Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

• 批准号: 10018419
• 负责人: Daniel Reich
• 金额: $ 322.42万
• 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/10018419
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Algorithms; American; Animal Model; Animals; Astrocytes; Autopsy; Axon; Biology; Blood - brain barrier anatomy; Brain; CNS degeneration; Callithrix; Cells; Central Vein; Cerebral cortex; Chronic; Clinic; Clinical; Clinical Trials; Collaborations; Collagen Type I; Communities; Conduct Clinical Trials; Correlative Study; Cross-Sectional Studies; Data; Demyelinations; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Event; Evolution; Experimental Autoimmune Encephalomyelitis; Extramural Activities; Fibrinogen; Functional disorder; Funding; Goals; Grant; Herpesviridae; Hour; Image; Impairment; Industry; Inflammation; Inflammatory; International; Investigation; Knowledge; Legal patent; Leptomeninges; Lesion; Location; Longitudinal Studies; Lymphocyte; Magnetic Resonance Imaging; Membrane; Methods; Microglia; Modeling; Molecular; Monkeys; Mononuclear; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; National Institute of Neurological Disorders and Stroke; Natural History; Neuraxis; Onset of illness; Outcome; Paper; Pathologic; Patients; Pattern; Permeability; Phase; Phenotype; Physiologic pulse; Plasma Proteins; Play; Positioning Attribute; Primates; Publishing; Radiology Specialty; Research; Resolution; Scanning; Serum; Spectrum Analysis; Spinal Cord Lesions; Syndrome; System; Techniques; Technology; Testing; Therapeutic Intervention; Three-Dimensional Imaging; Time; Tissues; United States National Institutes of Health; Veins; Vision; Work; accurate diagnosis; base; brain parenchyma; design; disability; disease diagnosis; experimental study; follow-up; imaging approach; imaging biomarker; imaging modality; improved; multimodality; neuroimmunology; nonhuman primate; novel; novel therapeutics; off-patent; outcome forecast; preclinical study; predicting response; prevent; radio frequency; remyelination; repaired; rituximab; spatiotemporal; systems research; targeted treatment; therapeutic target; tissue repair; white matter

Fiscal Year 2019 has seen significant progress toward accomplishing both 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 short-to-medium-term outcomes of acute lesions. To understand whether the presence of a central vein may help distinguish MS lesions from their mimickers -- an idea that remains controversial but to which we mostly subscribe -- we previously developed a rapid imaging approach for clinical 3-tesla 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 (9, 27), and a patent incorporating this technology has been submitted (22). We found that FLAIR* is able to significantly improve diagnostic confidence in a variety of settings, including the so-called radiologically isolated syndrome. Our technique is now in use at more than 30 around the world, and with the North American Imaging in MS (NAIMS) cooperative, we are conducting a multicenter pilot clinical trial to assess whether FLAIR* allows earlier and more confident diagnosis of the disease. A U01 grant to extend this to a full-scale trial has been submitted to NINDS extramural, and we will collaborate should it be funded. In related work, we have established the long-term deleterious consequences of perivenular inflammation in the white matter, finding that perivenular collagen type I deposition is widespread in the MS brain and may impair the proliferation and differentiation of myelin-repairing cells (1) With respect to lesion outcomes, 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. Among other things, 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. We also showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. In the past year, we have published a large cross-sectional and longitudinal study showing that such lesions can expand slowly over time and are associated with clinical disability progression (2). With the NINDS Neuroimmunology Clinic, we are conducting a clinical trial to test whether corticosteroids prevent the evolution of acute to chronically inflamed lesions, and we have recently initiated a new trial to assess whether the inflammation in these lesions can be abrogated. We have also increased our focus on the characterization of MS lesions affecting the cerebral cortex, which have proven 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 prior years, we described and are routinely using a method that more than doubles the sensitivity for cortical lesion detection, and we recently submitted a patent application for a new technique to visualize these lesions on clinical MRI scanners (20). We have also followed up our prior discovery of the imaging correlate of inflammation in the leptomeninges (the membranes that surround the brain) by collaborating with colleagues at Johns Hopkins on a clinical trial of intrathecal rituximab, which was unfortunately unsuccessful (4). Additionally under Aim 1, we have continued our work on improving methods for image acquisition and analysis (8, 10, 11, 13, 14, 18, 19, 23, 24, 26). For Aim 2, we described the imaging and cellular/molecular events in early inflammatory demyelinating lesions that develop in the brains of marmoset monkeys with experimental autoimmune encephalomyelitis (EAE). We previously suggested, using coarse MRI techniques, 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. We have since shown directly that the plasma protein fibrinogen leaks into the brain parenchyma prior to demyelination, and that fibrinogen can also be seen in chronically inflamed lesions in people with MS. In the past year, we have published the first radiological-pathological correlative study of spinal cord lesions in marmoset EAE 15). We also collaborated with NINDS colleagues to describe the effects of herpesvirus inoculation on the course of experimental disease in this model (16). The results will pave the way toward using the marmoset model in preclinical studies to predict the response of people to novel treatments. Finally, we continue to contribute to review and position papers with various national and international consortia (12, 17, 18).

2019财政年度在实现这两个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，以及急性病变的短期至中期结局。为了了解中央静脉的存在是否有助于将MS病变与模仿者区分开 - 这个想法仍然存在争议，但我们主要是为了认可的想法 - 我们以前为临床3-Tesla 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MS病变诊断和表征的研究（9，27），并提交了一项纳入该技术的专利（22）。我们发现Flair*能够显着提高对各种环境的诊断信心，包括所谓的放射学孤立综合征。现在，我们的技术正在全球30多个使用，并且随着MS（NAIMS）合作社的北美成像，我们正在进行一项多中心飞行员临床试验，以评估Flair*是否允许更早，更自信地诊断该疾病。 U01赠款将其扩展到全面试验已提交给Ninds外壁外，如果资助它，我们将合作。在相关工作中，我们确定了白质中细胞炎症的长期有害后果，发现在MS脑中，腹膜胶原蛋白I型沉积在MS脑中很普遍，可能会损害髓磷脂补给细胞的增殖和分化（1）（1） 关于病变的结果，我们先前确定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。除其他事项外，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疗效，可能包括透明度。我们还表明，我们可以可靠地鉴定出在临床MRI系统上长期发炎的病变。在过去的一年中，我们发表了一项大型的横断面和纵向研究，表明此类病变可以随着时间的流逝而缓慢扩展，并且与临床障碍进展有关（2）。通过Ninds神经免疫学诊所，我们正在进行一项临床试验，以测试皮质类固醇是否可以防止急性发展到长期发炎的病变，并且我们最近启动了一项新试验，以评估这些病变中的炎症是否可以消除。 我们还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（与白质对应物不同）。我们这里的方法是利用NIH的7-Tesla研究系统以及我们与NIH，NIH，行业社区和行业中的MRI Pulse Sequence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。 。在过去的几年中，我们通常使用一种将皮质病变检测敏感性增加一倍以上的方法，并且我们最近提交了一种新技术的专利应用，以在临床MRI扫描仪上可视化这些病变（20）。我们还通过与约翰·霍普金斯（Johns Hopkins）的同事合作进行了静脉内car症利妥昔单抗的临床试验（不幸的是，这是不成熟的（4），我们还通过与约翰·霍普金斯（Johns Hopkins）的同事合作，通过与约翰·霍普金斯（Johns Hopkins）的同事合作通过合作，跟踪了瘦脑（围绕大脑的膜）的成像相关的成像相关性（4）。 此外，在AIM 1下，我们继续在改进图像获取和分析方法方面的工作（8、10、11、13、14、18、19、19、23、24、26）。 对于AIM 2，我们描述了早期炎症性脱髓鞘病变中的成像和细胞/分子事件，这些病变在Marmoset猴子的大脑中伴有实验性自身免疫性脑脊髓炎（EAE）。我们先前提出，使用粗MRI技术，血脑屏障在脱髓鞘发作前长达四个星期就可以局部渗透，我们表明这种渗透性与周围的淋巴细胞和单核浸润性有关，并与微胶质细胞激活相关。星形胶质细胞。此后，我们直接表明，血浆蛋白纤维蛋白原在脱髓鞘之前泄漏到脑实质中，并且在患有MS的患者的长期发炎的病变中也可以看到纤维蛋白原。在过去的一年中，我们发表了关于Marmoset EAE 15中的脊髓病变的第一个放射学病理相关研究）。我们还与Ninds同事合作，描述了疱疹病毒接种对该模型中实验疾病进程的影响（16）。结果将为临床前研究中使用Marmoset模型的方式铺平道路，以预测人们对新治疗的反应。 最后，我们继续为各种国家和国际财团（12、17、18）做出贡献和定位论文。