Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8585, Japan.
Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
Acta Neuropathol Commun. 2016 Jun 23;4(1):61. doi: 10.1186/s40478-016-0335-2.
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.
额颞叶变性（FTLD）和肌萎缩侧索硬化症（ALS）是 TDP-43（43kDa TAR DNA 结合蛋白）蛋白病的主要类型。FTLD-TDP 病例的皮质 TDP-43 病理学已被详细分析，但 ALS 病例的情况仍不清楚。我们试图使用针对磷酸化 TDP-43（pTDP-43）的抗体，在日本散发性 ALS 病例（n=96）中阐明皮质和皮质下 TDP-43 病理学。将这些病例分为两组：海马齿状颗粒细胞中无 pTDP-43 阳性神经元胞质内含物的病例（1 型，n=63）和有此类内含物的病例（2 型，n=33）。此外，根据颞叶新皮质中 pTDP-43 阳性退行性神经突（DN）的半定量估计，将 2 型病例进一步分为两个亚组：2a 型（无或仅有少量 DN，n=22）和 2b 型（伴有丰富的 DN，n=11）。临床病理分析显示，认知障碍是 2a 型和 2b 型患者的特征，但 1 型患者没有，重要的是，2b 型是一种独特的亚型，其特点是尽管下运动神经元的丧失较轻，皮质 TDP-43 病理学中的神经胶质参与更为明显，但预后较差，皮质 TDP-43 病理学中的异常皮质下树突状棘突 pTDP-43 病理学和更为突出的。考虑到每位患者的生存时间和运动神经元丧失的严重程度，在疾病过程中从 1 型向 2 型或从 2a 型向 2b 型的转变似乎不太可能。因此，这三组被视为独立的亚型。
