Delineating Physiologic Mechanisms of Swallowing impairment and Decline in ALS

肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病，导致进行性肌肉 吞咽无力和功能障碍(吞咽困难)。吞咽困难导致营养不良、脱水、气管 吸入性疾病和肺炎占ALS死亡率的26%。目前的提议具有强烈的动机 由于基础知识差距导致ALS患者的临床护理不够理想 在渐进性肌萎缩侧索硬化症患者的进行性吞咽障碍的管理方面缺乏正式的实践指南。 这项工作的首要目标是通过以下方式改善临床实践：1)增加对 肌萎缩侧索硬化症吞咽困难的调控机制和进展及2)敏感生物标志物的鉴定 吞咽功能障碍构建临床吞咽困难危险指数工具。我们将表演连载器乐 100例ALS患者(球部和脊椎各50例)的吞咽功能评估 提供关键的纵向数据，以帮助建立第一个时程模型 肌萎缩侧索硬化症吞噬能力下降。需要这样的模型来指导最佳实践建议、最佳时机 干预措施，用于规划和设计未来的临床试验，并用于解释实验性治疗 效果。我们还将测试一组有希望的临床标志物的判别能力和临床实用价值。 吞咽下降，是务实的设计，易于传播到ALS临床环境。我们的长- 学期目标是改善ALS患者吞咽障碍的临床护理。拟议的研究将带来新的 对肌萎缩侧索硬化症患者不安全和低效吞咽的病理生理机制的见解 制定未来的干预策略，并导致更早和更准确地识别 吞咽障碍。肌萎缩侧索硬化症患者吞咽功能障碍的早期识别和更好的治疗策略 将导致口服摄入量、营养、肺部健康和生活质量的改善，并最终减少 在这一具有挑战性的人群中，吸入性肺炎与死亡率相关。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive muscle weakness and impairments in swallowing (dysphagia). Dysphagia leads to malnutrition, dehydration, tracheal aspiration and pneumonia that contribute to 26% of ALS mortality. The current proposal is strongly motivated by fundamental knowledge gaps that have contributed to sub-optimal clinical care of individuals with ALS and a lack of formal practice guidelines in the management of progressive swallowing impairment in ALS. The overarching goal of this work is to improve clinical practice by 1) increasing our understanding of governing mechanisms and progression of dysphagia in ALS and 2) identification of sensitive biomarkers of swallowing dysfunction to build a clinical dysphagia risk index tool. We will perform serial instrumental swallowing evaluations in 100 individuals with ALS (50 bulbar-onset, 50 spinal-onset) from disease diagnosis to feeding-tube dependence and provide critical longitudinal data to help establish the first time-course model of ALS swallowing decline. Such a model is needed to guide best practice recommendations, optimal timing of interventions, for planning and design of future clinical trials, and for interpretation of experimental treatment effects. We will also test the discriminant ability and clinical utility of a set of promising clinical markers of swallowing decline that are pragmatically designed for easy dissemination into ALS clinical settings. Our long- term goal is to improve clinical care of swallowing disorders in ALS. The proposed study will deliver new insights into the pathophysiologic mechanisms of unsafe and inefficient swallowing in ALS to drive the development of future intervention strategies and lead to earlier and more accurate identification of swallowing impairment. Earlier identification and better treatment strategies for swallowing dysfunction in ALS will lead to improvements in oral intake, nutrition, pulmonary health and quality of life and ultimately reduce aspiration pneumonia associated mortality in this challenging population.