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：
10915980
负责人：
Daniel Reich
金额：
$ 441.79万
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/10915980
关键词：
Acute Adrenal Cortex Hormones Affect Agammaglobulinaemia tyrosine kinase Animal Model Animals Arteries Astrocytes Atlases Autopsy Axon B cell therapy Biological Biological Markers Biology Blood Vessels Brain CNS degeneration Callithrix Categories Cells Central Vein Cerebral cortex Cerebrospinal Fluid Characteristics Chemicals Chronic Clinic Clinical Clinical Research Clinical Trials Collaborations Communities Conduct Clinical Trials Contrast Media Cooperative Research and Development Agreement DNA Data Demyelinations Detection Development Diagnosis Diagnostic Disease Early Diagnosis Evolution Experimental Autoimmune Encephalomyelitis Extramural Activities Extravasation Functional disorder Future Gadolinium Genetic Enhancement Genetic study Goals Image Individual Industry Inflammation Inflammatory Interleukin-1 Receptors International Internet Investigation Lesion Liquid substance Location Longitudinal Studies Magnetic Resonance Imaging Meninges Methods Microglia Modeling Molecular Monoclonal Antibodies Multiple Sclerosis Multiple Sclerosis Lesions Myelin National Institute of Neurological Disorders and Stroke Natural History Neuroglia Oligodendroglia Onset of illness Outcome Paper Pathologic Pathology Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physiologic pulse Play Positioning Attribute Primary Prevention Primates Prognosis Publishing Radiology Specialty Research Resolution Resources Review Literature Sampling Scanning Selection for Treatments Serial Magnetic Resonance Imaging Spectrum Analysis Subarachnoid Space System Testing Therapeutic Intervention Three-Dimensional Imaging Time Tissues United States National Institutes of Health Vision Work accurate diagnosis design diagnostic algorithm experimental study gray matter imaging biomarker imaging modality in silico inflammatory marker multimodality multiple sclerosis patient nervous system disorder neuroimaging neuroimmunology neuropathology nonhuman primate novel therapeutics oligodendrocyte precursor portability preclinical trial precursor cell prevent prognostic significance radio frequency remyelination repaired screening spatiotemporal systems research targeted treatment therapeutic target transcriptomics white matter

项目摘要

In Fiscal Year 2023, we continued to pursue our Specific Aims: to study the pathophysiology of MS through neuroimaging, to study the biology of inflammatory demyelination in a translationally relevant primate model of MS, and to develop markers, and design and conduct clinical trials, for treating chronic inflammation and promoting tissue protection and remyelination in MS. We have seen significant progress toward accomplishing all these Aims, some of which is detailed here. For Aim 1, we continued our analysis of perivenular lesion formation (the radiological central vein sign or CVS), a phenomenon that appears relatively specific to MS and hence may hold diagnostic and prognostic significance. We showed 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 (4), and we reviewed advanced imaging methods to identify lesions with the CVS (16). We also continued work on early development of MS lesions (10). In prior research, we showed that we can reliably identify chronically inflamed lesions on clinical MRI systems. Over the past year, we have further reviewed the radiological characteristics and clinical and biological associations of these lesions (14). We also demonstrated that such lesions are associated with inflammatory markers in the cerebrospinal fluid (9) and identified their signatures on high-resolution, postmortem MRI (8). We performed a longitudinal clinical study and in silico analysis to determine that such lesions are not resolved by the most potent current MS disease-modifying therapy, B cell depletion with monoclonal antibodies (18). 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 (Aim 3). 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 systems at NIH and of our collaborations with MRI pulse sequence developers at NIH (25), in the extramural community (3, 19), and in industry. Using a method we previously developed that more than doubles the sensitivity for cortical lesion detection, we have identified hotspots for cortical lesion development (2), and we are now analyzing scans acquired over several years to assess for new cortical lesions. Work in the last year has revived an earlier line of research in the lab, which aimed to image inflammation in the fluid spaces of the brain, including the subarachnoid and perivascular spaces. In addition to reviewing these topics in detail (12, 13, 22), we performed a correlative MRI and neuropathology study and showed that enlarged, MRI-visible perivascular spaces surround arteries and not veins (11). We further studied a highly sensitive MRI approach for assessing abnormal leakage of blood vessels in the subarachnoid space (21), a phenomenon we previously had shown to be related to inflammation in this compartment. To further Aim 2, we created a detailed single-cell transcriptomic atlas of the healthy marmoset brain, sampling different regions in white and gray matter (17). We found, among other things, that certain glial cells (microglia, astrocytes, and oligodendrocyte precursor cells) are highly specialized according to their location in the brain, whereas others (oligodendrocytes, principally) are not. This resource, and an accompanying web browser (http://cjpca.ninds.nih.gov), is now widely available to the research community. In the past year, we also published a study, performed under a Cooperative Research and Development Agreement (CRADA) with Vertex Pharmaceuticals, in which we showed that serial MRI can accurately assess whether individual demyelinating lesions in marmoset experimental autoimmune encephalomyelitis (EAE) repair successfully in the months after they form (5). This finding paves the way for proof-of-concept preclinical and clinical trials to test putative remyelinating drugs in MS. Under Aim 3, we reviewed the literature on circulating free DNA biomarkers of neurological disorders (7), a promising approach that could serve as an adjunct to imaging-based trials. We also pioneered the use of ultra-low-field, portable MRI in multiple sclerosis (1), which we believe will be useful not only for enhancing clinical trials but also for future screening and early detection efforts, a cornerstone of primary prevention. Such efforts are enhanced by genetic studies, which we undertook in collaboration for the first time during the past year (6). Finally, we continue to contribute to review and position papers with various national and international consortia (15, 24).

在2023财政年度，我们继续追求我们的具体目标：通过神经影像学研究MS的病理生理学，在MS的翻译相关灵长类动物模型中研究炎症性脱髓鞘的生物学，并开发标记物，并设计和进行临床试验，临床试验，并进行临床试验。用于治疗慢性炎症并促进MS中的组织保护和透明度。我们已经看到了实现所有这些目标的重大进展，其中有些是在此处详细介绍的。对于AIM 1，我们继续分析对植膜病变形成（放射学中心静脉或CVS），这一现象似乎对MS，因此可能具有诊断性和预后意义。我们表明，基于Gadolinium的对比剂与MRI结合使用会增加Flair*图像的CVS检测（一种我们开创性的MRI），从而提高了CVS对MS诊断的敏感性（4），我们审查了先进的成像方法以识别出高级成像方法带有简历的病变（16）。我们还继续致力于早期开发女士病变（10）。在先前的研究中，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，我们进一步审查了这些病变的放射学特征以及临床和生物学关联（14）。我们还证明了这种病变与脑脊液中的炎症标记有关（9），并在高分辨率后MRI（8）上鉴定出它们的签名。我们进行了一项纵向临床研究和计算机分析，以确定这种病变并未通过最有效的当前MS疾病改良疗法，B细胞耗尽单克隆抗体（18）来解决。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胶质分子对这些病变的抑制（AIM 3）。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。我们在这里的方法是利用NIH的7-Tesla研究系统以及我们与NIH的MRI Pulse序列开发人员（25）的合作，以比以前描述的方法更高的灵敏度评估新的MRI方法（25）（25）（25）（ 3，19），以及行业。使用一种方法，我们以前开发了对皮质病变检测的敏感性的一倍以上，我们已经鉴定出用于皮质病变发育的热点（2），现在我们正在分析几年来获得的扫描，以评估新的皮质病变。去年的工作已经恢复了实验室的早期研究，该研究旨在在包括蛛网膜下腔和周围空间在内的大脑流体空间中进行炎症。除了详细审查这些主题（12、13、22）之外，我们还进行了一项相关的MRI和神经病理学研究，并表明，围绕动脉而不是静脉的MRI-MRI-Visible可见周围空间扩大（11）。我们进一步研究了一种高度敏感的MRI方法，用于评估蛛网膜下腔空间中血管异常泄漏（21），这是我们以前证明与该隔室炎症有关的现象。为了进一步的目标2，我们创建了一个详细的健康马莫斯脑大脑的单细胞转录图，对白物质和灰质中的不同区域进行了采样（17）。我们发现，除其他外，某些神经胶质细胞（小胶质细胞，星形胶质细胞和少突胶质细胞前体细胞）根据其在大脑中的位置而高度专业，而其他细胞（主要是少突胶质细胞）却没有。该资源以及随附的Web浏览器（http://cjpca.ninds.nih.gov）现在已广泛可供研究社区使用。在过去的一年中，我们还发表了一项研究，该研究是根据与顶点药物的合作研究与开发协议（CRADA）进行的，其中我们表明串行MRI可以准确地评估单个脱髓的脱髓延髓实验性自动免疫性脑膜炎（EAE）成功修复。在它们形成后的几个月中（5）。这一发现为概念验证临床前和临床试验铺平了道路，以测试MS中推定的透明药物。在AIM 3下，我们回顾了有关神经系统疾病的循环自由DNA生物标志物的文献（7），这是一种有前途的方法，可以用作基于成像试验的辅助方法。我们还开创了多发性硬化症中超低场，便携式MRI的使用（1），我们认为这不仅对增强临床试验，而且对于将来的筛查和早期检测工作也是有用的，这是一级预防的基石。遗传研究加强了这种努力，在过去的一年中，我们首次在合作（6）进行了遗传研究。最后，我们继续为各种国家和国际财团（15、24）做出贡献和定位论文。

项目成果

期刊论文数量（89）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative MRI demonstrates abnormality of the fornix and cingulum in multiple sclerosis.

DOI：
10.1155/2013/838719
发表时间：
2013
期刊：
Multiple sclerosis international
影响因子：
2.5
作者：
Syc SB;Harrison DM;Saidha S;Seigo M;Calabresi PA;Reich DS
通讯作者：
Reich DS

Inversion Recovery Susceptibility Weighted Imaging With Enhanced T2 Weighting at 3 T Improves Visualization of Subpial Cortical Multiple Sclerosis Lesions.

DOI：
10.1097/rli.0000000000000698
发表时间：
2020-11
期刊：
Investigative radiology
影响因子：
6.7
作者：
Beck ES;Gai N;Filippini S;Maranzano J;Nair G;Reich DS
通讯作者：
Reich DS

The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis.

DOI：
10.3389/fnins.2023.1038011
发表时间：
2023
期刊：
FRONTIERS IN NEUROSCIENCE
影响因子：
4.3
作者：
Okar, Serhat V. V.;Hu, Fengling;Shinohara, Russell T. T.;Beck, Erin S. S.;Reich, Daniel S. S.;Ineichen, Benjamin V. V.
通讯作者：
Ineichen, Benjamin V. V.

B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

DOI：
10.1016/j.ebiom.2023.104701
发表时间：
2023-08
期刊：
EBIOMEDICINE
影响因子：
11.1
作者：
Maggi, Pietro;Vanden Bulcke, Colin;Pedrini, Edoardo;Bugli, Celine;Sellimi, Amina;Wynen, Maxence;Stolting, Anna;Mullins, William A.;Kalaitzidis, Grigorios;Lolli, Valentina;Perrotta, Gaetano;El Sankari, Souraya;Duprez, Thierry;Li, Xu;Calabresi, Peter A.;van Pesch, Vincent;Reich, Daniel S.;Absinta, Martina
通讯作者：
Absinta, Martina

Seven-tesla phase imaging of acute multiple sclerosis lesions: a new window into the inflammatory process.

DOI：
10.1002/ana.23959
发表时间：
2013-11
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Absinta, Martina;Sati, Pascal;Gaitan, Maria I.;Maggi, Pietro;Cortese, Irene C. M.;Filippi, Massimo;Reich, Daniel S.
通讯作者：
Reich, Daniel S.