Rutkove Seward B, Shah Priyansh, Hevenor Laura, Tiwari Gaurav, Patil Dhrumil, Mourey Tyler, Nagy Janice A, Nath Anjali K
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
Harvard Medical School, Boston, MA, 02115, USA.
Sci Rep. 2025 Oct 14;15(1):35810. doi: 10.1038/s41598-025-19830-w.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by loss of motor neurons and atrophy of skeletal muscle. Current FDA-approved drugs to treat ALS are only modestly effective at slowing the progression of the disease. Rodents have been the standard preclinical animal model for testing candidate ALS drugs; however, alternative animal models, including zebrafish, are being studied to accelerate therapeutic discovery. Here, we sought to advance a model of ALS in zebrafish with associated tools to serve as biomarkers of neuromuscular deterioration. Thus, we applied noninvasive, surface electrical impedance myography (EIM) methodology to SOD1 zebrafish and control animals to evaluate its ability to serve as an electrophysiological biomarker of disease in ALS zebrafish. Measurements were acquired from the caudal musculature of animals at 2 time points by applying an alternating current at 41 frequencies (1 kHz-1 MHz) and measuring the resulting voltages. At the first time point, SOD1 animals still exhibited normal body morphometrics, spinal cord motor neuron numbers, and skeletal muscle mass, while at the second time point, these SOD1 animals exhibited reduced weight, loss of motor neurons, type 1 and 2 myofiber atrophy, and decreased capacity for endurance swimming. We found that non-invasive surface EIM detected the alterations observed in diseased ALS zebrafish at the second time point. Specifically, EIM measurements (phase angle, reactance, and resistance) at 2 and 50 kHz were robust metrics that distinguished between healthy and diseased zebrafish. To assess the reliability of our EIM technique in healthy and ALS zebrafish, we calculated the intraclass correlation coefficient and conducted Bland-Altman analyses. The EIM methodology exhibited excellent reproducibility in both healthy and ALS zebrafish. In sum, these findings demonstrate that EIM is an effective tool to detect neuromuscular disease in symptomatic adult ALS zebrafish, and the approach described here offers a fast, noninvasive, and reliable platform that holds the potential to test candidate drug therapeutic efficacy.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征是运动神经元丧失和骨骼肌萎缩。目前美国食品药品监督管理局（FDA）批准的用于治疗ALS的药物在减缓疾病进展方面效果有限。啮齿动物一直是测试候选ALS药物的标准临床前动物模型；然而，包括斑马鱼在内的替代动物模型正在被研究，以加速治疗方法的发现。在此，我们试图改进一种斑马鱼ALS模型，并利用相关工具作为神经肌肉退化的生物标志物。因此，我们将非侵入性表面电阻抗肌电图（EIM）方法应用于SOD1斑马鱼和对照动物，以评估其作为ALS斑马鱼疾病电生理生物标志物的能力。通过在41个频率（1kHz - 1MHz）施加交流电并测量产生的电压，在两个时间点从动物的尾部肌肉组织获取测量数据。在第一个时间点，SOD1动物仍表现出正常的身体形态、脊髓运动神经元数量和骨骼肌质量，而在第二个时间点，这些SOD1动物体重减轻、运动神经元丧失、1型和2型肌纤维萎缩以及耐力游泳能力下降。我们发现，非侵入性表面EIM在第二个时间点检测到了患病ALS斑马鱼中观察到的变化。具体而言，在2kHz和50kHz时的EIM测量值（相位角、电抗和电阻）是区分健康斑马鱼和患病斑马鱼的可靠指标。为了评估我们的EIM技术在健康和ALS斑马鱼中的可靠性，我们计算了组内相关系数并进行了布兰德 - 奥特曼分析。EIM方法在健康和ALS斑马鱼中均表现出出色的可重复性。总之，这些发现表明EIM是检测有症状成年ALS斑马鱼神经肌肉疾病的有效工具，此处描述的方法提供了一个快速、非侵入性且可靠的平台，具有测试候选药物治疗效果的潜力。
