Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology
Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology
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DOI：
10.1007/s00401-008-0443-6
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发表时间：
2009-01-01
影响因子：
12.7
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Nishihira, Yasushi;Tan, Chun-Feng;Takahashi, Hitoshi
近年来，散发性肌萎缩性侧索硬化症（SALS）作为一种致命的神经系统疾病，已被证明是一种多系统的TDP-43蛋白病变，其中枢神经系统的神经元和胶质细胞均受到广泛影响。一般来说，SALS的自然病程较短（< 5年）。然而，也有少数患者即使没有人工呼吸支持（ARS）也能存活10年或更长时间。在本研究中，我们使用TDP-43免疫组织化学检查了6例长期（10-20年）无ARS的SALS患者的神经系统各区域，其中证实了伴有Bunina体和受影响的下运动神经元泛素化包裹体（UIs）的下运动显性疾病。1例海马齿状颗粒细胞（UDG）也可见UIs。在所有病例中，除一例UDG外，tdp -43免疫反应性（ir）神经元胞浆包体（NCIs）的发生仅限于脊髓和脑干的少数区域，包括前角。在1例UDG中，在黑质和大脑的一些区域，包括海马齿状回（颗粒细胞）中也检测到TDP-43-ir NCIs。每个区域显示NCIs的神经元数量非常少（除齿状回外，每个区域1-3个）。另一方面，TDP-43-ir胶质细胞质内含物（glial cytoplasmic incletes, GCIs）在中枢神经系统（包括脑白质）的发生更为广泛。然而，在每个区域显示gci的胶质细胞数量非常少（每个区域1-3个）。综上所述，与通常形式的SALS相比，长期SALS所表现出的TDP-43病理程度明显轻微，分布有限，与所观察到的相对良性的临床病程相对应。现在很明显，长时间的SALS实际上是TDP-43蛋白病变谱的一部分。
Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (< 5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.