Innovative Biomarkers of Orofacial Dysfunction in Amyotrophic Lateral Sclerosis

 描述(申请人提供)：肌萎缩侧索硬化症(ALS)过程中不可避免地会出现延髓功能障碍，大约25%的患者在发病时以延髓症状为主。除了表征可能导致相关口面部无力的肌肉结构演变外，识别新的生物标记物对于开发和测试新的治疗剂至关重要。定量超声(QUS)和电阻抗肌图(EIM)作为一种无痛、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，声能被应用于感兴趣的肌肉；由此产生的原始灰度级或后向散射图像数据被转换为反映图像肌肉健康的单一值。同样，在EIM中，将高频、低强度的交流电施加到单独的肌肉上，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、炎症和肌肉被脂肪或结缔组织取代。当应用于四肢时，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。尽管它们也被用于评估健康志愿者和原发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(QUS)和电阻抗肌图(EIM)测量可以为ALS患者的口面部肌肉健康提供一致的、有临床意义的信息。在一项对32名ALS患者和32名健康受试者进行的纵向自然历史研究中，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患者口腔QS和EIM的可靠性；2)确定ALS患者口腔面部肌肉的测量结果在18个月内如何演变；3)初步评估ALS患者的口腔QS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，它们可以用于提高概念验证治疗试验的效率。此外，这些创新技术可以更广泛地应用于其他中枢神经系统和周围神经系统疾病的诊断和监测。

 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.