Spasticity and spinal mechanisms of human motor control

虽然原发性侧索硬化症通常被认为是一种运动神经元疾病，但它与肌萎缩侧索硬化症(ALS)和其他运动神经元疾病的关系尚不确定。与诊断为肌萎缩侧索硬化症患者的中位生存期为3-5年相比，偏头痛患者的中位生存期超过10年。在PLS中，变性仅限于大脑中的皮质脊髓或上运动神经元，而脊髓和脑干中的运动神经元没有明显的变性。人们很感兴趣的是，偏头痛和肌萎缩侧索硬化症是否是同一种疾病，如果是，限制偏头痛疾病进展的因素。 我们一直在研究成像生物标记物，这些标记物可以区分PLS和ALS，或者与临床进展指标相对应。在2012财年，我们用定量成像技术完成了一项研究的纵向臂的分析，该研究用定量成像技术研究了偏头痛和肌萎缩侧索硬化症患者脑结构的MRI变化。在这项研究的横断臂中，我们发现ALS和PLS患者以及年龄匹配的健康对照组之间皮质脊髓束白质破坏的模式不同。一个一致的发现是，在两种情况下，偏头痛和肌萎缩侧索硬化症患者的运动纤维各向异性分数都降低了。大约一半的患者能够在平均1年(ALS)或2年(PLS)后完成随访测试。根据纵向数据，我们假设随着上运动神经元的退化，随着受影响的白质束的早期中断，影像的变化也会发生演变。对两名ALS患者的尸检研究显示，铁在运动皮质的小胶质细胞中积聚，对应于MRI研究中看到的特定信号，这在7Tesla成像中最为明显。该项目的下一步是确定在疾病进程早期发生变化的成像标志物。为此，在2012财年，我们在健康志愿者中开始了一项新的研究，以评估作为早期检测上运动神经元功能障碍候选的成像标记物和生理指标的重复性。 在2012财年，我们完成了与哥伦比亚大学研究人员多中心合作研究的站点应计目标，以检查氧化应激在运动神经元疾病进展中的作用。我们完成了对以前登记的患者的年度访问，并计划在3年内完成本研究的最后一次访问。

Although primary lateral sclerosis (PLS) is generally considered to be a motor neuron disorder, its relationship to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders is uncertain. Patients with PLS have a median survival of more than a decade, in contrast to the 3-5 year median survival of patients after diagnosis of ALS. In PLS, degeneration is restricted to the corticospinal, or upper motor neurons, in the brain, without significant degeneration of motor neurons in the spinal cord and brainstem. There is considerable interest in whether PLS and ALS are the same disorder and, if so, factors that limit disease progression in PLS. We have been studying imaging biomarkers that may distinguish PLS and ALS or correspond to clinical measures of progression. In FY12 we completed analysis of the longitudinal arm of a study of structural MRI changes in brains of PLS and ALS patients with quantitative imaging techniques. In the cross-sectional arm of this study, we found that the pattern of white matter disruption in the corticospinal tract differed between ALS and PLS patients and from healthy age-matched controls. A consistent finding was that fractional anisotropy in the motor fibers of the corpus callosum was reduced in both PLS and ALS patients. Approximately half of the patients were able to complete follow-up testing a mean of 1 year (ALS) or 2 years (PLS) later. Based on the longitudinal data, we hypothesize that there is an evolution of imaging changes as upper motor neurons degenerate, with early disruption of affected white matter tracts. Postmortem study of two ALS patients showed accumulation of iron within microglia in the motor cortex, corresponding to a particular signal seen on MRI studies, most evident with 7Tesla imaging. The next step in this project is to identify imaging markers that change earlier in the course of the disease. Toward that end, in FY12 we began a new study in healthy volunteers to assess the reproducibility of imaging markers and physiological measures that are candidates for earlier detection of upper motor neuron dysfunction. In FY12, we completed our sites accrual target for the multicenter collaborative study with investigators at Columbia University to examine the role of oxidative stress in progression of motor neuron diseases. We completed the annual visits on previously enrolled patients, and are on target for completing the last visit in this study in 3 years.