improved; in vivo; neocortical; neuroprotection; outcome forecast; prevent; radiofrequency; remyelination; repaired; research study; response; spatiotemporal; tissue repair; trial design; white matter

FY2015 has seen significant progress toward accomplishing all of the Specific Aims; some of this progress is detailed here. For Aim 1, the first project focuses on the early development of MS lesions. Previously, we studied two critical aspects of lesion development: the small veins around which white matter lesions form, and the spatiotemporal dynamics of vascular permeability as manifested in gadolinium-enhanced MRI. To understand whether the presence of a central vein may help distinguish MS lesions from their mimickers an idea that remains controversial and to which we only partially subscribe we developed a rapid imaging approach for clinical 3T MRI called FLAIR*. Studies to assess the utility of FLAIR* for diagnosis and characterization of MS lesions are currently underway in our lab and in several other labs worldwide. Preliminary results indicate that the FLAIR* technique is able to significantly improve diagnostic confidence in a variety of settings, and an international workshop is being convened in November 2015 to address this question. With respect to vascular permeability, we have established that there are two spatiotemporal patterns in MS lesions: a centrifugal pattern, in which serum contents leak from the center of the lesion and then proceed outward, over the course of minutes to hours, to fill the entire lesion; and a centripetal pattern, in which serum contents first appear on the periphery of the lesion and then proceed inward. These findings have important implications for understanding lesion development and its association with blood-brain-barrier permeability. In further work, we described how these permeability patterns help to determine the fashion in which acute MS lesions evolve into their chronic counterparts. Specifically, we have found that very early events, perhaps occurring within the first month after lesion formation, appear to determine the efficacy of tissue repair, possibly including remyelination. This finding paves the way for development of a specific clinical trial paradigm for testing new or repurposed agents that might facilitate this aspect of the repair process. Additionally under Aim 1, we have completed and published work on the evolution of inflammatory demyelinating lesions in the brains of marmoset monkeys with experimental autoimmune encephalomyelitis (EAE). We previously demonstrated that the blood-brain barrier becomes locally permeable up to four weeks prior to the onset of demyelination, and we showed that this permeability is associated with a perivascular lymphocytic and mononuclear infiltrate with parenchymal activation of microglia and astrocytes. Ongoing experiments are designed to dissect the cellular and radiological correlates of neuroprotection and lesion repair in marmoset EAE in a fashion that will have direct implications for our human studies. Finally, we completed recruitment of asymptomatic first-degree relatives of MS patients as part of the first stage of the nationwide Genes and Environment in Multiple Sclerosis (GEMS) study, a collaboration with colleagues at the Brigham & Womens Hospital of Harvard University (NCT01353547 and NCT01617395). At NIH, we characterized individuals possibly at relatively high and low risk for development of clinical MS. Preliminary results, which we hope to present publicly within the next year, show subtly but potentially meaningful differences between these two groups. For Aim 2, work in the past year has continued to focus on development of methodology for radiological-pathological correlation studies, particularly in the marmoset EAE model. We implemented high-resolution imaging of formalin-fixed brains using a variety of MRI approaches and developed a system to use those images to guide the histopathological analysis. This is accomplished by generating 3D-printed brain-cutting boxes that allow precise sectioning of the brain, such that small lesions observed on MRI (either in vivo or postmortem) can be localized and studied. We have demonstrated the value of this system for analyzing areas of neocortical demyelination and leptomeningeal inflammation. We have further shown its ability to analyze tiny abnormal disease foci in the marmoset model, which we are in the process of characterizing relative to their cellular components and for the presence or absence of heavy metals. Additional work has focused on development of a clinical trial paradigm for early-phase efficacy testing of new drugs to protect and repair brain tissue undergoing inflammatory demyelination. In this work, we have shown that the results of conventionally but carefully acquired MRI scans, analyzed using sophisticated statistical models, can be used to infer whether such a drug failed to achieve its desired effect. This is important because there is no current method to test such drugs in trials containing fewer than dozens or hundreds of individuals that last a year or more. Our approach holds the promise of greater efficiency and sensitivity, as it can be accomplished in 6 months or less with 20 study participants or potentially even fewer. In FY15, we began initial testing of one new agent, developed by our extramural collaborators, and we plan to start efficacy testing using our new trial design in the upcoming year.

2015财年在实现所有特定目标方面取得了重大进展。这里有一些进度在这里详细介绍。 对于AIM 1，第一个项目着重于MS病变的早期发展。以前，我们研究了病变发育的两个关键方面：围绕白质病变形成的小静脉，以及在Gadolinium增强的MRI中表现出的血管通透性的时空动力学。为了了解中央静脉的存在是否可以帮助将MS病变与模仿者区分开来，该想法仍然存在争议，我们仅部分订阅了我们为临床3T MRI开发了一种称为FLAIR*的快速成像方法。目前在我们的实验室和全球其他一些实验室中正在进行评估Flair*用于诊断和表征MS病变的诊断和表征的研究。初步结果表明，Flair*技术能够显着提高对各种环境的诊断信心，并在2015年11月召开了国际研讨会来解决这个问题。 关于血管渗透性，我们已经确定MS病变中有两种时空模式：一种离心模式，其中血清含量从病变中心泄漏，然后在几分钟到数小时内向外进行，以填补整个病变；和一个中心图模式，其中血清含量首先出现在病变的外围，然后向内进行。这些发现对理解病变发展及其与血脑屏障渗透性的关联具有重要意义。在进一步的工作中，我们描述了这些渗透性模式如何有助于确定急性MS病变将其演变成慢性对应物的方式。具体而言，我们发现，可能在病变形成后的第一个月内发生的非常早期的事件似乎决定了组织修复的疗效，可能包括包括再生。这一发现为开发特定的临床试验范式开发铺平了道路，用于测试可能促进维修过程这一方面的新型或重新使用的药物。 此外，在AIM 1下，我们完成并发表了有关具有实验性自身免疫性脑脊髓炎（EAE）的果猴猴子大脑中炎症性脱髓鞘病变演变的工作。我们先前证明，血脑屏障在脱髓鞘发作前的四个星期内在局部渗透，我们表明这种渗透性与亲实质激活小胶质细胞和星形胶质细胞的实质激活与血管周淋巴细胞和单核浸润有关。正在进行的实验旨在剖析Marmoset EAE中神经保护和病变修复的细胞和放射学相关性，这种方式将对我们的人类研究产生直接影响。 最后，我们完成了MS患者的无症状一级亲戚的招募，这是多发性硬化症（GEMS）研究的第一阶段的一部分，这是哈佛大学Brigham＆Womens医院（NCT01353547和NCT01617395）与同事的合作。在NIH，我们表征了可能处于临床MS发展风险相对较高和低风险的个体。初步结果，我们希望在明年内公开展示，这两个群体之间存在微妙但潜在的有意义的差异。 对于AIM 2，过去一年的工作一直集中在放射病理学相关研究的方法论的发展上，尤其是在Marmoset EAE模型中。我们使用各种MRI方法对福尔马林固定大脑进行了高分辨率成像，并开发了一种系统来使用这些图像来指导组织病理学分析。这是通过生成允许大脑精确切片的3D打印的脑切割盒来完成的，因此可以定位和研究在MRI上观察到的小病变（体内或后术后）。我们已经证明了该系统对于分析新皮质脱髓鞘和瘦脑炎症区域的价值。我们进一步显示了其在果果棒模型中分析微小异常疾病灶的能力，我们正在与其相对于其细胞成分的表征以及存在或不存在重金属的表征。 其他工作集中在开发临床试验范式上，用于对新药的早期疗效测试，以保护和修复经历炎症性脱髓鞘的脑组织。在这项工作中，我们已经表明，使用复杂的统计模型分析的常规但精心获得的MRI扫描结果可用于推断这种药物是否无法实现其所需效应。这很重要，因为目前没有在包含持续一年或更长时间的数十个或数百个人的试验中测试此类药物的方法。我们的方法具有提高效率和敏感性的希望，因为可以在6个月或更短的时间内完成20个研究参与者或更少的效率。在2015财年，我们开始对由壁外合作者开发的一个新代理进行初步测试，并计划在下一年使用我们的新试验设计开始有效性测试。