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.

肌萎缩性横向硬化症（ALS）是致命的，迅速发展的神经运动疾病 具有影响的上（UMN）和下运动神经元（LMN）的变性的特征 在美国〜6/100,000人。 ALS案例预计在全球范围内将上涨69％（2015年约222K至 2040年约376K）。大多数患有ALS的人在诊断的3 - 5年内死亡，多达一个人 第一年内第三次死亡。然而，从ALS症状发作到接受诊断的时间 通常，从8-15个月的范围内剪裁个人的生活质量，计划的能力， 和治疗选择在已经存在的短时间内。找到坚固而可靠的 ALS中皮质脊髓功能障碍的生物标志物对于改善诊断至关重要 较早阶段的确定性，管理疾病异质性，跟踪疾病进展，改善 患者分层并评估临床试验中的有效性。经颅磁刺激 （TMS）是通过测量UMN和LMN评估功能完整性的有效工具 皮质脊髓驱动的程度 - 一种称为设施的措施。因为皮质脊髓系统 在ALS中退化，可以使用相同的工具来量化促进程度 该疾病的指标，为将来的研究铺平了道路，将其用作早期的生物标志物 疾病发作。在拟议项目的目标1中，我们将检验健康中的两个关键假设 关于皮质脊髓系统中促进和促进之间的基本关系的个人 行为。然后在拟议项目的目标2中，我们将测试患有ALS的个人是否展示 与健康或患有ALS模拟障碍的人相比，促进的失败， 促进程度是否与评估的疾病严重程度有关 UMN功能障碍的标准临床电池和神经生理测试。这个项目将有 通过促进我们对神经机制的理解，可以取得重大科学和临床影响 用于自愿产生的运动设施，并提供最初的概念证明 促进失败是ALS中UMN功能障碍和疾病进展的有用生物标志物。