In vivo assessment of meningeal inflammation and its clinical impact in multiple sclerosis by 7 Tesla MRI

7 特斯拉 MRI 体内评估脑膜炎症及其对多发性硬化症的临床影响

• 批准号: 10427326
• 负责人: Daniel M Harrison
• 金额: $ 58.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427326
• 关键词: Address; Anatomy; Autopsy; B-Lymphocytes; Biological Markers; Blast Cell; Blood - brain barrier anatomy; Brain; Brain imaging; CCL19 gene; CCL21 gene; CXCL13 gene; Cell Lineage; Cerebrospinal Fluid; Cessation of life; Chronic; Clinical; Clinical Data; Clinical Trials; Cognitive deficits; Data; Demyelinations; Deterioration; Development; Disease; Drug Design; Failure; Fatigue; Flow Cytometry; Follicular Dendritic Cells; Future; Gadolinium; Generations; Helper-Inducer T-Lymphocyte; Image; Imaging Device; Inflammation; Inflammatory; Inflammatory Infiltrate; Injections; Injury; Interferon Type II; Intrathecal Space; Lesion; Light; Link; Lymphoid Follicle; Magnetic Resonance Imaging; Maps; Measurement; Measures; Memory; Meningeal; Meninges; Methods; Monitor; Multiple Sclerosis; Nerve Degeneration; Neuronal Injury; Neurons; Optical Coherence Tomography; Outcome; Outcome Measure; Participant; Pathologic; Pathology; Patient Care; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Plasma Cells; Predisposition; Production; Resolution; Role; Special Population; Spinal Cord; Spinal Puncture; Structure of germinal center of lymph node; TNF gene; Thick; Thinness; Time; Validation; Visit; Visualization software; axon injury; brain magnetic resonance imaging; cerebral atrophy; clinical phenotype; clinically relevant; cognitive disability; cohort; contrast enhanced; cytokine; diagnostic tool; disability; gray matter; in vivo; interleukin-21; monocyte; multiple sclerosis patient; nervous system disorder; neuroimaging; physically handicapped; prognostic tool; retinal nerve fiber layer; therapy development; tool; treatment response

Although MRI is the major diagnostic and prognostic tool used in the care of patients with multiple sclerosis (MS), many aspects of MS pathology are still not well visualized. Recent histopathologic studies in MS have shed light on a previously unrecognized phenomenon without a proven MRI correlate- meningeal inflammation. Pathologic data suggests that meningeal inflammation in MS is not a bystander phenomenon, with strong links found between meningeal inflammation and pathologic findings of cortical pathology and neurodegeneration and a clinical phenotype characterized by rapid disability accumulation, progressive subtypes, and an earlier time to death. To date, explorations of the role of meningeal inflammation in MS have been primarily limited to autopsy studies. In this application, we propose to use gadolinium-enhanced 7 Tesla (7T) MPFLAIR MRI as a non- invasive biomarker of meningeal inflammation in MS. Our preliminary data utilizing this approach demonstrates leptomeningeal contrast enhancement, which we propose as a marker of meningeal inflammation, in 76% of participants with MS. We will use this tool to investigate a hypothesis that meningeal inflammation in MS may be more ubiquitous than previously thought, is not effectively targeted by current treatments, and is related to some of the more damaging and poorly addressed aspects of MS (cortical injury, cognitive deficits, fatigue, and progressive disability accumulation). Participants with MS will undergo annual study visits including a 7T MRI of the brain, physical and cognitive disability assessments, and optical coherence tomography (OCT), in addition to a one-time lumbar puncture. The choice of leptomeningeal enhancement on 7T MPFLAIR MRI as an in vivo biomarker of meningeal inflammation will be justified through comparisons to other MRI sequences and other field strengths in addition to demonstration of a link between leptomeningeal enhancement and spinal fluid markers of meningeal inflammation through cytokine profiling and flow cytometry. We will also use this imaging tool to demonstrate an association between meningeal inflammation and a more disabling MS phenotype through clinical data, in addition to cognitive and physical disability scales. Finally, we will use this imaging tool to demonstrate an association between meningeal inflammation and cortical pathology (cortical lesions and cortical relaxometry alterations on 7T MRI) and neurodegeneration (retinal nerve fiber layer thinning on OCT). Validation of neuroimaging methods for in vivo quantification of meningeal pathology and confirmation of its clinical relevance has the potential to change the treatment landscape in MS. The tools developed in this study would find future use as non-invasive surrogate outcome measures in clinical trials of drugs designed to reduce meningeal inflammation and its impact, in addition to acting as a means to select patients in whom such treatments would be justified and to monitor treatment response.

虽然MRI是用于多个肿瘤患者护理的主要诊断和预后工具， 尽管多发性硬化症（MS）的发病率很高，但MS病理学的许多方面仍然没有很好地可视化。近期组织病理学研究 MS揭示了一种以前未被认识到的现象，但没有证实与MRI相关-脑膜 炎症病理学数据表明MS中的脑膜炎不是旁观者现象， 在脑膜炎症和皮质病理学的病理学发现之间发现了很强的联系， 神经变性和临床表型，其特征在于快速残疾积累，进行性 亚型和更早的死亡时间 迄今为止，对脑膜炎在MS中的作用的探索主要限于尸检 问题研究在此应用中，我们建议使用钆增强的7特斯拉（7 T）MPFLAIR MRI作为非 我们利用这种方法的初步数据表明， 软脑膜对比度增强，我们建议作为脑膜炎症的标志，在76%的 我们将使用这个工具来研究一个假设，即MS中的脑膜炎症 可能比以前认为的更普遍，目前的治疗方法不能有效地靶向， 与MS的一些更具破坏性和解决不好的方面（皮质损伤，认知障碍）有关。 缺陷、疲劳和进行性残疾累积）。MS受试者将接受年度研究 访视包括大脑的7 T MRI、身体和认知障碍评估以及光学相干性 断层扫描（OCT），以及一次性腰椎穿刺。 7 T MPFLAIR MRI软脑膜强化作为脑膜瘤活体生物标志物的选择 炎症将通过与其他MRI序列和其他场强的比较来证明 证明软脑膜增强和脑膜炎的脊髓液标记物之间的联系， 炎症通过细胞因子谱和流式细胞术。我们还将使用这个成像工具来演示 通过临床数据发现脑膜炎症与更致残的MS表型之间的关联， 除了认知和身体残疾量表。最后，我们将使用此成像工具演示 脑膜炎和皮质病理学（皮质病变和皮质松弛测量）之间的关系 7 T MRI上的改变）和神经变性（OCT上的视网膜神经纤维层变薄）。 脑膜病理学活体定量和确认的神经影像学方法的验证 其临床相关性有可能改变MS的治疗前景。 这项研究将在未来的药物临床试验中用作非侵入性替代结果指标， 减少脑膜炎症及其影响，除了作为选择患者的一种手段外， 这些治疗将是合理的，并监测治疗反应。

项目成果

Meningeal contrast enhancement in multiple sclerosis: assessment of field strength, acquisition delay, and clinical relevance.

多发性硬化症的脑膜对比增强：场强、采集延迟和临床相关性的评估。

• DOI: 10.1101/2024.03.04.24303491
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Harrison,DanielM;Allette,YohanceM;Zeng,Yuxin;Cohen,Amanda;Dahal,Shishir;Choi,Seongjin;Zhuo,Jiachen;Hua,Jun
• 通讯作者: Hua,Jun

A pilot trial of ocrelizumab for modulation of meningeal enhancement in multiple sclerosis.

ocrelizumab 用于调节多发性硬化症脑膜增强的初步试验。

• DOI: 10.1016/j.msard.2023.105344
• 发表时间: 2024
• 期刊: Multiple sclerosis and related disorders
• 影响因子: 4
• 作者: Dahal,Shishir;Allette,YohanceM;Naunton,Kerry;Harrison,DanielM
• 通讯作者: Harrison,DanielM