EXAMINATION OF NATURAL HISTORY AND THERAPY OF MULTIPLE SCLEROSIS USING MRI

使用 MRI 检查多发性硬化症的自然史和治疗

• 批准号: 6111894
• 负责人: Henry F McFarland
• 金额: --
• 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/6111894
• 关键词: brain stem; clinical research; clinical trials; diethylenetriaminepentaacetate; gadolinium; histopathology; human subject; human therapy evaluation; immunotherapy; interferon beta; magnetic resonance imaging; multiple sclerosis; nervous system disorder chemotherapy; pathologic process; relapse /recurrence; remission /regression; spinal cord imaging /visualization

Over the past decade, the use of MRI to study multiple sclerosis (MS) has lead to substantial advances in understanding the disease process. Disease activity as detected by new lesions on T2-weighted images or contrast enhancing lesions on T1-weighted images have established that the level of activity seen on MRI is considerably greater than that seen clinically. Further, MRI has become an important and powerful tool for the assessment of the effect of new experimental therapies in MS. Recent work continues to focus on defining the natural history of the disease using MRI and in examining the effect of experimental treatments on disease activity as measured by MRI. Specifically, recent studies have focused on the following questions; 1. What is the natural history of new lesions in MS identified by contrast enhancement? Components of this question include a comparison of disease activity using contrast enhancement, lesion load on T2-weighted images and advanced imaging techniques including magnetization transfer imaging and proton spectroscopy. 2. What is the level of disease activity seen in patients who are early in the relapsing remitting course of the disease? 3. Interferon beta 1b is approved for the treatment of MS and has been shown to produce over the short term a reduction in disease activity as measured by MRI. Does the treatment effect persist and what, if any, effect does the development of neutralizing antibodies have on the efficacy of the treatment? 4. What effect do treatments that are chosen to target various aspects of the MS lesion have on disease activity and which MRI measures are best for studying treatments that target the various stages of the lesion? Serial studies of patients with early,relapsing-remitting MS using contrast enhanced MRI have shown that nearly two thirds of the patients have evidence of active new lesion formation. Recent studies in the NIB have examined the evolution of the MS lesion using imaging techniques that measure tissue destruction such as lesion load on T2-weighted images or T1 hypointensities, alterations in magnetization transfer ratios and alterations seen using proton spectroscopy. Findings have demonstrated that progression of disease as measured by overall burden of disease increases during the early phase of the disease. However, only a modest correlation can be found between the frequency of acute enhancing lesions and the level of accumulated disease burden suggesting that distinct mechanisms may contribute to lesion progression. In a cohort of 35 patients treated with interferon beta 1b and studied longitudinally by MRI, clinical evaluation and interferon neutralizing antibody status, development of neutralizing antibodies was found in 12 patient (34%). In almost all cases some change in the treatment effect of interferon on acute contrast enhancing lesion activity was observed corresponding to the development of neutralizing antibodies. However, 6 of the patients had a spontaneous reduction or disappearance of neutralizing antibody; these patients continued to have a substantial reduction in disease activity as measured by contrast enhancing activity. Thus, while a relationship seems to exist between the effect of the treatment and the presence of neutralizing antibody, the use of single antibody determinations have limited usefulness. Studies of the effect of experimental treatments on various stages of the MS lesion can provide valuable information at several levels. In addition to providing evidence that a treatment may be effective in the disease, changes in the evolution of the MS lesion on MRI during the use of an experimental treatment can help establish the mechanism involved in the pathogenesis of the lesion. Consequently, recent studies in the NIB have focused on treatments that are thought to modify different aspects of lesion development. Studies have been started which examine the effect of a treatment designed to modify the T cell response to myelin basic protein and a treatment that may protect the oligodendrocyte from damage or stimulate some regeneration. Patients treated with interferon beta 1b have been studied using multiple MRI techniques in order to establish the stage of the MS lesion modified by this treatment. Evidence indicates that while interferon treatment is very effective in many patients in reducing the frequency of new inflammatory lesions, the treatment does not prevent the enlargement of existing lesions nor does it lead to any significant remyelination. These finding not only help in understanding the mechanism of interferon in MS but also indicate that the MS lesion may have multiple components and that these components are not necessarily a continuum but instead distinct process that can operate independently.

在过去的十年中，使用MRI学习 多发性硬化症（MS）已导致了很大的进步 了解疾病过程。疾病活动被检测到 T2加权图像或对比度增强病变的新病变 在T1加权图像上已经确定了活动水平 在MRI上看到的要比临床上看到的要大得多。 此外，MRI已成为重要而强大的工具 评估MS新实验疗法的影响。 最近的工作继续专注于定义的自然历史 该疾病使用MRI并检查实验的影响 通过MRI测量的疾病活动的治疗方法。具体来说， 最近的研究集中在以下问题上； 1。是 MS中新病变的自然史与对比确定 增强？这个问题的组成部分包括比较 使用对比度增强，病变负荷的疾病活动 T2加权图像和高级成像技术，包括 磁化转移成像和质子光谱。 2。是 在早期的患者中看到的疾病活动水平 复发疾病的病程？ 3。干扰素β1B是 已批准用于治疗MS，并已显示出产生 在短期内，疾病活动的减少 MRI。治疗效果是否持续吗？ 中和抗体的发展对 治疗？ 4.选择的治疗方法是什么 针对MS病变的各个方面对疾病活动和 哪种MRI措施最适合研究针对的治疗方法 病变的各个阶段？患者的连续研究 使用对比度增强的MRI早期，复发复发的MS具有 表明将近三分之二的患者有活跃的证据 新病变形成。 NIB的最新研究检查了 使用测量的成像技术的MS病变演变 组织破坏，例如T2加权图像上的病变负荷或T1 低强度，磁化转移比的改变和 使用质子光谱法看到的改变。发现有 证明疾病的进展是通过总体上测量的 疾病的早​​期阶段的疾病负担增加。 但是，在 急性增强病变的频率和累积的水平 疾病负担表明不同的机制可能有助于 病变进展。在一组35例接受治疗的患者中 干扰素Beta 1B，并通过MRI纵向研究 评估和干扰素中和抗体状态，发育 在12名患者中发现中和抗体的中和抗体。几乎 所有情况都会改变干扰素对急性的治疗效果 观察到对应于与 中和抗体的发展。但是，有6个 患者自发减少或消失 中和抗体；这些患者继续有大量 通过增强对比度测量的疾病活动的减少 活动。因此，尽管效果似乎存在关系 治疗和中和抗体的存在，使用 单抗体测定的实用性有限。研究 实验治疗对MS的各个阶段的影响 病变可以在多个层面提供有价值的信息。此外 提供证据表明治疗可能在 疾病，在MRI上的MS病变演变的变化 实验治疗的使用可以帮助建立 病变发病机理涉及的机制。 因此，NIB的最新研究集中在治疗上 人们认为可以修改病变发展的不同方面。 已经开始研究治疗的效果 设计用于修改T细胞对髓磷脂碱性蛋白的反应和A 可以保护少突胶质细胞免受损害或 刺激一些再生。用干扰素β治疗的患者 使用多种MRI技术研究了1B 建立通过此处理修饰的MS病变的阶段。 证据表明，干扰素治疗非常有效 在许多患者中，降低了新炎症的频率 病变，治疗并不能阻止现有的扩大 病变也不会导致任何明显的再生。这些 寻找不仅有助于理解干扰素的机制 在MS中，但也表明MS病变可能具有多个 组件，这些组件不一定是 连续性但可以操作的独特过程 独立。