Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
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DOI：
10.1001/jamaneurol.2013.5489
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发表时间：
2014-02
期刊：
影响因子：
29
通讯作者：
Y. Riku;Hirohisa Watanabe;Mari Yoshida;S. Tatsumi;M. Mimuro;Y. Iwasaki;M. Katsuno;Y. Iguchi;M. Masuda;J. Senda;S. Ishigaki;T. Udagawa;G. Sobue
中科院分区：
文献类型：
--
作者：
Y. Riku;Hirohisa Watanabe;Mari Yoshida;S. Tatsumi;M. Mimuro;Y. Iwasaki;M. Katsuno;Y. Iguchi;M. Masuda;J. Senda;S. Ishigaki;T. Udagawa;G. Sobue
43 kDa的TAR dna结合蛋白（TDP-43）在额颞叶变性（FTLD）和肌萎缩侧索硬化症（ALS）的发病机制中起重要作用。虽然已经提出FTLD和ALS之间的病理连续性，但据我们所知，尚未评估tdp -43相关FTLD （FTLD- tdp）中下运动神经元（LMN）系统的神经病理变化。目的通过比较FTLD-TDP和ALS各自运动神经元系统的神经病理变化，探讨两者之间的病理连续性。设计与设置回顾性临床医疗记录回顾，并在尸检时对颅运动神经核和脊髓进行半定量神经病理学评估。我们从269例连续尸检的TDP-43蛋白病变患者中纳入了43例散发性FTLD-TDP， A型、B型或C型。患者被分为无ALS的FTLD、FTLD-ALS （FTLD症状/体征出现在ALS之前）或ALS-FTLD （ALS症状/体征出现在FTLD之前）。神经元TDP-43的病理改变和神经元丢失。结果43例患者纳入临床分析，29例患者纳入神经病理分析。FTLD-ALS组和ALS-FTLD组的生存时间明显短于无ALS FTLD组（P < 0.001）。在神经病理学检查中，无ALS FTLD组89%的患者在脊髓运动神经元中出现TDP-43的聚集。ALS-FTLD患者LMN损失最严重，其次是FTLD-ALS和未发生ALS的FTLD。所有患有A型或C型FTLD- tdp的患者均为未患ALS的FTLD组，所有患有B型病理改变的患者均为FTLD-ALS或ALS-FTLD组。在所有病理亚型中均观察到较低的运动神经元损失和tdp -43阳性的束状包涵体。结论和相关性FTLD-TDP的LMN系统经常表现出与ALS相对应的神经病理改变。因此，在LMN系统水平上，FTLD-TDP和ALS之间的病理连续性得到了支持。
IMPORTANCE TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge. OBJECTIVE To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system. DESIGN AND SETTING A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD). MAIN OUTCOMES AND MEASURES Neuronal TDP-43 pathological changes and neuronal loss. RESULTS Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes. CONCLUSIONS AND RELEVANCE The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.