TAR DNA 结合蛋白 43kDa 相关的额颞叶痴呆和肌萎缩性侧索硬化症中的下运动神经元受累。

Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

机构信息

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.

出版信息

JAMA Neurol. 2014 Feb;71(2):172-9. doi: 10.1001/jamaneurol.2013.5489.

DOI:10.1001/jamaneurol.2013.5489

PMID:24378564

Abstract

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.

摘要

重要性

TAR DNA 结合蛋白 43 kDa（TDP-43）在额颞叶变性（FTLD）和肌萎缩侧索硬化症（ALS）的发病机制中起主要作用。尽管已经提出 FTLD 和 ALS 之间存在病理连续性，但据我们所知，TDP-43 相关 FTLD（FTLD-TDP）的下运动神经元（LMN）系统的神经病理学变化尚未得到评估。

目的

通过比较 FTLD-TDP 和 ALS 各自的运动神经元系统的病理学变化，来研究 FTLD-TDP 和 ALS 之间的病理连续性。

设计和设置

对 269 例连续尸检的 TDP-43 蛋白病患者进行了回顾性临床病历回顾和颅神经核和脊髓的半定量神经病理学评估。我们纳入了 43 例散发性 FTLD-TDP 型 A、B 或 C 的患者。患者分为无 ALS 的 FTLD、FTLD-ALS（FTLD 症状/体征先于 ALS）或 ALS-FTLD（ALS 症状/体征先于 FTLD）。

主要结果和测量指标

神经元 TDP-43 病理改变和神经元丢失。

结果

43 例患者纳入临床分析，其中 29 例患者脊髓纳入神经病理学分析。FTLD-ALS 和 ALS-FTLD 组的生存时间明显短于无 ALS 的 FTLD 组（P < .001）。神经病理学检查显示，无 ALS 的 FTLD 组 89%的患者脊髓运动神经元存在 TDP-43 聚集。ALS-FTLD 组的 LMN 丢失最严重，其次是 FTLD-ALS 和无 ALS 的 FTLD。所有 A 型或 C 型 FTLD-TDP 的患者均纳入无 ALS 的 FTLD 组，所有 B 型病理变化的患者均纳入 FTLD-ALS 或 ALS-FTLD 组。所有病理亚型均观察到下运动神经元丢失和 TDP-43 阳性缠结样包涵体。