Intermuscular coherence: A novel biomarker for upper motor neuron dysfunction in ALS

项目概要/摘要 肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种由神经元死亡引起的致死性神经退行性疾病 大脑和脊髓的运动系统会导致全身逐渐虚弱， 通常在症状出现后3年内死于呼吸衰竭。治疗开始和药物 发展受到阻碍，部分原因是缺乏该疾病的定量生物标志物。拟议 项目将进行多中心研究，以验证和进一步表征潜在的生物标志物， 肌萎缩侧索硬化症（ALS），又称肌间连贯性（IMC）。IMC测量两块肌肉之间活动的相关性 并且代表从大脑和脊髓中的运动神经元到肌肉的共享输入。体内研究 在非人类灵长类动物和人类中的研究表明，在15-40 Hz（β-至-γ频率）范围内的IMC 代表从上运动神经元到肌肉对的输入。当大脑中的运动神经元受损时， 在肌萎缩侧索硬化中，IMC在βγ频率范围内降低。在一份初步报告中，我们发现， 与年龄和性别匹配的对照组相比，ALS患者在βγ范围内的IMC较低。因为 IMC的测量是快速的、非侵入性的、无痛的，并且仅需要标准临床中发现的设备。 神经生理学实验室，该方法，如果验证，将是一个重要的生物标志物ALS。 拟定的是临床环境中IMC的多中心验证研究。首先，准确性，灵敏度， 并且将在到神经科诊所进行初始诊断的患者中确定生物标志物的特异性。 当怀疑ALS时进行评估。为了提供最大的特异性，IMC值的分布将 在几个人口统计学亚组的神经典型受试者中进行表征。最后，IMC将 在ALS患者中随时间监测，以确定IMC如何随ALS疾病进展而变化。 初步数据表明，IMC可能是诊断ALS的有用生物标志物， ALS从ALS-模拟疾病，它可以用来客观地监测ALS的进展， 时间在这种方法能够应用于临床之前，一项多中心研究来测试这些初步发现的有效性是很重要的。 这将有助于加快诊断速度，并为患者提供更快的ALS治疗。

Project Summary/Abstract Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disease caused by neuronal death in the motor system, both in the brain and spinal cord. It results in progressive weakness throughout the body, with death typically from respiratory failure within 3 years of symptom onset. Therapy initiation and drug development are hindered, in part, by the lack of quantitative biomarkers for the disease. In the proposed project a multi-center study will be carried out to validate and further characterize a potential biomarker for ALS, known as intermuscular coherence (IMC). IMC measures the correlation of activity between two muscles and represents the shared input to the muscles from motor neurons in the brain and spinal cord. In vivo studies in both non-human primates and humans suggest that IMC in the range of 15-40 Hz (β-to-γ frequencies) represents input to muscle pairs from upper motor neurons. When motor neurons in the brain are damaged, as happens in ALS, IMC decreases in the βγ frequency range. In a preliminary report we showed that patients with ALS have lower IMC in the βγ range than do age- and sex-matched control subjects. Because the measurement of IMC is quick, non-invasive, painless, and requires only equipment found in standard clinical neurophysiology labs, the method, if validated, would be an important biomarker for ALS. Proposed is a multi-center validation study of IMC in the clinical environment. First, the accuracy, sensitivity, and specificity of the biomarker will be determined in patients who present to neurology clinic for an initial evaluation when ALS is suspected. In order to provide the most specificity, the distribution of IMC values will be characterized in neurotypical subjects across several demographic subgroups. Finally, IMC will be monitored over time in patients with ALS to determine how IMC changes with ALS disease progression. Preliminary data suggest that IMC could be a useful biomarker for diagnosing ALS, allowing differentiation of ALS from ALS-mimic disorders, and that it can be used to objectively monitor the progression of ALS over time. A multi-center study to test the validity of these preliminary findings is important before this method can be implemented to speed diagnosis and provide faster access to treatments of ALS for patients.