Bulbar Motor Deterioration in ALS

描述（由申请人提供）：本申请的目的是提高对肌萎缩侧索硬化症（ALS，也称为“Lou Gehrig病”）的延髓（头部）恶化的理解，肌萎缩侧索硬化症是一种由运动皮层、脑干和脊髓中的运动神经元变性引起的致命神经系统疾病。尽管延髓恶化（包括言语和吞咽障碍）对ALS患者的生存和生活质量造成了毁灭性的后果，但与ALS脊柱受累的研究相比，只有少数研究对ALS延髓症状进行了研究。该应用程序通过纵向研究延髓衰退并全面使用已建立和创新的方法记录，测量和分析言语行为来应对临床和科学知识的这一差距。每三个月将对100名ALS患者进行研究，为期两年。每个参与者的语音恶化的过程将使用延髓性能的多个测量来纵向跟踪，其中每个测量被广泛地分类为全局的代表性语音性能（即，语音系统）级别或子系统级别。语音子系统测量将代表已知支持语音产生的多个延髓区域的功能完整性，包括呼吸、发声、共振和发音子系统。每个语音系统和子系统水平的下降模式将用于实现四个具体目标：（1）确定在疾病的早期阶段言语子系统表现的速率是否准确地预测了长期的下降速率，（2）确定言语子系统测量是否准确地预测了言语下降的开始和随后的口头交流的丧失，（3）确定延髓恶化的发生和速率的敏感定量指标，和（4）确定延髓ALS的几种假定亚型。在短期内，识别延髓受累的敏感指标将提高早期检测和预后的准确性，并解决未来实验性药物试验中对客观结局指标的迫切需求。研究结果还将提供急需的信息，语音子系统恶化对语音清晰度的影响。从长远来看，更精确的内表型（即，从这项研究中获得的延髓受累的遗传特征（遗传特征）可能会加强未来的努力，以确定ALS的遗传位点，并提高疾病的诊断和治疗特异性。 公共卫生相关性：ALS或Lou Gehrig病是全球最常见和最具破坏性的神经肌肉疾病之一，影响所有种族和民族背景的女性和男性。语言丧失最终将发生在大多数ALS患者中，无论疾病是在头部/颈部区域还是在脊柱中开始，并且是疾病的最衰弱的结果之一。这项针对ALS患者的研究解决了这一人群中三个被广泛认可的需求：早期检测，提高预测准确性，以及提高对疾病进展中个体差异的理解。

DESCRIPTION (provided by applicant): The goal of this application is to improve the understanding of bulbar (head) deterioration in Amyotrophic lateral sclerosis (ALS, also known as "Lou Gehrig's disease"), which is a fatal neurologic disease caused by degeneration of the motor neurons in the motor cortex, brainstem, and spinal cord. Despite the devastating consequences of bulbar deterioration, including impaired speech and swallowing, on the survival and quality of life of individuals with ALS, only a few studies have been conducted on ALS bulbar symptoms compared to research on ALS spinal involvement. This application responds to this gap in clinical and scientific knowledge by studying bulbar decline longitudinally and comprehensively using established and innovative methods for recording, measuring, and analyzing speech behaviors. One hundred persons with ALS will be studied every three months for a period of two years. The course of deterioration in each participant's speech will be tracked longitudinally using multiple measures of bulbar performance, with each measure broadly classified as either a representing speech performance at the global (i.e., speech system) level or subsystem level. The speech subsystem measures will represent the functional integrity of multiple bulbar regions known to support speech production, including the respiratory, phonatory, resonatory, and articulatory subsystems. Patterns of decline at each speech system and subsystem level will be used to address four specific aims: (1) determine if the rate of speech subsystem performance in the early stage of the disease accurately predicts the long-term rate of decline, (2) determine if speech subsystem measures accurately predict the onset of speech decline and the subsequent loss of oral communication, (3) identify sensitive quantitative indicators of the onset and rate of bulbar deterioration, and (4) identify several putative subtypes of bulbar ALS. In the short term, the identification of sensitive measures of bulbar involvement will improve early detection and prognostic accuracy and address the critical need for objective outcome measures in future experimental drug trials. The findings will also provide much needed information regarding the implications of speech subsystem deterioration on speech intelligibility. In the long term, the more refined endophenotype (i.e., hereditary characteristic) of bulbar involvement obtained from this research may strengthen future efforts at identifying the genetic loci of ALS and improving diagnostic and treatment specificity of the disease. PUBLIC HEALTH RELEVANCE: ALS, or Lou Gehrig's disease, is one of the most common and devastating neuromuscular diseases worldwide, affecting both women and men of all races and ethnic backgrounds. Loss of speech will eventually occur in most individuals with ALS whether the disease starts in the head/neck region or in the spine and is among the most debilitating outcomes of the disease. This research with ALS patients addresses three widely recognized needs in this population: early detection, improved prediction accuracy, and improved understanding of individual variation in the progression of the disease.