MECHANISMS OF NEURODEGENERATION AND STRATEGIES FOR NEUROPROTECTION IN MS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多发性硬化症(MS)研究的一个基本目标是阐明 参与了永久残疾的调解。临床、放射学和病理学研究表明 在疾病的急性临床恶化和慢性进展期，都可能导致残疾。 我们研究的基本假设是，无论多发性硬化症处于什么阶段，都会出现永久性残疾 疾病，是轴突受损的结果。在这里，我们计划定义细胞和分子机制 MS的轴突损伤，开发残疾的成像生物标记物，从而检验合理的神经保护和 神经修复策略。 将多发性硬化症的神经保护和神经修复策略从长凳移植到床边的一个主要目标是 开发髓鞘和轴突完整性的替代措施，可用于II期临床试验，以筛选 初步疗效。Gd增强病变作为II/I期炎症的替代标志物的应用 免疫调节药物的III试验现在被广泛接受。尽管如此，即使没有明显的 炎症，临床残疾的进展。这被认为是轴突变性的结果，由 下游因素众多。放射学研究已经证明了远距离沃勒变性的证据。 和萎缩，在活动性炎性脱髓鞘后几个月到几年。两者之间的关联性 残疾和常规测量，如T1体积(Gd后)、T2体积和萎缩或T1黑色 空洞只是适度的(在各种研究中，相关系数在0.3到0.6之间)，想必是因为 这些措施缺乏永久性脑组织病理的特异性。磁共振研究的最新进展 成像(MRI)，例如磁化转移成像(MTI)、质子磁共振波谱(1H-MRS)、 弥散张量成像(DTI)为潜在结构的更敏感和更具体的测量提供了希望 病理学。迫切需要发展和优化这些措施，以便能够非侵入性地 量化MS患者脱髓鞘和轴突变性的程度。 我们将专注于发展DTI和MTI，以允许沿着白质对病理进行定量测量 束，然后可用作潜在的神经保护和临床试验的结果衡量标准 神经修复剂。DTI提供关于白质束的方向性和完整性的信息，包括 轴突和髓鞘的信息。MTI已被证明与轴突密度和髓鞘有关 完整性，因此可能与追踪穿过脑区的轴突的局部和远程变化有关。 髓鞘受损，以及髓鞘修复的一种措施。光纤跟踪软件允许3维 重建感兴趣区(ROI)远端和近端或两个或多个感兴趣区之间的特定路径。 通过这种方式，可以从本地和远程站点获取多种类型的定量信息 急性炎症性病变。此外，我们可以询问重建的路径来测量变化 在单个病人身上的时间。因为所有的MR图像都是共同配准的，所以我们可以比较DTI和MTI特定的轨迹 信息，这可能会提高我们辨别轨迹上不同病理的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A fundamental objective in multiple sclerosis (MS) research is to elucidate the cellular and molecular pathways that are involved in mediating permanent disability. Clinical, radiographic, and pathological studies suggest that disability can ensue both from acute clinical exacerbations and during the chronic progressive stages of the disease. The underlying hypothesis in our research is that permanent disability in MS, regardless of the stage of the disease, is a result of damage to the axon. Herein, we plan to define the cellular and molecular mechanisms of axonal injury in MS, develop imaging biomarkers of disability, and thereby test rational neuroprotective and neuroreparative strategies. A major goal in translating neuroprotective and neuroreparative strategies for MS from the bench to the bedside is to develop surrogate measures of myelin and axon integrity that can be used in phase II clinical trials to screen for preliminary efficacy. The utility of gadolinium-enhancing lesions as a surrogate marker of inflammation in phase II/ III trials of immunomodulatory drugs is now well accepted. Nonetheless, even in the absence of apparent inflammation, clinical disability progresses. This is thought to occur as a result of axon degeneration mediated by numerous downstream factors. Radiological studies have demonstrated evidence of distant Wallerian degeneration and atrophy that ensue months to years after active inflammatory demyelination. The correlation between disability and conventional measures such as T1 volume (post-gadolinium), T2 volume, and atrophy or T1 black holes is only modest (correlation coefficients between 0.3 and 0.6 in a variety of studies), presumably because all of these measures lack specificity for permanent brain tissue pathology. Recent advances in magnetic resonance imaging (MRI) such as magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI) offer promise as more sensitive and specific measures of underlying structural pathology. There is a great need to develop and optimize these measures so as to be able to non-invasively quantify the extent of demyelination and axon degeneration in MS patients. We will focus on developing DTI and MTI to allow quantitative measurement of pathology along white-matter tracts, which can then be used as outcome measures for clinical trials of potential neuroprotective and neuroreparative agents. DTI gives information on the directionality and integrity of white-matter tracts, containing both axonal and myelin information. MTI has been shown to be associated with both axon density and myelin integrity, and therefore may be relevant to tracking local and distant changes in axons that pass through areas of damaged myelin, as well as a measure of myelin repair. Fiber-tracking software allows the 3 dimensional reconstruction of specific pathways distal and proximal to a region of interest (ROI) or between two or more ROIs. In this way, multiple types of quantitative information can then be acquired both locally and at distant sites from an acute inflammatory lesion. Moreover, we can interrogate the reconstructed pathways to measure changes over time in an individual patient. Since all of the MR images are coregistered we can compare DTI and MTI tract specific information, which may improve our ability to discern different pathologies along the trajectories.