Spasticity and Upper Motor Neuron Disorders

痉挛和上运动神经元疾病

• 批准号: 8940053
• 负责人: Mary Kay Floeter
• 金额: $ 123.82万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8940053
• 关键词: Accounting; Affect; Aging; Amyotrophic Lateral Sclerosis; Biological Markers; Brain; C9ORF72; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Markers; Clinical Research; Clinical Trials; Collaborations; Detection; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dysmetria; Early Diagnosis; Endogenous Retroviruses; Enrollment; Familial Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Future; Genes; Goals; Image; Incidence; Individual; Institutes; Intramural Research Program; Manuscripts; Measures; Monitor; Motor; Motor Cortex; Motor Neuron Disease; Motor Neurons; Movement; Multimodal Imaging; Mutation; Myography; National Institute of Neurological Disorders and Stroke; Natural History; Neurodegenerative Disorders; Neurons; Oxidative Stress; Participant; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Physiology; Plasma Cells; Primary Lateral Sclerosis; Process; Property; Publishing; Research; Research Personnel; Resolution; Rest; Role; Serum; Signal Transduction; Site; Spinal; Symptoms; Syndrome; Transcranial magnetic stimulation; Transcriptase; United States; Universities; Viral; Work; cognitive neuroscience; cohort; exome sequencing; follow-up; indexing; nervous system infection; progression marker; protein misfolding; response; showing emotion; treatment effect

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.

原发性侧索硬化症 (PLS)、肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是相关疾病，被认为代表同一神经退行性疾病谱的不同表型。病理学研究表明，ALS 和部分 FTD 患者的大脑神经元包涵体中存在常见的错误折叠蛋白，其中包括由基因 C9ORF72 的扩展突变引起的 ALSFTD，该突变已被发现在美国占家族性 ALS 和 FTD 的很大一部分。最近的一个假设是，变性可以通过轴突束或错误折叠蛋白质的局部扩散传播。如果属实，PLS 可能代表一种特殊情况，其中退行性过程未能在很大程度上蔓延到运动皮层之外。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。 该项目的首要目标是了解运动神经元疾病谱中疾病之间的关系。 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 患者纵向队列中症状传播模式的图表回顾分析中，我们发现了轴突和邻近变性传播的证据。图表审查还显示，PLS 患者的假性延髓情感 (PBA) 发生率高于散发性 ALS 患者。无论 ALS 或 PLS 诊断如何，PBA 都与皮质桥小脑回路中轴突通路的弥散张量成像特性的改变相关，这与 PBA 可被视为情绪表达障碍的观点一致。此外，去年与前认知神经科学部门合作，继续开展工作，比较 FTD、ALS、PLS 和皮质基底节综合征患者之间的弥散张量成像测量结果。 该项目的第二个目标是确定可靠的、最好是非侵入性的标记物，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 财年启动了一项重大新项目，前瞻性地记录 C9ORF72 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，我们正在研究有症状的患者和症状前携带者的生物标志物。目标之一是识别可以在未来临床试验中提供早期反应信号的生物标志物。我们的研究单位正在协调这项研究的临床部分并评估影像和生理生物标志物。多模态成像电池包括静息态功能 MRI、扩散张量成像和高分辨率 T1 成像。生理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指数测量。合作研究人员正在评估脊髓液、血浆和细胞衍生标记物。 2014 财年注册了 14 名参与者。我们还对 20 名健康对照者进行了 2 个疗程的相同多模式成像电池测试，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，我们还在 2014 财年继续参与了两项合作研究。我们继续参与哥伦比亚大学组织的一项合作研究，以研究氧化应激在运动神经元疾病进展中的作用。我们将在2015年初完成对我们站点所有患者的3年随访。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 神经系统感染部门合作寻找内源性逆转录病毒的证据，但在 30 名 PLS 患者的血清中没有发现转录酶活性，病毒序列分析仍在继续。