Monitoring brain atrophy during the course of MS

这项提议将检验这样一种假设，即脑萎缩的测量将证明是多发性硬化症患者疾病过程的实用、敏感和相关的替代标记物。对替代标记物的需求是基于新出现的证据，即MS的病理过程不可逆转地损害髓鞘和轴突，这一过程从疾病开始就是活跃的，但临床症状仅粗略地反映了疾病复发缓解期潜在病理的严重程度。当多发性硬化症患者进入二次进展阶段时，组织破坏已经超过了代偿机制可以维持神经功能的程度。为了实现前三个特定目标，将使用一种高度可重复性的方法来量化脑实质丢失的程度，称为脑实质分数(BPF)。在目标1中，将使用包括145名MS患者和30名健康对照的纵向研究设计来确定MS患者发生萎缩的模式。目标2的目的是确定脑萎缩的临床相关性，并检验MS复发期的脑萎缩预示着以后转变为继发性进展性MS的假设。在目标3中，将确定脑萎缩的MRI和脑脊液相关性。特异性MR病变的意义。类型将从它们与脑萎缩的关系中推断出来。这些特定的MR病变类型的重要性将直接使用AIM 4中的尸检材料衍生的临床-MRI相关性进行测试。该项目将导致改进监测MS过程中的病理过程的方法。该项目的长期临床目标是开发方法以促进对MS患者个体的疾病管理，并为实验治疗开发改进的监测技术，包括神经保护因素。

This proposal will test the hypothesis that measures of brain atrophy will prove to practical, sensitive, and relevant surrogate markers of the disease process in multiple sclerosis patients. The need for a surrogate marker is based on emerging evidence that the pathologic process in MS irreversibly damages myelin and axons, that this process is active from disease onset, but that clinical symptoms only loosely reflect the severity of the underlying pathology in the relapsing remitting stage of the disease. By the time an MS patient enters the secondary progressive stage, tissue destruction has progressed beyond the point where compensatory mechanisms can sustain neurologic function. A highly reproducible method for quantifying the extent of brain parenchymal loss, termed the brain parenchymal fraction (BPF), will be used to accomplish the first three specific aims. In aim 1, the pattern with which MS patients develop atrophy will be determined using a longitudinal study design involving 145 MS patients and 30 healthy controls. The purpose of aim 2 is to determine clinical correlates of cerebral atrophy and to test the hypothesis that cerebral atrophy in the relapsing phase of MS predicts later conversion to secondary progressive MS. In aim 3, MRI and CSF correlates of cerebral atrophy will be determined. The significance of specific MR lesion. Types will be inferred from their relationship to cerebral atrophy. The significance of these specific MR lesion types will be directly tested using clinical-MRI correlation derived from autopsy material in aim 4. This project will lead to improve methods for monitoring the pathologic process during the course of MS. The long term clinical goals of this project are to develop methods to promote improved disease management for individual MS patients, and to develop improved monitoring techniques for experimental therapies, including neuroprotective factors.