Innovative Biomarkers of Orofacial Dysfunction in Amyotrophic Lateral Sclerosis

 描述（由申请人提供）：延髓功能障碍不可避免地在肌萎缩侧索硬化症（ALS）的过程中发展，大约25%的患者在疾病发作时主要有延髓症状。除了表征可能导致相关口面无力的肌肉结构的演变之外，识别新的生物标志物对于开发和测试新型治疗药物至关重要。定量超声（QUS）和电阻抗肌电图（EIM）作为无痛、无创、便携的技术，可以满足客观测量延髓功能障碍的需要。在QUS中，声能被施加到感兴趣的肌肉;所得到的原始灰度或反向散射图像数据被转换为反映图像肌肉健康状况的单个值。类似地，在EIM中，将高频、低强度的交流电流施加于个体肌肉，并测量产生的电压。阻抗值反映肌肉结构的变化，包括纤维萎缩、炎症以及脂肪或结缔组织替代肌肉。当应用于肢体时，这两种用户友好的方法都可以提供神经肌肉疾病状态的敏感指标。虽然它们也被用于评估健康志愿者和原发性肌肉疾病患者的口面部肌肉，但它们尚未在ALS社区进行系统研究。我们假设定量超声检查（QUS）和电阻抗肌电图（EIM）测量可以提供一致的，临床上有意义的信息口面部肌肉健康的ALS。在对32名ALS患者和32名健康受试者进行的纵向自然史研究中，我们将通过三个目标来验证这一假设：1。评估ALS患者和非ALS患者口面QS和EIM的可靠性; 2）确定ALS患者18个月内口面肌肉的测量结果如何演变; 3）初步评估ALS患者口面QUS和EIM测量结果是否与功能测试结果相关。如果QUS和EIM确实像预期的那样提供了关于ALS状态的可靠、有意义的替代信息，它们可以用来使概念验证治疗试验更有效。此外，创新技术可以更广泛地应用于诊断和监测其他涉及延髓的中枢和周围神经系统疾病。

 DESCRIPTION (provided by applicant): Bulbar dysfunction inevitably develops in the course of amyotrophic lateral sclerosis (ALS), and approximately 25% of patients have predominantly bulbar symptoms at the time of disease onset. In addition to characterizing the evolution in muscle architecture that could underlie associated orofacial weakness, identifying new biomarkers is critical to the development and testing of novel therapeutic agents. As painless, non-invasive, portable technologies, quantitative ultrasonography (QUS) and electrical impedance myography (EIM) could meet the need for objective measures of bulbar dysfunction. In QUS, acoustic energy is applied to a muscle of interest; the resultant raw gray-scale or backscatter pictorial data are translated into a single value that reflects the health of the image muscle. Similarly, in EIM, a high-frequency, low-intensity alternating electrical current is applie to individual muscles, and the resulting voltages measured. Impedance values reflect changes in muscle architecture, including fiber atrophy, inflammation, and the replacement of muscle with fat or connective tissue. Both of these user-friendly methods can provide sensitive indicators of neuromuscular disease status when applied to the limbs. Although they have also been used to evaluate orofacial muscles in healthy volunteers and patients with primary muscle disorders, they have not yet been systematically studied in the ALS community. We hypothesize that quantitative ultrasonography (QUS) and electrical impedance myography (EIM) measurements can provide consistent, clinically meaningful information about orofacial muscle health in ALS. In a longitudinal natural history study of 32 individuals with ALS and 32 healthy subjects, we will test this hypothesis via three aims: 1.) To assess the reliability of orofacial QS and EIM in individuals with and without ALS; 2) To determine how the measurements of selected orofacial muscles in individuals with ALS evolve over an 18-month period; 3) To evaluate preliminarily whether orofacial QUS and EIM measurements in ALS patients correlate with results of functional tests. If QUS and EIM do provide reliable, meaningful surrogate information about ALS status as expected, they could be used to make proof-of- concept therapeutic trials more efficient. Furthermore, the innovative technologies could have broader application to the diagnosis and surveillance of other central and peripheral nervous system disorders with bulbar involvement.