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：
8342290
负责人：
Daniel Reich
金额：
$ 200.86万
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/8342290
关键词：
Animal Disease Models Animal Model Area Atrophic Axon Blood - brain barrier anatomy Blood Vessels Brain Cell Membrane Permeability Characteristics Chronic Disease Clinical Clinical Protocols Clinical Trials Cohort Analysis Cross-Sectional Studies Data Demyelinations Diffusion Disease Disease Progression Drug effect disorder Enrollment Equipment Fiber Histologic Image Imaging Techniques Individual Inflammation Inflammatory Lesion Location Magnetic Resonance Imaging Magnetism Manuscripts Measurement Metabolic Microscope Monitor Multiple Sclerosis Multiple Sclerosis Lesions Myelin National Institute of Neurological Disorders and Stroke Natural History Neuraxis Neurologic Neurons Neuroprotective Agents Outcome Measure Participant Pathogenesis Pathologic Processes Patient Care Patients Pattern Permeability Phase II Clinical Trials Predisposition Preparation Process Property Protocols documentation Resolution Sample Size Scanning Serum Spinal Cord Structure System Techniques Testing Time Tissues Veins Visual system structure Weight Work Wound Healing arm base clinically relevant disability gray matter imaging Segmentation improved in vivo insight longitudinal analysis neuroimmunology repaired research study spatiotemporal tool water diffusion white matter young adult

项目摘要

FY2011 has seen significant progress toward accomplishing all of the Specific Aims. For Aim 1, we have demonstrated that magnetic susceptibility-weighted imaging at ultra-high field strength (7 T) is sensitive to the presence and orientation of myelinated white matter tracts, a prerequisite for demonstrating that this technique can detect demyelination (12, 17). Specifically, our work has shown that myelinated fiber bundles contain a component of rapidly decaying magnetization that is quantifiable, and that the decay time constant can vary by as much as 50% when the tissue is rotated with respect to the MRI system. We believe on theoretical and experimental grounds that these findings are due to the structure and contents of myelin sheets in white matter. Preliminary results from experiments performed under this Aim also indicate that the diffusion properties of intra-axonal metabolites are deranged in multiple sclerosis and suggest that the directionality of metabolite diffusion may be a more straightforward readout of axonal damage than the directionality of water diffusion (manuscript in preparation). This raises the possibility that damaged but not yet moribund axons can be detected and quantified, which would potentially allow assessment of the efficacy of putative neuroprotective drugs in clinical trials. For Aim 2, we have uncovered previously unknown dynamics of blood-brain-barrier opening in newly developing MS lesions (3, 14), providing new insights into the processes by which those lesions form and opening new avenues for investigating the mechanisms of action of drugs that modulate blood-brain-barrier permeability. Specifically, we have shown that the blood-brain barrier is initially open in the center of newly forming lesions, which probably corresponds to the small, inflamed vein around which these lesions form. Under these conditions, serum contents fill the lesion from the center to the periphery, a pattern we call centrifugal dynamics. Subsequently, as the lesions expand, the location of blood-brain-barrier opening moves to the lesions periphery, which histologically corresponds to the most active area of inflammation. Under these conditions, serum contents fill the lesion from the periphery to the center (centripetal dynamics). We interpret these differences as evidence of distinct pathological processes, perhaps corresponding to tissue damage and repair, and further work in patients and animal models is investigating this hypothesis. These experiments underline the importance of neurovascular interactions in the pathogenesis if multiple sclerosis. For Aim 3, we have developed new and fully automated image segmentation techniques that can identify the volumes of healthy and diseased portions of the brain, including gray matter, white matter, and lesions (1, 11, 13). In a cross-sectional analysis of a multiple sclerosis cohort, this analysis revealed an inverse correlation between white matter volume in the brain and clinical disability scores, despite the absence of frank white matter atrophy (manuscript under review). We suspect that this finding may be related to more successful tissue repair, perhaps even remyelination, in some individuals. We have also demonstrated that MRI techniques, including diffusion-weighted and magnetization transfer-weighted imaging, are sensitive to MS-related tissue damage, and that they can be used in a clinically relevant way to quantify progressive tissue damage over time (2, 9, 10, 15, 16). Specific applications in 2011 have been to the visual system, a portion of the brain that is especially susceptible to multiple sclerosis-related tissue damage and that can now be interrogated by a variety of imaging and clinical techniques. Finally, we have developed powerful statistical tools that take advantage of the rich spatiotemporal information available in longitudinal MRI studies in order more accurately to assess that damage (4-8). In particular, a longitudinal analysis of yearly scans in 78 people with multiple sclerosis revealed that these techniques could be used as outcome measures in Phase II clinical trials with relatively small sample sizes (on the order of 40 people per arm) (9). This is one of the first confirmations that such advanced techniques can feasibly be used for clinical trial purposes.

2011 财年在实现所有具体目标方面取得了重大进展。对于目标 1，我们已经证明超高场强 (7 T) 下的磁化率加权成像对有髓鞘白质束的存在和方向敏感，这是证明该技术可以检测脱髓鞘的先决条件 (12, 17 ）。具体来说，我们的工作表明，有髓纤维束包含可量化的快速衰减磁化强度的成分，并且当组织相对于 MRI 系统旋转时，衰减时间常数可能变化高达 50%。我们从理论和实验的角度相信，这些发现是由于白质中髓磷脂片的结构和内容造成的。根据该目标进行的实验的初步结果还表明，轴突内代谢物的扩散特性在多发性硬化症中被扰乱，并表明代谢物扩散的方向性可能比水扩散的方向性更直接地读出轴突损伤（手稿准备）。这提出了可以检测和量化受损但尚未垂死的轴突的可能性，这可能允许在临床试验中评估假定的神经保护药物的功效。对于目标 2，我们发现了新发生的多发性硬化症病变中血脑屏障开放的先前未知的动态 (3, 14)，为这些病变形成的过程提供了新的见解，并为研究多发性硬化症的作用机制开辟了新途径。调节血脑屏障通透性的药物。具体来说，我们已经表明，血脑屏障最初在新形成的病变中心是开放的，这可能对应于这些病变周围形成的发炎的小静脉。在这些条件下，血清内容物从中心到外围填充病变，我们将这种模式称为离心动力学。随后，随着病灶扩大，血脑屏障开口的位置移动到病灶外围，这在组织学上对应于炎症最活跃的区域。在这些条件下，血清内容物从外围到中心填充病变（向心动力学）。我们将这些差异解释为不同病理过程的证据，可能与组织损伤和修复相对应，并且在患者和动物模型中的进一步工作正在研究这一假设。这些实验强调了神经血管相互作用在多发性硬化症发病机制中的重要性。对于目标 3，我们开发了新的全自动图像分割技术，可以识别大脑健康和患病部分的体积，包括灰质、白质和病变 (1, 11, 13)。在对多发性硬化症队列的横断面分析中，该分析揭示了大脑白质体积与临床残疾评分之间的负相关性，尽管没有明显的白质萎缩（手稿正在审查中）。我们怀疑这一发现可能与某些个体更成功的组织修复甚至髓鞘再生有关。我们还证明了 MRI 技术，包括扩散加权成像和磁化转移加权成像，对 MS 相关的组织损伤很敏感，并且它们可以以临床相关的方式用于量化随时间推移的渐进性组织损伤 (2, 9 、10、15、16）。 2011 年的具体应用是视觉系统，这是大脑的一部分，特别容易受到多发性硬化症相关组织损伤的影响，现在可以通过各种成像和临床技术进行研究。最后，我们开发了强大的统计工具，利用纵向 MRI 研究中丰富的时空信息，以便更准确地评估这种损害 (4-8)。特别是，对 78 名多发性硬化症患者的年度扫描进行的纵向分析表明，这些技术可以用作样本量相对较小（每组 40 人左右）的 II 期临床试验的结果测量 (9)。这是此类先进技术可以切实用于临床试验目的的首批确认之一。