Quantitative MR Imaging and Proton Spectroscopy in MS

描述(申请人提供)：多发性硬化症(MS)是美国年轻人最常见的神经系统疾病，患病率估计为40万，每年的医疗费用和生产力损失约为95亿美元。我们假设(中央假说)微血管异常(已知的多发性硬化症静脉周围炎症的结果)是导致中枢神经系统损伤的最终常见途径。这一假设是基于我们收集的初步数据，并得到此类损伤的病理证据的支持。随之而来的对轴突/神经元的微血管缺血性损伤干扰了正常的铁稳态，导致过量的铁在深部灰质中积聚。多发性硬化症患者所经历的神经认知障碍和疲劳是由于基底节和丘脑中铁蓄积造成的氧化损伤的后果。为了验证这一假设，我们提出了四个具体目标：具体目标1定义了30例早期复发缓解期MS患者和年龄/性别匹配的对照组在高场强(3特斯拉)下的基线灌注(脑血流量；脑血容量；平均通过时间)、磁共振(MR)波谱(N-乙酰天冬氨酸)和定量MR指标(扩散张量；扩散峰度；磁场相关性；结构体积)。特定目标2测量基线认知损伤和疲劳，并将这些结果与深部灰质的定量磁共振指标相关联。特指目标3，持续4年，深部灰质铁蓄积，这些结构受损，进行性脑实质丧失。具体目标4在4年的时间里，神经认知功能的下降和伴有深部灰质损伤的疲劳。这项研究将为多发性硬化症的病理生理学和MS患者经历的常见疾病(认知功能减退和疲劳)提供新的见解。这将导致采取更适当的措施来检测和量化疾病的影响，并将为创新的治疗制度提供理由。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the most common neurological disease of young adults in the United States, with a prevalence estimated to be 400,000 and with annual medical expenses and lost productivity costs of approximately $9.5 billion. We hypothesize (Central Hypothesis) that microvascular abnormalities (a consequence of the perivenous inflammation known to occur in MS) are a final common pathway leading to injury of the central nervous system. This hypothesis is based upon preliminary data we have gathered and is supported by pathological evidence of such injury. Ensuing microvascular ischemic damage to axons/neurons interferes with normal iron homeostasis, resulting in accumulation of excess iron in the deep gray matter. Neurocognitive deficits and fatigue experienced by MS patients are consequences of oxidative injury by iron accretion in the basal ganglia and thalamus. To test this hypothesis, we propose four Specific Aims: Specific Aim 1 defines baseline perfusion (cerebral blood flow; cerebral blood volume; mean transit time), magnetic resonance (MR) spectroscopy (N-acetyl aspartate), and quantitative MR metrics (diffusion tensor; diffusion kurtosis; magnetic field correlation; structural volume) at high-field (3 Tesla) in 30 early relapsing remitting MS patients and age/sex matched controls. Specific Aim 2 measures baseline cognitive impairment and fatigue and associates these results with quantitative MR metrics of the deep gray matter. Specific Aim 3 associates, over a 4 year duration, deep gray matter iron accumulation with both damage to these structures and progressive brain parenchymal loss. Specific Aim 4 associates, over a 4 year duration, the decline in neurocognitive function and fatigue with deep gray matter injury. This research will provide new insights into the pathophysiology of Multiple Sclerosis and common morbidities (cognitive decline and fatigue) experienced by MS patients. It will result in more appropriate measures to detect and quantitate the effect of the disease and will provide a rationale for innovative treatment regimes.