Failure of Facilitation as a Biomarker in ALS

肌萎缩侧索硬化症(ALS)是一种致命的、进展迅速的神经运动病 以上运动神经元(UMN)和下运动神经元(LMN)变性为特征，影响 在美国，大约有6/10万人。预计全球肌萎缩侧索硬化症病例将增加69%(2015年∼222K达到 2040年∼为376k)。大多数肌萎缩侧索硬化症患者在确诊后3-5年内死亡，多达一年 第三个在第一年内死亡。然而，从ALS症状出现到接受诊断的时间 一般从8-15个月不等，进一步削弱个人的生活质量、计划能力、 以及在剩下的很短的时间内的治疗选择。寻找一个健壮可靠的 ALS患者皮质脊髓功能障碍的生物标志物对提高诊断率至关重要 在早期阶段确定、管理疾病异质性、跟踪疾病进展、改进 患者分层，并在临床试验中评估疗效。经颅磁刺激 (TMS)是评估UMN和LMN功能完整性的有效工具，通过测量 皮质脊髓驱动力的程度--一种称为易化的衡量标准。因为皮质脊髓系统 在肌萎缩侧索硬化症中，同样的工具可以用来量化促进失败的程度 一种疾病的指示物，为未来的研究使用它作为早期生物标志物铺平了道路 疾病发作。在拟议项目的目标1中，我们将在Health中测试两个关键假设 关于皮质脊髓系统中的易化和 行为。然后，在拟议项目的目标2中，我们将测试ALS患者是否表现出 与健康或患有肌萎缩侧索硬化症模似障碍的人相比，促进功能障碍 促通畅失败的程度是否与疾病的严重程度有关 UMN功能障碍的标准临床电池和神经生理学测试。这个项目将会有 通过促进我们对神经机制的理解，产生重大的科学和临床影响 用于促进自愿产生力量的运动，并提供初步的概念证明 易化失败是肌萎缩侧索硬化症患者UMN功能障碍和疾病进展的有用生物标志物。

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing, neuromotor disease characterized by degeneration of upper (UMN) and lower motor neurons (LMN) affecting ~6/100,000 people in the US. ALS cases are projected to rise 69% globally (∼222K in 2015 to ∼376K in 2040). Most individuals with ALS die within 3-5 years of diagnosis, and as many as one third die within the first year. Yet, the time from onset of ALS symptoms to receive a diagnosis generally ranges from 8-15 months further crippling an individual’s quality of life, ability to plan, and treatment options in the already short time that remains. Finding a robust and reliable biomarker of corticospinal dysfunction in ALS is of paramount importance to improve diagnostic certainty at earlier stages, manage disease heterogeneity, track disease progression, improve patient stratification, and evaluate efficacy in clinical trials. Transcranial magnetic stimulation (TMS) is an effective tool to assess the functional integrity of UMN and LMN by measuring the degree of corticospinal drive – a measure called facilitation. Because the corticospinal system degenerates in ALS, the same tool can be used to quantify the degree of Failure of Facilitation as an indicator of the disease, paving the way for future studies to use this as an early biomarker of disease onset. In Aim 1 of the proposed project, we will test two key hypotheses in healthy individuals about the underlying relationship between facilitation in the corticospinal system and behavior. Then in Aim 2 of the proposed project, we will test whether individuals with ALS exhibit Failure of Facilitation, compared to those who are healthy or have an ALS mimic disorder, and whether the degree of Failure of Facilitation relates to the severity of the disease assessed with standard clinical batteries and neurophysiological tests of UMN dysfunction. This project will have significant scientific and clinical impact by advancing our understanding of the neural mechanisms for motor facilitation for voluntary force generation and providing an initial proof of concept that failure of facilitation is a useful biomarker of UMN dysfunction and disease progression in ALS.