Spasticity and Upper Motor Neuron Disorders

原发性侧索硬化症（PLS）、肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）是被认为代表相同神经退行性疾病谱上的不同表型的相关疾病。病理学研究显示，ALS和一部分FTD患者脑中神经元内含物中存在常见的错误折叠蛋白，包括由基因C9 ORF 72扩增突变引起的ALSFTD，该基因C9 ORF 72被发现是美国家族性ALS和FTD的重要原因。最近的一个假说是，变性可以通过轴突束或错误折叠的蛋白质的局部扩散传播。如果是真的，PLS可能代表一种例外的情况，其中退行性过程未能扩散到运动皮层以外的显着程度。了解限制PLS患者扩散的因素可能为阻止变性进展的机制提供线索。 该项目的第一个目的是了解运动神经元疾病谱中疾病之间的关系。在2014财年，我们完成并发表了两项关于PLS和散发性ALS患者表型特征的研究。在对PLS患者纵向队列的症状传播模式的图表回顾分析中，我们发现了变性轴突和连续传播的证据。图表回顾还显示，PLS患者比散发性ALS患者有更高的假性延髓情感（PBA）发生率。无论ALS或PLS诊断，PBA与皮质-桥脑-小脑回路中轴突通路的扩散张量成像特性的改变相关，这与PBA可被视为情绪表达的测量障碍的提议一致。此外，在过去一年中，继续与前认知神经科学部分合作，比较FTD、ALS、PLS和皮质基底综合征患者之间的弥散张量成像测量。 该项目的第二个目的是确定可靠的，最好是非侵入性的标志物，用于检测和测量运动神经元疾病的进展，特别是亚临床进展。我们在2014财年开始了一项重大的新项目，以前瞻性记录C9 ORF 72相关家族性ALS-FTD的自然史。在这个与国家老龄化研究所和约翰霍普金斯大学的研究人员合作的项目中，我们正在检查有症状的患者和症状前携带者的生物标志物。一个目标是确定生物标志物，可以在未来的临床试验中提供早期反应信号。我们的研究单位正在协调本研究的临床部分，并评估成像和生理生物标志物。多模态成像组合包括静息态功能MRI、扩散张量成像和高分辨率T1成像。生理学候选生物标志物包括经颅磁刺激、电阻抗肌电图和运动单位数量指数测量。合作研究人员正在评估脊髓液，血浆和细胞衍生的标志物。FY 14入组了14名参与者。我们还对20名健康对照组进行了相同的多模式成像组合，进行了2次治疗，以确定成像标记物的可重复性。 除了该项目的两个主要目标外，我们在2014财年继续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。我们将在2015年初完成对所有患者的3年随访，从我们的site.in开始。哥伦比亚大学已经对41名PLS患者的基线特征进行了初步分析，包括外显子组测序，手稿正在起草中。与NINDS神经系统感染科合作寻找内源性逆转录病毒的证据，在30名PLS患者的血清中没有发现转录酶活性，病毒序列的分析仍在继续。

Primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are related disorders that are thought to represent different phenotypes on the same spectrum of neurodegenerative disorders. Pathological studies have shown common misfolded proteins in neuronal inclusions in brains of ALS and a subset of FTD patients, including in ALSFTD caused by an expansion mutation in the gene C9ORF72 that has been found to account for a significant portion of familial ALS and FTD in the United States. A recent hypothesis is that degeneration can be transmitted through axonal tracts or by local spread of misfolded proteins. If true, PLS may represent an exceptional condition in which the degenerative process fails to spread to a significant extent beyond the motor cortex. Understanding factors that limit spread in PLS patients may provide clues to mechanisms for halting progression of degeneration. The first aim of this project is to understand the relationship between disorders on the motor neuron disease spectrum. During FY14, we completed and published two studies of phenotypic characteristics of PLS and sporadic ALS patients. In a chart review analysis of the pattern of symptom spread in our longitudinal cohort of PLS patients, we found evidence for both axonal and contiguous spread of degeneration. A chart review also revealed that PLS patients had a higher incidence of pseudobulbar affect (PBA) than sporadic ALS patients. Regardless of ALS or PLS diagnosis, PBA was associated with alterations in diffusion tensor imaging properties of axonal pathways in the cortico-ponto-cerebellar circuit, consistent with the proposal that PBA can be viewed as a dysmetria of emotional expression. Additionally, work continued in the past year to compare diffusion tensor imaging measures between FTD, ALS, PLS and corticobasal syndrome patients in collaboration with the former Cognitive Neuroscience section. A second aim of the project is to identify reliable, preferably non-invasive markers for detection and measuring progression, particularly subclinical progression, in motor neuron disorders. We began a major new project in FY14 to prospectively document the natural history of C9ORF72- related familial ALS-FTD. In this collaborative project with the National Institute of Aging and investigators at the Johns Hopkins University, we are examining proposed biomarkers in symptomatic patients and presymptomatic carriers. One goal is to identify biomarkers that may provide an early signal of response in future clinical trials. Our research unit is coordinating the clinical component of this study and assessing imaging and physiological biomarkers. The multimodal imaging battery includes resting-state functional MRI, diffusion tensor imaging, and high resolution T1 imaging. Physiological candidate biomarkers include transcranial magnetic stimulation, electroimpedance myography, and the motor unit number index measure. Collaborating investigators are assessing spinal fluid, plasma, and cell-derived markers. Fourteen participants were enrolled in FY14. We have also carried out the same multimodal imaging battery on a cohort of 20 healthy controls for 2 sessions to determine the repeatability of imaging markers. In addition to the two primary aims of this project, we continued participation in two collaborative studies in FY14. 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. We will complete the 3-year follow-up on all patients from our site.in early 2015. Columbia University has carried out a preliminary analysis of the baseline characteristics of the 41 PLS patients, including exome sequencing, and the manuscript is in draft. The collaboration with the NINDS Section on Infections of the Nervous System to look for evidence of endogenous retroviruses did not find transcriptase activity in the serum of 30 PLS patients, and analysis for viral sequences continues.