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 财年在实现所有具体目标方面取得了重大进展；这里详细介绍了其中一些进展。 对于目标 1，第一个项目侧重于 MS 病变的早期发展。此前，我们研究了病变发展的两个关键方面：白质病变周围形成的小静脉，以及钆增强 MRI 中显示的血管通透性的时空动态。为了了解中央静脉的存在是否有助于区分多发性硬化症病变与其模仿者，这一想法仍然存在争议，我们仅部分同意这一想法，我们开发了一种称为 FLAIR* 的临床 3T MRI 快速成像方法。我们的实验室和世界各地的其他几个实验室目前正在进行评估 FLAIR* 在 MS 病变诊断和表征方面的实用性的研究。初步结果表明，FLAIR* 技术能够显着提高各种环境下的诊断信心，并且将于 2015 年 11 月召开国际研讨会来解决这个问题。 关于血管通透性，我们已经确定多发性硬化症病变存在两种时空模式：离心模式，其中血清内容物从病变中心渗漏，然后向外移动，在几分钟到几小时的过程中，填充血管整个病变；以及向心模式，其中血清内容物首先出现在病变的外围，然后向内前进。这些发现对于理解病变发展及其与血脑屏障通透性的关系具有重要意义。在进一步的工作中，我们描述了这些渗透性模式如何帮助确定急性多发性硬化症病变演变为慢性病变的方式。具体来说，我们发现非常早期的事件，可能发生在病变形成后的第一个月内，似乎决定了组织修复的功效，可能包括髓鞘再生。这一发现为开发特定的临床试验范式铺平了道路，该范式用于测试可能促进修复过程这一方面的新药物或重新调整用途的药物。 此外，在目标 1 下，我们还完成并发表了关于患有实验性自身免疫性脑脊髓炎 (EAE) 的狨猴大脑中炎症性脱髓鞘病变演变的研究。我们之前证明，在脱髓鞘开始前四周，血脑屏障变得局部可渗透，并且我们表明，这种渗透性与血管周围淋巴细胞和单核细胞浸润以及小胶质细胞和星形胶质细胞的实质激活有关。正在进行的实验旨在剖析狨猴 EAE 中神经保护和病变修复的细胞和放射学相关性，其方式将对我们的人类研究产生直接影响。 最后，我们完成了对多发性硬化症患者无症状一级亲属的招募，作为全国多发性硬化症基因与环境 (GEMS) 研究第一阶段的一部分，该研究是与哈佛大学布莱根妇女医院 (NCT01353547 和NCT01617395）。在 NIH，我们对可能处于临床多发性硬化症发展风险相对较高和较低的个体进行了特征分析。我们希望在明年公开的初步结果显示了这两个群体之间微妙但可能有意义的差异。 对于目标 2，过去一年的工作继续侧重于放射病理相关性研究方法的开发，特别是狨猴 EAE 模型。我们使用各种 MRI 方法对福尔马林固定的大脑进行高分辨率成像，并开发了一个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 3D 打印的大脑切割盒来实现的，这些切割盒可以对大脑进行精确切片，从而可以定位和研究 MRI（体内或死后）上观察到的小病变。我们已经证明了该系统对于分析新皮质脱髓鞘和软脑膜炎症区域的价值。我们进一步展示了它分析狨猴模型中微小异常疾病灶的能力，我们正在对其细胞成分以及重金属是否存在进行表征。 其他工作重点是开发临床试验范式，用于新药早期疗效测试，以保护和修复正在经历炎症性脱髓鞘的脑组织。在这项工作中，我们表明，通过传统方式仔细采集的 MRI 扫描结果，并使用复杂的统计模型进行分析，可用于推断此类药物是否未能达到其预期效果。这很重要，因为目前还没有方法可以在少于数十或数百人的持续一年或更长时间的试验中测试此类药物。我们的方法有望提高效率和灵敏度，因为它可以在 6 个月或更短的时间内由 20 名甚至更少的研究参与者完成。 2015 财年，我们开始对由我们的校外合作者开发的一种新药物进行初步测试，我们计划在来年使用我们的新试验设计开始功效测试。