Importance Degeneration of neuromuscular junctions and axons is considered an important aspect of the pathomechanism of amyotrophic lateral sclerosis (ALS). However, a mechanism including the role of transactive response DNA-binding protein 43 (TDP-43) in axons has not been pathologically clarified. Objective To identify and characterize the histopathology of peripheral axons in the skeletal muscle of patients with ALS. Design, Setting, and Participants This study comprised 2 parts: a postmortem case-control study and a retrospective population-based cohort study with a minimum of 1 year of follow-up. Patients in the cohort study were enrolled from January 1, 2004, to September 30, 2019. The postmortem study included patients with sporadic ALS (SALS) with TDP-43 pathology and control patients with non-ALS disease. The cohort study enrolled patients without a family history of ALS or other neuromuscular disease and those not diagnosed with a muscle disease at biopsy. Patients were excluded if their clinical records were not screened after biopsy, if they were diagnosed with a muscular disease, and if they were harboring known causative genes of ALS. Data were collected between September 2019 and June 2021 and analyzed in June 2021. Exposures Muscle biopsy or postmortem muscle tissue examination. Main Outcomes and Measures Clinical information and muscle pathological characteristics. Results A total of 10 patients with autopsy-confirmed SALS (mean [SD] age at death, 76.1 [8.5] years; 8 men [80%]) exhibited axonal phosphorylated TDP-43 (pTDP-43)-positive accumulations in intramuscular nerve bundles; the 12 control patients without ALS did not. Among the 114 patients in the cohort study (mean [SD] age, 62.3 [16.1] years; 76 men [67%]), 71 patients (62.3%) exhibited intramuscular nerve bundles; 43 (37.7%) did not. Among those who exhibited pTDP-43-positive intramuscular nerve bundles, 33 patients (22 men [66.7%]; mean [SD] age, 65.2 [15.6] years) were later diagnosed with ALS. The other 38 patients (26 men [68.4%]; mean [SD] age, 59.3 [18.0] years) showed no pTDP-43-positive bundles and did not develop ALS. Among those without evident nerve bundles (28 men [65.1%]; mean [SD] age, 61.3 [15.3] years), 3 were later diagnosed with ALS. Among patients with ALS in the biopsy cohort, 9 with pTDP-43-positive bundles showed only lower motor neuron symptoms at biopsy. Conclusions and Relevance Results of this dual case-control and retrospective cohort study suggest that axonal pTDP-43 accumulations may be characteristic for patients with ALS. As such findings precede clinical fulfillment of the Gold Coast criteria, TDP-43 in nerve bundles may be a novel diagnostic biomarker for ALS.

中文翻译：

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肌萎缩侧索硬化症患者肌内神经束内 TDP-43 的积累。

重要性 神经肌肉接头和轴突的退化被认为是肌萎缩侧索硬化症 (ALS) 病理机制的一个重要方面。然而，包括反式反应 DNA 结合蛋白 43 (TDP-43) 在轴突中的作用在内的机制尚未从病理学上阐明。目的 鉴定和表征 ALS 患者骨骼肌周围轴突的组织病理学。设计、背景和参与者 本研究由两部分组成：尸检病例对照研究和基于人群的回顾性队列研究，随访时间至少为 1 年。该队列研究的患者入组时间为2004年1月1日至2019年9月30日。尸检研究包括具有TDP-43病理学的散发性ALS（SALS）患者和患有非ALS疾病的对照患者。该队列研究纳入了没有 ALS 或其他神经肌肉疾病家族史的患者以及活检时未诊断出患有肌肉疾病的患者。如果患者的临床记录在活检后未经过筛查、被诊断患有肌肉疾病、以及携带已知的 ALS 致病基因，则患者将被排除在外。数据收集于 2019 年 9 月至 2021 年 6 月期间，并于 2021 年 6 月进行分析。 暴露 肌肉活检或死后肌肉组织检查。主要结果和措施临床信息和肌肉病理特征。结果 共有 10 名尸检确诊的 SALS 患者（平均 [SD] 死亡年龄，76.1 [8.5] 岁；8 名男性 [80%]）在肌内神经中表现出轴突磷酸化 TDP-43 (pTDP-43) 阳性积聚捆绑; 12 名没有 ALS 的对照患者则没有。在队列研究的 114 名患者中（平均 [SD] 年龄，62.3 [16.1] 岁；76 名男性 [67%]），71 名患者（62.3%）表现出肌内神经束；43 人（37.7%）没有。在那些表现出 pTDP-43 阳性肌内神经束的患者中，有 33 名患者（22 名男性 [66.7%]；平均 [SD] 年龄，65.2 [15.6] 岁）后来被诊断患有 ALS。其他 38 名患者（26 名男性 [68.4%]；平均 [SD] 年龄，59.3 [18.0] 岁）没有出现 pTDP-43 阳性束，也没有发展为 ALS。在没有明显神经束的患者中（28 名男性 [65.1%]；平均 [SD] 年龄，61.3 [15.3] 岁），3 名后来被诊断患有 ALS。在活检队列中的 ALS 患者中，9 名 pTDP-43 阳性束在活检时仅显示出较低的运动神经元症状。这项双重病例对照和回顾性队列研究的结论和相关性结果表明，轴突 pTDP-43 积聚可能是 ALS 患者的特征。由于这些发现先于黄金海岸标准的临床实现，神经束中的 TDP-43 可能是 ALS 的新型诊断生物标志物。