Multimodal MRI in Multiple Sclerosis

多模态 MRI 在多发性硬化症中的应用

• 批准号: 8746845
• 负责人: Daniel Reich
• 金额: $ 231.12万
• 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/8746845
• 关键词: Accounting; Acute; Address; Animal Disease Models; Animal Model; Animals; Axon; Behavior; Blood - brain barrier anatomy; Blood Vessels; Brain; Callithrix; Cell Nucleus; Cells; Central Vein; Characteristics; Chemistry; Chronic; Clinic; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Data; Demyelinations; Deposition; Detection; Development; Diagnosis; Diffusion; Disease; Equipment; Event; Evolution; Experimental Autoimmune Encephalomyelitis; Fibrosis; Foundations; Frequencies; Functional Imaging; Funding; Goals; Growth; Human; Image; Image Analysis; Imaging Techniques; Individual; Inflammation; Inflammatory; Laboratories; Lead; Learning; Legal patent; Lesion; Literature; Magnetic Resonance Imaging; Marshal; Measurement; Meningeal; Methods; Modeling; Monitor; Monkeys; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; N-acetylaspartate; National Institute of Neurological Disorders and Stroke; Neurons; Paper; Pathogenesis; Pathology; Pattern; Permeability; Phase; Predisposition; Prevention; Process; Property; Protocols documentation; Protons; Publishing; Recovery; Relapsing-Remitting Multiple Sclerosis; Relative (related person); Relaxation; Reporting; Research; Resolution; Scanning; Signal Transduction; Specificity; Spectrum Analysis; Spinal Cord; Structure; Subarachnoid Space; System; Techniques; Technology; Testing; Therapy Evaluation; Time; Tissues; Translating; Veins; Ventricular; Water; Weight; Work; base; blood cerebrospinal fluid barrier; blood perfusion; brain tissue; brain volume; clinical care; cohort; design; experience; gray matter; healthy volunteer; imaging Segmentation; improved; in vivo; magnetic field; molecular imaging; neuroprotection; outcome forecast; remyelination; repaired; research study; response; spatiotemporal; technique development; tissue repair; water diffusion; white matter

FY2013 has seen significant progress toward accomplishing all of the Specific Aims. For Aim 1, a major effort in the Translational Neuroradiology Unit (TNU) has been to define the relationship between MS lesions and the small veins around which they form. Based on images acquired at 3 and 7 tesla MRI, we have shown that central veins can be identified within most white matter MS lesions as well as lesions in an experimental autoimmune encephalomyelitis (EAE) model induced in the marmoset monkey. We have optimized and reported a technique for the detection and analysis of perivenular lesions in clinical care and research, which we call FLAIR*. We have used this technique to demonstrate that intralesional MS veins are smaller than uninvolved control veins, perhaps compressed by perivascular inflammatory cells or by fibrosis of the vascular wall. We have also found that extralesional MS veins appear larger than their counterparts in non-MS cases. By investigating developing MS lesions at high resolution using 7 tesla MRI, we have confirmed and extended earlier work in the lab demonstrating that opening of the blood-brain barrier in new MS lesions is a dynamic process that changes over time as lesions grow and begin to repair. Moreover, we have demonstrated that this opening of the blood-brain barrier is detectable on noncontrast 7 tesla imaging as a reduction of the T2* relaxation time constant and, more substantially, a shift in the phase of the MRI signal. In addition to perivascular abnormalities within the brain parenchyma itself, we have preliminarily reported the presence of blood-cerebrospinal fluid barrier opening within the subarachnoid space in up to 25% of MS cases, a new finding that is consistent with the presence of inflammation in this compartment. This may represent the first noninvasive demonstration of meningeal inflammation in vivo in MS, and studies to understand the characteristics of this finding, as well as its specificity and correlation with histopathological changes, are ongoing in the lab. Overall, our observations support a reinterpretation of blood-brain barrier opening in terms of a competition between tissue damage, which at least initially proceeds outward from the central vein, and tissue repair (or the prevention of damage), which is most intense at the periphery. For Aim 2, in collaboration with the Advanced MRI Section (PI: Jeff Duyn) in the Laboratory of Functional and Molecular Imaging in NINDS, we are pursuing a related approach to myelin imaging. This approach, which uses gradient-echo imaging to assess the T2* time constants and frequency distribution of the MRI signal, offers several advantages over conventional approaches: It can be applied more readily on high-field MRI systems (3T and above) due to lower power deposition, amplifying both signal and contrast relative to background; data can be obtained much more rapidly; and sensitivity to myelin is increased because myelin itself, due both to its chemistry and to its highly ordered structure in white matter, induces susceptibility changes. Studies from this collaboration published during the current funding period have characterized the MRI signal that arises from a distinct pool of water protons with short relaxation times and substantial frequency shifts. The characteristics of this pool appear to be different in MS cases and within EAE lesions in the marmoset, and ongoing work is designed to more fully characterize these changes in both humans and animals. The results are accounted for by a quantitative model that fairly accurately describes the behavior of the myelin water signal at high field strength. We are also investigating the imaging correlates of axonal damage using a technique known as diffusion-weighted spectroscopy, which allows measurement of the diffusion properties of intracellular metabolites, particularly the intraneuronal metabolite N-acetylaspartate (NAA). So far, we have shown that that diffusion of NAA parallel to the axon is significantly lower in MS cases than in healthy volunteers and is moreover inversely correlated with the diffusion of water in the same direction. This result has been confirmed in a second cohort of MS cases and is consistent with biophysical models that suggest that axonal damage should reduce diffusivity and helps to resolve a paradox in the literature. Our results suggest that NAA diffusivity is a more specific marker of white matter integrity than water diffusivity. For Aim 3, we have developed new and fully automated image segmentation techniques to identify the volumes of brain structures, including lesions. Two US patents are pending from this work were submitted during the current funding period. These methods allow us to investigate patterns of lesion growth and recovery and to learn how such patterns change over the course of the disease and in response to the initiation of different disease-modifying therapies. During the current funding period, we have also published a paper that develops a technique to integrate data derived from multiple scanners and scanning protocols in order to assess long-term changes in brain volume over time, a fundamental result of the MS disease process. The lack of a method to accomplish this is a substantial drawback in MS clinical research because scanning technology has been improving rapidly, and these improvements limit the ability to compare current scans with those obtained a decade or more earlier from the same individuals. The results demonstrate essentially linear decreases in gray matter volume over long periods of time with concomitant exponential increases in ventricular volume. Outside of technique development, in collaboration with the Myelin Repair Foundation we have developed a schema for proof-of-concept, short-term evaluation of therapies that promote tissue protection and repair in acute MS lesions. Such a trial design, which requires 6 months of testing in 15-20 people, improves dramatically on currently used methods that are based on 2 years of observation in 80-100 individuals. Detailed planning to test this trial design in relapsing-remitting MS is underway.

2013财年取得了重大进展，以实现所有特定目标。 对于AIM 1，转化神经放射学部（TNU）的主要努力是定义MS病变与它们形成的小静脉之间的关系。根据在3和7 Tesla MRI中获得的图像，我们表明可以在大多数白质MS病变中鉴定中静脉，以及在Marmoset猴子中诱导的实验自身免疫性脑脊髓炎（EAE）模型中的病变。我们已经优化并报告了一种用于检测和分析临床护理和研究中植膜病变的技术，我们称之为天赋*。我们已经使用该技术证明了病情内MS静脉小于未参与的对照静脉，可能是由血管周炎性细胞或血管壁纤维化压缩的。我们还发现，在非MS病例中，室外的MS静脉似乎比其对应物大。通过使用7 Tesla MRI进行高分辨率开发MS病变，我们在实验室中确认并扩展了较早的工作，证明新MS病变中的血脑屏障的打开是一个动态过程，随着病变的增长并开始修复，随着时间的流逝而变化。此外，我们已经证明，在非对比度7 Tesla成像上可以检测到血脑屏障的这种开口，这是T2*弛豫时间常数的减少，并且更重要的是，MRI信号的相位变化。除了脑实质本身内血管周期异常外，我们还报告了在高达25％的MS病例中，在亚蛛网膜下腔空间内存在血红脊髓液屏障的存在，这一新发现与该隔间中炎症的存在一致。这可能代表了MS中体内脑膜炎的第一个非侵入性证明，并研究了该发现的特征及其特异性和与组织病理学变化的特异性和相关性，在实验室中正在进行中。总体而言，我们的观察结果支持在组织损伤之间的竞争中重新诠释血脑屏障的开口，至少最初从中静脉向外进行，组织修复（或预防损害），这在周围是最激烈的。 对于AIM 2，在NINDS中功能和分子成像实验室中与高级MRI部分（PI：Jeff Duyn）合作，我们正在采用相关的髓磷脂成像方法。这种方法使用梯度回声成像来评估T2*时间常数和MRI信号的频率分布，它比常规方法具有多种优势：由于较低的功率沉积，较低的功率沉积，放大了相对于背景的信号和对比，因此可以更容易地应用于高场MRI系统（3T及以上）；数据可以更快地获得；对髓磷脂的敏感性增加了，因为髓磷脂本身由于其化学性质和其在白质中高度有序的结构都引起了敏感性的变化。在当前资助期间发表的这一合作的研究表明，MRI信号是由不同的水质子池产生的，这些水质子的松弛时间短，频率大量转移。该池的特征在MS病例和Marmoset的EAE病变中似乎有所不同，并且持续的工作旨在更充分地表征人类和动物的这些变化。结果是由一个定量模型解释的，该模型可准确地描述高场强度下的髓磷脂水信号的行为。 我们还使用称为扩散加权光谱的技术研究了轴突损伤的成像相关性，该技术允许测量细胞内代谢物的扩散特性，尤其是神经内代谢物N-乙酰基酯（NAA）。到目前为止，我们已经表明，在MS病例中平行于轴突的NAA的扩散明显低于健康的志愿者，并且与在同一方向上的水扩散呈呈呈呈互相关的相关性。该结果已在第二个MS病例队列中得到证实，并且与生物物理模型一致，这些模型表明轴突损伤应降低扩散率并有助于解决文献中的悖论。我们的结果表明，NAA扩散率比水扩散率更具体。 对于AIM 3，我们开发了新的和完全自动化的图像分割技术，以识别包括病变在内的大脑结构的体积。目前的资助期间提交了这项工作的两项美国专利。这些方法使我们能够研究病变生长和恢复的模式，并了解这种模式在整个疾病过程中如何变化，并回应启动不同疾病改良疗法的情况。在当前的融资期间，我们还发表了一篇论文，该论文开发了一种整合来自多个扫描仪和扫描协议的数据，以评估MS疾病过程的基本结果，以评估大脑体积的长期变化。缺乏实现这一目标的方法是MS临床研究的一个重大缺点，因为扫描技术一直在迅速改善，这​​些改进限制了将当前扫描与从同一个体中获得十年或更早的扫描进行比较的能力。结果表明，长时间的灰质体积基本上降低，伴随指数呈倍数增加。在技​​术开发之外，与髓磷脂维修基金会合作，我们开发了一种用于概念验证的模式，短期评估疗法，以促进急性MS病变中的组织保护和修复。这种试验设计需要在15-20人中进行6个月的测试，在目前使用的方法基于80-100个人的2年观察方法上，可显着改善。正在进行重新安装MS的试验设计测试该试验设计的详细计划正在进行中。