Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

基本信息

批准号：
9358593
负责人：
Daniel Reich
金额：
$ 218.23万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
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/9358593
关键词：
3-Dimensional 3D Print Acute Address Adrenal Cortex Hormones Algorithms American Animal Model Animals Area Astrocytes Autopsy Blood - brain barrier anatomy Boxing Brain CNS degeneration Callithrix Central Vein Cerebral cortex Chronic Clinic Clinical Clinical Trials Collaborations Correlation Studies Data Demyelinations Development Diagnosis Diagnostic Disease 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 Medical center Methodology Methods Microglia Modeling Monkeys Mononuclear Multi-Institutional Clinical Trial Multiple Sclerosis Multiple Sclerosis Lesions Myelin National Institute of Neurological Disorders and Stroke Natural History Neuraxis New Agents Onset of illness Outcome Paper Participant Pattern Peer Review Permeability Pharmaceutical Preparations Phase Positioning Attribute Primates Process Publishing Reporting 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 clinical care design disease diagnosis efficacy testing gadolinium oxide healthy volunteer improved in vivo meetings neocortical neuroimmunology neuroprotection novel therapeutics outcome forecast prevent radiofrequency remyelination repaired research study response spatiotemporal tissue repair trial design white matter

项目摘要

FY2016 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 previously developed a rapid imaging approach for clinical 3T MRI called FLAIR*. Two studies to assess the utility of FLAIR* for diagnosis and characterization of MS lesions have been published in the last year (10, 25); we found that the FLAIR* technique is able to significantly improve diagnostic confidence in a variety of settings. The technique is now in use at several centers around the world, and with the North American Imaging in MS cooperative, we are planning a multi-center clinical trial to assess whether FLAIR* allows earlier and more confident diagnosis of the disease. With respect to vascular permeability, we previously 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 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 (4). Based on this research, we have started a clinical trial to test whether corticosteroids improve lesion repair, in collaboration with our colleagues in the NINDS Neuroimmunology Clinic. 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. Preliminary results indicate that the model recapitulates MS extremely well for this purpose. Finally, we completed recruitment of asymptomatic first-degree relatives of people with MS, as well as matched healthy volunteers, as part of the first stage of the nationwide Genes and Environment in Multiple Sclerosis (GEMS) study. This is a collaboration with colleagues at the Brigham & Womens Hospital of Harvard University and the University of Pittsburgh Medical Center (NCT01353547 and NCT01617395) (29). At NIH, we characterized individuals possibly at relatively high and low risk for development of clinical MS. We have presented the results of this study at several national and international meetings, and a report has been submitted to peer review. 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 (11), 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 (20). 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 FY16, in collaboration with the NINDS Neuroimmunology Clinic, we continued our initial testing of one new agent, developed by our extramural collaborators. We hope to complete the initial study in FY17 and move on to efficacy testing using our new trial design. We continue to make improvements to the ways in which MS lesions are imaged (6, 9, 14, 16, 18, 21, 28), using the results of those investigations to study how lesions impact short- and long-term clinical outcomes (7, 12, 17, 22, 23, 26). We have recently reviewed our research over the past few years, in the context of related studies in MS (2, 3, 5). These contributions have also made their way into position papers of several international organizations working to harmonize the diagnosis and clinical care of people with this disease (8, 15, 27).

2016财年取得了重大进展，以实现所有具体目标。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，我们仅部分订阅了以前我们以前为临床3T MRI开发了一种称为FLAIR*的快速成像方法。去年已经发表了两项评估Flair*用于诊断和表征的诊断和表征的研究（10，25）；我们发现Flair*技术能够显着提高对各种环境的诊断信心。该技术现已在世界各地的几个中心使用，并且随着北美成像在MS合作社中，我们计划进行一项多中心临床试验，以评估Flair*是否允许对疾病进行更早，更自信的诊断。关于血管通透性，我们先前确定MS病变中存在两个时空模式：一种离心模式，其中血清含量从病变的中心泄漏，然后在几分钟到几个小时内向外进行，以填充整个病变；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。具体来说，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功效，可能包括包括透明度（4）。基于这项研究，我们已经开始了一项临床试验，以测试皮质类固醇是否可以改善病变维修，并与Ninds Neuroumumumumumumumumumumumumunology Clinic的同事合作。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。初步结果表明，为此，该模型对MS的概括非常好。最后，作为多发性硬化症（GEMS）研究中全国基因和环境的第一阶段的一部分，我们完成了MS患者的无症状一级亲戚的招募，并招募了健康的志愿者。这是哈佛大学Brigham＆Womens医院和匹兹堡大学医学中心（NCT01353547和NCT01617395）的合作（29）。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。我们已经在几次国家和国际会议上介绍了这项研究的结果，并提交了同行评审的报告。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（11），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。额外的工作集中在开发临床试验范式上，用于对新药进行早期疗效测试，以保护和修复经历炎症性脱髓鞘的脑组织（20）。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2016财年，在与Ninds神经免疫学诊所合作的情况下，我们继续对由我们的外壁外合作者开发的一种新代理进行初步测试。我们希望完成2017财年的初步研究，并使用我们的新试验设计进行疗效测试。我们继续使用这些调查的结果来研究病变如何影响短期和长期临床结果（7、12、17、22、23、26），继续改善MS病变成像的方式（6、9、9、14、16、18、21、28）。在MS中相关研究的背景下，我们最近审查了过去几年的研究（2、3、5）。这些贡献还进入了几个国际组织的位置论文，以协调对这种疾病患者的诊断和临床护理（8、15、27）。