Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

• 批准号: 9563158
• 负责人: Daniel Reich
• 金额: $ 328.37万
• 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/9563158
• 关键词: 3-Dimensional; 3D Print; Acute; Address; Adrenal Cortex Hormones; Affect; Algorithms; American; Animal Model; Animals; Area; Area Analyses; Astrocytes; Autopsy; Blood - brain barrier anatomy; Brain; CNS degeneration; Callithrix; Central Vein; Cerebral cortex; Childhood; Chronic; Clinic; Clinical; Clinical Trials; Collaborations; Communities; Correlation Studies; Data; Demyelinations; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Environment; Event; Evolution; Experimental Autoimmune Encephalomyelitis; Extramural Activities; First Degree Relative; Formalin; Gadolinium; Genes; Goals; Guidelines; Heavy Metals; Hospitals; Hour; Human; Image; Individual; Industry; Inflammation; Inflammatory; Inherited; Investigation; Leptomeninges; Lesion; Location; Longitudinal Studies; Lymphocyte; Magnetic Resonance Imaging; Medical center; Membrane; 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; Onset of illness; Paper; Pathologic; Pattern; Permeability; Phase; Physiologic pulse; Primates; Process; Publishing; Radiology Specialty; Recruitment Activity; Reporting; Research; Risk; Scanning; Selection for Treatments; Serum; System; Systems Analysis; Techniques; Testing; Time; Tissues; United States National Institutes of Health; Universities; Vascular Permeabilities; Veins; Woman; Work; axon injury; base; clinical development; design; diagnostic accuracy; disease diagnosis; experimental study; follow-up; healthy volunteer; high resolution imaging; imaging approach; imaging study; improved; in vivo; individual patient; multimodality; neocortical; neuroimmunology; neuroinflammation; neuroprotection; novel therapeutics; outcome forecast; prevent; radiofrequency; remyelination; repaired; response; spatiotemporal; systems research; tissue repair; white matter

Fiscal Year 2017 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*. One study to assess the utility of FLAIR* for diagnosis and characterization of MS lesions have been published in the last year (3); 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 have published a set of guidelines for central vein detection (15) and 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. In the past year, we have published a paper describing the very-long-term (10-20-year) evolution of MS lesions, showing that most lesions shrink over time (17). This research is ongoing, and based on it we have started a clinical trial to test whether corticosteroids improve lesion repair, in collaboration with our colleagues in the NINDS Neuroimmunology Clinic. We are also planning additional clinical trials over the next several years. In the past year, we have increased our focus on the characterization of MS lesions affecting the cerebral cortex, which have proved difficult to detect by MRI (unlike their white matter counterparts). Our approach here has been to evaluate new MRI approaches with potentially higher sensitivity than previously described methods, taking advantage of the 7-tesla research system at NIH and of our collaborations with MRI pulse sequence developers at NIH, in the extramural community, and in industry. In the past year, we have published an initial study on cortical lesions in pediatric-onset MS (7), and we have contributed to the in-print debate about the importance of cortical lesions (14). We have also followed up our prior discovery of the imaging correlate of inflammation in the leptomeninges (the membranes that surround the brain) by reporting similar observations in other neuroinflammatory diseases (1). 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). At NIH, we characterized individuals possibly at relatively high and low risk for development of clinical MS, and in the past year we have published a paper describing our results (22). 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 (9), which we are in the process of characterizing relative to their cellular components and for the presence or absence of heavy metals. We continue to make improvements to the ways in which MS is imaged (4, 5, 6, 12, 21), focusing with our collaborators on harmonizing imaging across multiple centers (11, 18), and using our approaches to improve diagnostic accuracy (19) and uncover new findings in individual patients (8). We have recently reviewed our research in MS and other neuroinflammatory diseases (2, 10, 13, 16). Finally, we have weighed in on the ongoing controversy about gadolinium deposition in the brain (20) and have devoted some effort to studying this phenomenon in our own lab.

2017财政年度在实现所有具体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。一项评估Flair*用于诊断和表征MS病变的效用的研究已在去年发表（3）；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，我们已经发布了一套中央静脉检测指南（15），并计划进行多中心临床试验，以评估Flair*是否允许早期和更自信的疾病诊断。 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。在过去的一年中，我们发表了一篇论文，描述了MS病变的长期（10 - 20年）演变，表明大多数病变随着时间的流逝而收缩（17）。这项研究正在进行中，基于此，我们已经开始了一项临床试验，以测试皮质固醇是否可以改善病变修复，并与Ninds Neuroumumumumumumumumumumumumumumumanology诊所的同事合作。我们还计划在未来几年内进行其他临床试验。 在过去的一年中，我们增加了对影响大脑皮层的MS病变表征的关注，事实证明，MRI很难检测到（与它们的白质对应物不同）。我们在这里的方法是利用NIH的7-Tesla研究系统以及我们与NIH，NIH，外壁外社区和行业中的MRI Pulse序列开发人员的合作，以比以前描述的方法更高的敏感性评估新的MRI方法。在过去的一年中，我们发表了一项关于儿科发作MS的皮质病变的初步研究（7），并为有关皮质病变的重要性的辩论做出了贡献（14）。我们还通过报告了其他神经炎症性疾病中的相似观察结果（1），还跟踪了我们先前发现瘦脑（围绕大脑的膜）炎症的成像相关的。 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。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人，在过去的一年中，我们发表了一篇论文描述了我们的结果（22）。 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属模型中分析微小异常疾病灶的能力（9），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。 我们继续改进MS成像的方式（4、5、6、12、21），与我们的合作者集中在跨多个中心（11、18）之间进行和谐成像，并使用我们的方法来提高诊断准确性（19），并在个别患者中发现了新发现（8）。我们最近回顾了我们在MS和其他神经炎症性疾病方面的研究（2、10、13、16）。最后，我们权衡了关于大脑中gadolin量沉积的持续争议（20），并致力于在我们自己的实验室中研究这种现象。