Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

• 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
• 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

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财年在实现所有特定目标方面取得了重大进展。对于AIM 1，我们已经证明了在超高场强度下的磁化率加权成像（7 t）对髓白质区的存在和方向敏感，这是证明该技术可以检测到脱髓鞘的先决条件（12，17）。具体而言，我们的工作表明，髓纤维束包含可量化的迅速衰减磁化的组成部分，当组织相对于MRI系统旋转时，衰减时间常数可能会变化多达50％。我们以理论和实验的理由相信这些发现是由于白质中髓磷脂片的结构和内容所致。在此目标下进行的实验的初步结果还表明，轴内代谢产物的扩散特性在多发性硬化症中被毁灭，并表明代谢物扩散的方向性可能是轴突损伤的更直接读数，而不是水扩散的方向性（手稿）。这增加了可以检测和量化受损但尚未损坏但尚未丧失的轴突的可能性，这有可能在临床试验中评估假定神经保护药物的疗效。 对于AIM 2，我们已经发现了新发育的MS病变中血脑屏障开口的以前未知的动态（3，14），为这些病变形成的过程提供了新的见解，并为调节血液 - 大脑驾驶仪的药物机制开辟了新的途径。具体而言，我们已经表明，血脑屏障最初在新形成的病变的中心开放，这可能与这些病变形成的小静脉相对应。在这些条件下，血清含量填充了从中心到外围的病变，我们称之为离心动力学的模式。随后，随着病变的扩展，血脑屏障开口的位置移至病变周围，组织学上与最活跃的炎症区域相对应。在这些条件下，血清含量填充了从周围到中心的病变（中心动力学）。我们将这些差异解释为不同病理过程的证据，也许对应于组织损伤和修复，并且在患者和动物模型中进一步研究了这一假设。这些实验强调了如果多发性硬化症，神经血管相互作用在发病机理中的重要性。 对于AIM 3，我们开发了新的和完全自动化的图像分割技术，可以识别大脑健康和患病部分的量，包括灰质，白质和病变（1、11、13）。在对多发性硬化队列队列的横截面分析中，尽管没有坦克的白质萎缩（手稿），但该分析显示了大脑中的白质体积与临床障碍评分之间存在反比相关性。我们怀疑这一发现可能与某些人更成功的组织修复，甚至可能是再髓关系有关。我们还证明，包括扩散加权和磁化转移加权成像在内的MRI技术对与MS相关的组织损伤敏感，并且可以以临床相关的方式使用它们来量化随时间的逐步量化渐进组织损伤（2，9，9，10，10，15，16）。 2011年的特定应用是对视觉系统的，这是大脑的一部分，特别容易受到多发性硬化症相关的组织损伤，现在可以通过各种成像和临床技术来询问。最后，我们开发了强大的统计工具，可以利用纵向MRI研究中获得丰富的时空信息，以更准确地评估该损害（4-8）。特别是，对78例多发性硬化症患者进行的年度扫描的纵向分析表明，这些技术可以用作II期临床试验中的结果度量，该试验的样本量相对较小（每只手臂40人）（9）。这是最早证实这种先进技术可用于临床试验目的的确认。