Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
JAMA Neurol. 2022 Jul 1;79(7):693-701. doi: 10.1001/jamaneurol.2022.1113.
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.
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.
Muscle biopsy or postmortem muscle tissue examination.
Clinical information and muscle pathological characteristics.
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.
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.
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）发病机制的一个重要方面。然而，轴突中包括反式激活反应 DNA 结合蛋白 43（TDP-43）作用的机制尚未在病理学上得到明确。
确定并描述 ALS 患者骨骼肌中周围轴突的组织病理学特征。
设计、地点和参与者：本研究包括 2 部分：尸检病例对照研究和回顾性基于人群的队列研究，随访时间至少 1 年。队列研究中的患者于 2004 年 1 月 1 日至 2019 年 9 月 30 日入组。尸检研究纳入了具有 TDP-43 病理学的散发性 ALS（SALS）患者和无 ALS 疾病的对照患者。队列研究纳入了无 ALS 家族史或其他神经肌肉疾病且在活检时未被诊断为肌肉疾病的患者。如果患者的临床记录在活检后未被筛查、被诊断为肌肉疾病或携带已知的 ALS 致病基因，则将其排除在外。数据于 2019 年 9 月至 2021 年 6 月收集，并于 2021 年 6 月进行分析。
肌肉活检或尸检肌肉组织检查。
临床信息和肌肉病理特征。
10 名经尸检证实的 SALS 患者（死亡时的平均[标准差]年龄，76.1[8.5]岁；8 名男性[80%]）表现出肌内神经束中磷酸化 TDP-43（pTDP-43）阳性积聚；12 名无 ALS 的对照患者则没有。在队列研究的 114 名患者中（平均[标准差]年龄，62.3[16.1]岁；76 名男性[67%]），71 名患者（62.3%）存在肌内神经束；43 名患者（37.7%）不存在。在那些表现出 pTDP-43 阳性肌内神经束的患者中，33 名患者（22 名男性[66.7%]；平均[标准差]年龄，65.2[15.6]岁）后来被诊断为 ALS。其他 38 名患者（26 名男性[68.4%]；平均[标准差]年龄，59.3[18.0]岁）未表现出 pTDP-43 阳性束，也未发展为 ALS。在那些没有明显神经束的患者中（28 名男性[65.1%]；平均[标准差]年龄，61.3[15.3]岁），有 3 人后来被诊断为 ALS。在活检队列中的 ALS 患者中，9 名具有 pTDP-43 阳性束的患者在活检时仅表现出下运动神经元症状。
这项病例对照和回顾性队列研究的结果表明，轴突 pTDP-43 积聚可能是 ALS 患者的特征。由于这些发现先于满足 Gold Coast 标准的临床表现，因此神经束中的 TDP-43 可能是 ALS 的一种新的诊断生物标志物。
