Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

中文翻译：

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肌萎缩侧索硬化症的快速进展与脊髓中更大的 TDP-43 负担有关

上下运动神经元病变对于肌萎缩侧索硬化症 (ALS) 的尸检诊断至关重要。需要进一步调查以确定这些病理的相对负担如何影响疾病进程。我们对 38 名 ALS 患者进行了一项盲法回顾性研究，检查运动皮层、舌下核和腰脊髓的病理测量与临床数据之间的关联，包括进展率和疾病持续时间、症状发作部位以及上下运动神经元迹象。我们研究中最关键的发现是腰髓和舌下核中的 TAR DNA 结合蛋白 43 kDa (TDP-43) 病理负荷与更快的进展速度和降低的存活率显着相关 (p < 0.02)。TDP-43 负荷与细胞丢失严重程度之间没有相关性，并且没有发现运动皮层 TDP-43 负荷或运动皮层细胞丢失严重程度的显着临床关联。C9orf72 扩增与较短的疾病持续时间相关（p < 0.001），但与这些地区的病理测量没有显着相关性。下运动神经元 TDP-43 负荷与 ALS 快速进展与生存率降低之间的关联为 TDP-43 作为疾病生物标志物的研究提供了进一步的支持。