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性侧索硬化症（ALS，也称为“Lou Gehrig’s病”）的球（头）恶化的认识，肌萎缩性侧索硬化症是一种致命的神经系统疾病，由运动皮层、脑干和脊髓中的运动神经元变性引起。尽管球恶化会对ALS患者的生存和生活质量造成毁灭性的后果，包括言语和吞咽障碍，但与ALS脊髓受损伤的研究相比，针对ALS球症状的研究很少。该应用程序通过使用已建立的创新方法来记录、测量和分析言语行为，对球衰退进行纵向和全面的研究，从而弥补了临床和科学知识上的这一空白。100名ALS患者将在两年内每三个月接受一次研究。每个参与者的语音恶化过程将使用多个球性能指标进行纵向跟踪，每个指标大致分为全局（即语音系统）水平或子系统水平的代表语音性能。语音子系统测量将代表已知支持语音产生的多个球区域的功能完整性，包括呼吸、发音、共振和发音子系统。每个语音系统和子系统级别的下降模式将用于解决四个具体目标：(1)确定疾病早期言语子系统表现的速度是否能准确预测长期的下降速度；(2)确定言语子系统的测量是否能准确预测言语能力下降的开始和随后的口头交流的丧失；(3)确定球退化的开始和速度的敏感定量指标；(4)确定几种假定的球性ALS亚型。在短期内，确定球受累的敏感测量将提高早期发现和预后准确性，并解决未来实验性药物试验中对客观结果测量的关键需求。该研究结果还将为语音子系统退化对语音可理解性的影响提供急需的信息。从长远来看，从这项研究中获得的更精细的球受累的内表型（即遗传特征）可能会加强未来识别ALS遗传位点的努力，提高疾病的诊断和治疗特异性。

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.