Failure of Facilitation as a Biomarker in ALS

促进作为 ALS 生物标志物的失败

• 批准号: 10742288
• 负责人: Oscar Soto
• 金额: $ 23.47万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742288
• 关键词: ALS patients; Affect; Amyotrophic Lateral Sclerosis; Anatomy; Animal Model; Behavior; Biological Markers; Cessation of life; Clinical; Clinical Trials; Clinical assessments; Code; Data; Data Collection; Dependence; Diagnosis; Diagnostic; Disease; Disease Management; Disease Progression; Early Diagnosis; Electrodes; Evaluation; Exhibits; Failure; Functional disorder; Future; Generations; Hand; Heterogeneity; Human; Impairment; Individual; Investigation; Isometric Contraction; Measures; Motor; Motor Evoked Potentials; Motor Neurons; Muscle; Neurodegenerative Disorders; Neuronal Dysfunction; Onset of illness; Output; Pathology; Pattern; Persons; Physiological; Population; Process; Production; Quality of life; Ramp; Research; Rest; Severity of illness; Signal Transduction; Speed; Stimulus; Surface; Symptoms; System; Testing; Time; Transcranial magnetic stimulation; Trees; Vertebral column; awake; density; disease heterogeneity; early detection biomarkers; efficacy evaluation; grasp; improved; innovation; motor neuron function; neural; neuromechanism; neurophysiology; novel; novel therapeutics; patient stratification; rate of change; recruit; response; tool

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.

肌萎缩侧索硬化症（ALS）是一种致命的、进展迅速的神经运动疾病 特征在于上运动神经元（UMN）和下运动神经元（LMN）的变性， 在美国，约为每10万人中的6人。ALS病例预计将在全球范围内增加69%（2015年为222 K， 2040年的376 K）。大多数ALS患者在确诊后3-5年内死亡， 第三个在第一年内死亡。然而，从ALS症状发作到接受诊断的时间 一般为8-15个月，进一步损害个人的生活质量，计划能力， 以及治疗方案的选择。找到一个强大而可靠的 ALS中皮质脊髓功能障碍生物标志物对于改善诊断至关重要 早期阶段的确定性，管理疾病异质性，跟踪疾病进展，改善 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， 皮质脊髓驱动的程度-一种称为促进的措施。因为皮质脊髓系统 ALS中的退化，相同的工具可用于量化促进失败的程度， 这是疾病的一个指标，为未来的研究铺平了道路，将其用作疾病的早期生物标志物。 发病在拟议项目的目标1中，我们将测试健康的两个关键假设， 个体之间的潜在关系促进皮质脊髓系统和 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ALS模拟障碍的人相比，易化失败， 易化失败的程度是否与疾病的严重程度相关， 标准临床电池和UMN功能障碍的神经生理学测试。该项目将有 通过推进我们对神经机制的理解， 为自发力量生成提供运动促进，并提供初步的概念证明， 易化失败是ALS中UMN功能障碍和疾病进展的有用生物标志物。