Spasticity and Upper Motor Neuron Disorders

我们目前的研究重点是运动神经元疾病患者，特别是影响皮质脊髓（上）运动神经元的疾病，如原发性侧索硬化症（PLS）。已经提出PLS、肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是代表相同神经退行性疾病谱上的不同表型的相关疾病。其他研究人员的病理学研究发现，ALS和FTD患者的大脑神经元内含物中存在相同的蛋白质，在遗传学研究中，最近发现基因C9ORF72的突变占家族性ALS和FTD的很大一部分。据推测，PLS是这些疾病的一种变体，其中退行性过程在很大程度上仅限于运动皮质，未能进展到额颞叶皮质和脊髓。如果这一假设是正确的，了解是什么限制了PLS患者的疾病程度，可能会为阻止神经变性进展的机制提供线索。 本项目的第一个目的是了解PLS和运动神经元疾病谱上其他疾病之间的关系。为了确定临床表型是否是经历变性的大脑区域的功能，过去几年的工作利用了定量磁共振成像（MRI）。在2013财年，我们完成并发表了一项对ALS和PLS患者与认知能力相关的白色物质束的分析，使用基于半自动化图谱的分析来比较11个白色物质关联束的弥散张量成像（DTI）测量。在上级纵束，扣带，和胼胝体的部分扩散措施的变化被认为是与特定的执行功能和记忆测试的性能。性能是不相关的灰质体积的焦点变化，突出了正确的时间编码的信息在认知网络的轴突束的完整性的重要性。与NINDS认知神经科学部分合作，我们现在正在扩展这项工作，包括与采用相同方法研究的FTD患者进行比较，目的是确定区分不同诊断和临床表现患者的成像指标。我们也开始研究是否其他非运动表现，如假性延髓影响，可以解释的改变，特别是白色物质网络。为了研究疾病是否在PLS中开始并通过轴突网络传播或传播到大脑和脊髓的相邻区域，我们开始对在我们诊所随访的PLS患者队列进行图表审查，以记录症状如何传播。 该项目的第二个目的是确定可靠的，非侵入性的标记物，用于检测和测量运动神经元疾病中大脑参与的进展。在2013财年，我们发表了一项ALS和PLS患者的纵向MRI研究，发现DTI指标的变化以及皮质厚度和萎缩进展的测量在不同的时间尺度上。我们假设MRI结果代表了一系列结构变化，这些变化伴随着轴突断裂和清除，随后是可测量的皮质灰质变薄和萎缩。ALS和PLS患者组之间的差异可能代表同一过程的早期和晚期，PLS患者的结构重塑时间较长。白色物质DTI测量的变化发生相对较早。我们目前正在研究功能性MRI静息态网络是否显示运动神经元疾病的改变，并将评估功能性变化是否可以比弥散测量的变化更早地检测到。 迄今为止，大多数运动神经元疾病的影像学研究描述了患者组和对照组之间的差异。这是一个挑战，以开发成像措施，在个别患者的上运动神经元的完整性的状态的指标。作为第一步，我们目前正在健康对照队列中重复获得多模态成像，以确定候选成像标记物的会话间变异性。这些数据将用于选择最具信息性的技术，用于未来前瞻性评估运动神经元疾病患者。 除了该项目的两个主要目标外，我们还在2013财年参与了两项合作研究。我们继续作为一个合作研究的网站，以检查氧化应激在运动神经元疾病的进展中的作用，由哥伦比亚大学组织。本研究在我们的研究中心全部入组，所有患者均完成了年度访视。两名患者完成了整个研究，我们的研究中心有望在两年内完成。此外，我们开始与NINDS神经系统感染科进行新的合作，以寻找运动神经元疾病患者中内源性逆转录病毒的证据。 最后，与NIA神经肌肉疾病科合作，我们为C9ORF72基因突变的症状和症状前携带者的自然史和生物标志物研究奠定了基础。人体受试者研究方案现已获得IRB批准，我们预计将在2013财年结束前入组首例患者。

Our current research focuses on patients with motor neuron disorders, particularly disorders affecting corticospinal (upper) motor neurons such as primary lateral sclerosis (PLS). It has been proposed that PLS, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are related disorders that represent different phenotypes on the same spectrum of neurodegenerative disorders. Pathological studies by other investigators found the same proteins within neuronal inclusions in brains of ALS and a subset of FTD patients, and in genetic studies, a mutation in the gene C9ORF72 was recently found to account for a significant portion of familial ALS and FTD. It has been hypothesized that PLS is a variant of these disorders in which the degenerative process remains largely limited to the motor cortex, failing to progress to frontotemporal cortex and the spinal cord. If this hypothesis is correct, understanding what limits the extent of disease in PLS patients may provide clues to mechanisms for halting progression of neurodegeneration. The first aim of this project is to understand the relationship between PLS and other disorders on the motor neuron disease spectrum. To determine whether clinical phenotypes are a function of the brain regions undergoing degeneration, work over the last few years has utilized quantitative magnetic resonance imaging (MRI). During FY13, we completed and published an analysis of white matter tracts associated with cognitive performance in ALS and PLS patients, using a semi-automated atlas-based analysis to compare diffusion tensor imaging (DTI) measures in eleven white matter association tracts. Changes in diffusivity measures in the superior longitudinal fasciculus, cingulum, and portions of the corpus callosum were found to be associated with performance on particular executive function and memory tests. Performance was not related to focal changes in grey matter volume, highlighting the importance of the integrity of axonal tracts for proper temporal encoding of information in cognitive networks. In collaboration with the NINDS Cognitive Neuroscience section, we are now extending that work to include comparisons with FTD patients studied with the same methods, with a goal of identifying imaging measures that discriminate between patients with different diagnoses and clinical presentations. We have also begun examining whether other non-motor manifestations, such as pseudobulbar affect, can be explained by alterations in particular white matter networks. To examine the question whether disease begins focally in PLS and spreads thorough axonal networks or by propagation to adjacent areas of the brain and spinal cord, we began a chart review of the cohort of PLS patients followed in our clinic to document how symptoms spread. A second aim of the project is to identify reliable, non-invasive markers for detection and measuring progression of brain involvement in motor neuron disorders. During FY13, we published a longitudinal MRI study in ALS and PLS patients that found that changes in DTI metrics and measures of cortical thickness and atrophy progress over different time scales. We hypothesized that MRI findings represent a sequence of structural changes that occur with axonal breakdown and clearance, followed by measureable thinning and atrophy of cortical grey matter. Differences between ALS and PLS patient groups may represent early and late stages of the same process, with longer time for structural remodeling to evolve in PLS patients. Changes in white matter DTI measures occurred relatively early. We are currently looking to see whether functional MRI resting state networks show alterations in motor neuron disease, and will be assessing whether functional changes can be detected earlier than changes in diffusion measures. To date, most imaging studies in motor neuron disease describe differences between groups of patients and controls. It is a challenge to develop imaging measures that are indicators of the state of upper motor neuron integrity in individual patients. As a first step, we are currently obtaining multi-modal imaging in repeated sessions in a cohort of healthy controls in order to determine the intersession variability of candidate imaging markers. These data will be used to select the most informative techniques for prospectively assessing patients with motor neuron disorders in the future. In addition to the two primary aims of this project, we participated in two collaborative studies in FY13. We continued as a site in a collaborative study to examine the role of oxidative stress in progression of motor neuron diseases organized by Columbia University. The study was fully enrolled at our site and all patients completed their annual visits. Two patients completed the entire study, and our site is on track for completion in two years. Additionally, we began a new collaboration with the NINDS Section on Infections of the Nervous System to look for evidence of endogenous retroviruses in motor neuron disease patients. Lastly, in collaboration with the NIA Neuromuscular Diseases Section, we have laid the groundwork for a natural history and biomarker study of symptomatic and presymptomatic carriers of the C9ORF72 gene mutation. The human subject research protocol has now been approved by the IRB and we anticipate enrollment of the first patient before the end of FY13.