ANALYSIS OF THE AXONAL DEGENERATION FOLLOWING INFLAMMATORY DEMYELINATION IN MULT

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。 将多发性硬化症的神经保护和神经修复策略从试验台转移到床边的一个主要目标是开发髓鞘和轴突完整性的替代指标，这些指标可用于II期临床试验，以筛选初步疗效。在免疫调节药物的II/III期试验中，Gd增强病变作为炎症的替代标志物的用途现在已被广泛接受。尽管如此，即使在没有明显炎症的情况下，临床残疾也会进展。这被认为是许多下游因素介导的轴突退化的结果。放射学研究已经证实了活动性炎性脱髓鞘后数月至数年的远端沃勒变性和萎缩的证据(230)。残疾与常规测量指标如T1体积(后Gd)、T2体积、萎缩或T1黑洞之间的相关性很小(在各种研究中相关系数在0.3到0.6之间)，可能是因为所有这些测量都缺乏永久性脑组织病理的特异性。 磁共振成像(MRI)的最新进展，如磁化传递成像(MTI)、质子磁共振波谱(1H-MRS)和扩散张量成像(DTI)为潜在结构病理的更敏感和更特异的指标提供了前景。非常需要开发和优化这些措施，以便能够无创地量化MS患者脱髓鞘和轴突变性的程度。 我们正专注于开发DTI和MTI，以允许对白质束上的病理进行定量测量，然后将其用作潜在神经保护和神经修复药物临床试验的结果指标。DTI提供有关白质束的方向性和完整性的信息。MTI已被证明与轴突密度和髓鞘完整性有关，因此可能与追踪穿过受损髓鞘区域的轴突的局部和远程变化以及髓鞘修复的措施有关。纤维跟踪软件允许对感兴趣区域(ROI)的远端和近端或两个或更多ROI之间的特定路径进行三维重建。通过这种方式，可以从急性炎性病变的局部和远程位置获取多种类型的定量信息。此外，我们可以询问重建的通路，以测量单个患者随时间的变化。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轨迹的特定信息，这可能会提高我们识别沿轨迹的不同病理的能力。 这个项目的目标是基于这样的概念：(1)在急性炎症性脱髓鞘MS斑块内和远离斑块的地方都有显著的轴突损伤；(2)轴突完整性的进行性变化发生在慢性脱髓鞘的环境中，并解释了疾病的残疾进展阶段。我们假设：(1)分数各向异性(FA)主要反映轴突完整性的破坏，而磁化转移率(MTR)主要反映髓鞘完整性的变化；(2)由FA和MTR测量的MS患者白质束损害的范围和持续时间将对与所涉及的通路相关的功能损害具有同步和预测的有效性。

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 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 (230). 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 are focusing 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. 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. The aims of this project are based on the notions that: (1) there is significant axon damage both within and distant from the acute inflammatory demyelinating MS plaque; and (2) progressive changes in axon integrity occur in the chronically demyelinated setting and account for the disabling progressive stages of the disease. We hypothesize that: (1) fractional anisotropy (FA) predominantly reflects disruption of the integrity of axons whereas the magnetization transfer ratio (MTR) predominantly reflects changes in myelin integrity; and (2) the extent and duration of white-matter tract damage in MS patients, as measured by FA and MTR will have concurrent and predictive validity for functional impairment related to the involved pathways.