Department of Neurology, Kitasato Institute Hospital Kitasato University, Tokyo, Japan.
Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo, Japan.
Neuropathology. 2018 Apr;38(2):171-178. doi: 10.1111/neup.12430. Epub 2017 Sep 14.
Transactivation response DNA-binding protein 43 kDa (TDP-43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP-43 (p-TDP-43) is a major pathological protein that accumulates in sporadic ALS. p-TDP-43 is found not only in primary motor neurons, but often propagates to non-motor systems as well. However, pallido-nigro-luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68-year-old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson's disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non-invasive positive-pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p-TDP-43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p-TDP-43 C-terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p-TDP-43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features.
转活化反应 DNA 结合蛋白 43kDa（TDP-43）是散发性肌萎缩侧索硬化症（ALS）的关键蛋白，磷酸化的 TDP-43（p-TDP-43）是一种主要的病理蛋白，在散发性 ALS 中积累。p-TDP-43 不仅存在于主要运动神经元中，而且经常传播到非运动系统。然而，苍白球黑质路易体变性（PNLD）很少与 ALS 相关。我们在此描述了一位 68 岁的 ALS 患者，其表现为严重的 PNLD。他因右腿运动困难而行走困难，并因运动不能而被诊断为帕金森病。发病约 2 年后，左手和腿无力导致 ALS 诊断。开始进行管饲和无创正压通气。他在 71 岁时因呼吸衰竭死亡。他没有神经障碍或痴呆的家族史。神经病理学检查显示，除了上下运动神经元系统外，PNL 系统还存在严重的神经元丧失和神经胶质增生。p-TDP-43 病理学广泛存在于 PNL 和运动神经元系统中，也存在于杏仁核和海马体中，在这些区域未发现明显的神经胶质增生或神经元丧失。在研究区域未观察到突触核蛋白病理学。p-TDP-43 C 端片段的免疫印迹分析显示出与散发性 ALS 一致的 B 型带模式。这是首例伴有 PNLD 的 ALS 病例，其中 p-TDP-43 分布广泛，海马结构（Nishihira 型 2 和 Brettschneider 期 4），并证实了 B 型免疫印迹模式。我们的病例表明，PNL 系统虽然很少，但也可能参与散发性 ALS 病例的疾病过程。我们还回顾了以前伴有 PNLD 的 ALS 尸检病例，以阐明其临床病理特征。
