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：
10688931
负责人：
Daniel Reich
金额：
$ 392.91万
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/10688931
关键词：
Acute Adrenal Cortex Hormones Affect Agammaglobulinaemia tyrosine kinase Age Animal Model Animals Architecture Astrocytes Autopsy Axon Biology Brain CNS degeneration COVID-19 pandemic Callithrix Caring Cell Nucleus Central Nervous System Central Vein Cerebral cortex Cerebrospinal Fluid Characteristics Chronic Clinic Clinical Clinical Research Collaborations Communities Complement Conduct Clinical Trials Contrast Media Data Demyelinations Detection Development Diagnosis Diagnostic Disease Event Evolution Experimental Autoimmune Encephalomyelitis Extramural Activities Functional disorder Gadolinium Image Imaging Techniques Immune system Industry Inflammation Inflammatory Innate Immune System Interleukin-1 Receptors International Investigation Knowledge Lesion Location Longitudinal Studies MRI Scans Magnetic Resonance Imaging Measures Methods Microglia Modeling Molecular Monkeys Multiple Sclerosis Multiple Sclerosis Lesions Myelin National Institute of Neurological Disorders and Stroke Natural History Neuroglia Neurologic Onset of illness Outcome Paper Pathologic Patients Peripheral Persons Phase Phenotype Physiologic pulse Play Positioning Attribute Primates Process Prognosis Progressive Disease Radiology Specialty Reporting Research Resolution Role Scanning Spectrum Analysis Surface System Techniques Technology Testing Therapeutic Intervention Three-Dimensional Imaging Time Tissues United States National Institutes of Health Vision Work accurate diagnosis automated algorithm base brain cell burden of illness clinical development design diagnostic algorithm disability experimental study imaging biomarker imaging modality improved inflammatory marker magnetic field multimodality nervous system disorder neuroimmunology nonhuman primate novel novel therapeutics portability preclinical study predicting response prevent prognostic significance radio frequency radiomics repaired spatiotemporal systems research targeted treatment therapeutic development therapeutic target tissue repair transcriptome sequencing translational goal white matter

项目摘要

In Fiscal Year 2022, we continued to pursue our two Specific Aims: to study the pathophysiology of MS through high-resolution MRI, and to study the biology of inflammatory demyelination in a translationally relevant primate model of MS. We have seen significant progress toward accomplishing both Aims, some of which is detailed here. For Aim 1, the first project focuses on the early development of MS lesions. We continued our analysis of perivenular lesion formation (the radiological central vein sign or CVS), which is a phenomenon that appears relatively specific to MS and hence may hold diagnostic and prognostic significance. We showed that younger age and higher CVS+ percentage at baseline are associated with new CVS+ lesion development (2), that lesion-size measures add important information when using CVS+ lesion counts for MS diagnosis (3), that the CVS determined radiologically is histopathologically specific (3), and that gadolinium-based contrast agent use in conjunction with MRI increases CVS detection on FLAIR* images (a type of MRI that we pioneered), thereby increasing sensitivity of CVS for MS diagnosis (8). In prior work, we showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. Over the past year, we have further defined the radiological characteristics and clinical associations of these lesions, demonstrating that they can be identified at 1.5 tesla, the most common clinical magnetic field strength (13), and that they are associated with inflammatory markers in the cerebrospinal fluid (12). We also described a new automatic method to identifying such lesions in images using advanced radiomic techniques (17). In a study that utilized single-nucleus RNA sequencing technology from postmortem tissue, we showed that chronic inflammation in these lesions is sustained by glial cells (principally microglia and astrocytes) under the influence of the peripheral immune system, and that the evolutionarily ancient innate immune system known as complement plays an important role in this process (1, 10). With the NINDS Neuroimmunology Clinic, we are conducting clinical trials to test whether corticosteroids prevent the evolution of acute to chronically inflamed lesions, assess whether the inflammation in these lesions can be abrogated by IL-1 receptor blockade, and determine the effect of Brutons tyrosine kinase inhibition on these lesions using a small brain-penetrant molecule to whose clinical development we have substantially contributed (22). We also continue to characterize MS lesions affecting the cerebral cortex, which are 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. Using a method we previously developed that more than doubles the sensitivity for cortical lesion detection, we have shown that cortical lesions are highly prevalent and are associated with disability and progressive disease, and that the burden of an important type of cortical lesion, which form at the surface of the cortex, is not strongly correlated with white matter lesion burden, suggesting differences in inflammation and repair mechanisms (7); this may be relevant for therapeutic development. To assist in further research into cortical lesions, we developed an automated algorithm to detect and segment them from MRI scans (16). Additionally under Aim 1, we have continued our work on improving methods for image acquisition (4) and analysis (9, 14, 18, 19, 21) and have used our imaging techniques to study other neurological diseases. Notable is the first report of MS lesions visualized using a portable, ultra-low magnetic field scanner, which is suitable for integration into a mobile clinical research unit (4). This technology, while less capable of uncovering disease biology than high- and ultra-high-field systems, has important clinical implications, especially with respect to bringing cutting-edge care to the neurologically underserved. 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). Work on this Aim was significantly slowed by the COVID-19 pandemic, but we continued to make progress on understanding the cellular and molecular architecture of healthy and inflamed brain cells and to lay the groundwork for resumption of our marmoset studies, which occurred in mid-2022. Results from these ongoing and planned studies 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 (5, 11, 15, 23, 24).

在2022财政年度，我们继续追求我们的两个具体目标：通过高分辨率MRI研究MS的病理生理学，并研究MS的翻译相关灵长类动物模型中炎症性脱髓鞘的生物学。我们已经看到了实现这两个目标的重大进展，其中有些是在此处详细介绍的。对于AIM 1，第一个项目着重于MS病变的早期发展。我们继续分析植膜病变形成（放射学中心静脉或CVS），这是一种现象，似乎对MS相对特异，因此可能具有诊断性和预后意义。我们表明，基线时年龄较小和CVS+百分比与新的CVS+病变发展有关（2），当使用CVS+病变计数进行MS诊断时，病变大小的措施增加了重要信息（3），CVS在放射学上确定的CVS在组织病理学上是组织病理学特异性特异性的。（3），以及基于Gadolinium的对比剂与MRI结合使用，增加了Flair*图像的CVS检测（我们开创性的MRI），从而提高了CVS对MS诊断的敏感性（8）。在先前的工作中，我们表明我们可以可靠地识别出临床MRI系统上长期发炎的病变。在过去的一年中，我们进一步定义了这些病变的放射学特征和临床关联，表明它们可以在1.5 Tesla（最常见的临床磁场强度（13））下被鉴定出来（13），并且它们与它们与炎症标记有关脑脊液（12）。我们还描述了一种使用高级放射线技术在图像中识别图像中此类病变的新自动方法（17）。在一项研究后，在验尸组织利用单核RNA测序技术的研究中，我们表明，这些病变中的慢性炎症是由神经胶质细胞（主要是小胶质细胞和星形胶质细胞）在外围免疫系统的影响下维持被称为补体的系统在此过程中起着重要作用（1，10）。在NINDS神经免疫学诊所中，我们正在进行临床试验，以测试皮质类固醇是否可以防止急性促进慢性发炎的病变的演变，评估这些病变中的炎症是否可以被IL-1受体阻滞剂消除，并确定Brutons Tyrosine酪氨酸激酶激酶的作用使用小脑渗透剂分子对这些病变的抑制作用，我们对其临床发育产生了显着贡献（22）。我们还继续表征影响大脑皮层的MS病变，与白质对应物不同，MRI很难检测到。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。。使用一种方法，我们先前开发了对皮质病变检测的敏感性的一倍以上皮质的表面与白质病变负担不密切相关，表明炎症和修复机制的差异（7）；这可能与治疗发展有关。为了帮助进一步研究皮质病变，我们开发了一种自动化算法来检测和从MRI扫描中分割它们（16）。此外，在AIM 1下，我们继续进行改进图像获取方法（4）和分析（9、14、18、19、21），并使用我们的成像技术来研究其他神经系统疾病。值得注意的是使用便携式，超低磁场扫描仪可视化的MS病变的第一份报告，该报告适合整合到移动临床研究单元中（4）。这项技术虽然比高高和超高场系统的能力较低，但具有重要的临床意义，尤其是在为神经系统贫乏的服务带来尖端护理方面。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）。 COVID-19的大流行使这一目标的工作显着放缓，但是我们继续在了解健康和发炎的脑细胞的细胞和分子结构方面取得了进展，并为恢复我们的摩尔莫斯群岛研究奠定了基础，这发生在我们的中期。 2022。这些正在进行的和计划的研究的结果将为临床前研究中使用Marmoset模型的方式铺平道路，以预测人们对新型治疗的反应。最后，我们继续为各种国家和国际财团（5、11、15、23、24）做出贡献和定位论文。