Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
Acta Neuropathol Commun. 2019 Oct 28;7(1):165. doi: 10.1186/s40478-019-0824-1.
Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients.
The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs.
Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7).
Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration.
The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.
肌萎缩侧索硬化症（ALS）的病理特征是中枢神经系统中出现磷酸化 TDP-43（pTDP-43）免疫反应性神经元和神经胶质包含物。最近的研究表明，在一定比例的 ALS 患者的骨骼肌中也存在 pTDP-43 聚集物。
本研究旨在阐明 ALS 患者骨骼肌和心肌中 pTDP-43 聚集物的分布和发生率，以及神经肌肉疾病（NMDs）和非神经肌肉疾病（non-NMDs）患者的分布和发生率。
对 30 例 ALS 患者、13 例 NMD 患者和 7 例非 NMD 患者的 5 个肌肉区域（舌、颈肌、膈肌、髂腰肌和心脏）进行组织学和免疫组织化学检查。
两种形态可区分的 pTDP-43 聚集物：密集丝状和短线性包含物。在所有 30 例 ALS 病例中，至少在 5 个肌肉区域中的一个区域发现了这些包含物；28 例骨骼肌和 12 例心肌。在包括肌炎、肌营养不良症和线粒体肌病在内的 13 例 NMD 患者中，以及在 7 例非 NMD 患者中的 3 例中，也发现了 pTDP-43 聚集物。在 ALS 中，膈肌（19 例）最常出现 pTDP-43 聚集物。ALS 中 pTDP-43 聚集物的平均密度明显高于 NMDs 和 non-NMDs。在苏木精和伊红与抗 pTDP-43 染色的连续切片中，具有密集丝状包含物的肌纤维表现出单纤维萎缩伴空泡变性。
本研究结果表明，骨骼肌和心肌中的 pTDP-43 聚集物是包括 ALS 在内的多种疾病中的肌源性病理标志物。
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