Department of Neurology, Mayo Clinic, 200 1st St S.W, Rochester, MN, 55905, USA.
J Neurol. 2022 Aug;269(8):4030-4054. doi: 10.1007/s00415-022-11073-3. Epub 2022 Mar 23.
Frontotemporal lobar degeneration (FTLD) with TDP-43-immunoreactive inclusions (FTLD-TDP) is a neurodegenerative disease associated with clinical, genetic, and neuropathological heterogeneity. An association between TDP-43, FTLD and amyotrophic lateral sclerosis (ALS) was first described in 2006. However, a century before immunohistochemistry existed, atypical dementias displaying behavioral, language and/or pyramidal symptoms and showing non-specific FTLD with superficial cortical neuronal loss, gliosis and spongiosis were often confused with Alzheimer's or Pick's disease. Initially this pathology was termed dementia lacking distinctive histopathology (DLDH), but this was later renamed when ubiquitinated inclusions originally found in ALS were also discovered in (DLDH), thus warranting a recategorization as FTLD-U (ubiquitin). Finally, the ubiquitinated protein was identified as TDP-43, which aggregates in cortical, subcortical, limbic and brainstem neurons and glial cells. The topography and morphology of TDP-43 inclusions associate with specific clinical syndromes and genetic mutations which implies different pathomechanisms that are yet to be discovered; hence, the TDP-43 journey has actually just begun. In this review, we describe how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.
额颞叶变性（FTLD）伴 TDP-43 免疫反应性包含物（FTLD-TDP）是一种与临床、遗传和神经病理学异质性相关的神经退行性疾病。TDP-43、FTLD 和肌萎缩侧索硬化症（ALS）之间的关联于 2006 年首次被描述。然而，在免疫组织化学出现之前的一个世纪，表现出行为、语言和/或锥体症状的非典型痴呆症，以及显示非特异性 FTLD 伴有皮质浅层神经元丢失、神经胶质增生和海绵状变性，常与阿尔茨海默病或皮克病混淆。最初，这种病理学被称为缺乏特征性组织病理学的痴呆症（DLDH），但后来当在 ALS 中最初发现的泛素化包含物也被发现时，它被重新命名为 FTLD-U（泛素）。最后，鉴定出聚集在皮质、皮质下、边缘和脑干神经元和神经胶质细胞中的泛素化蛋白为 TDP-43。TDP-43 包含物的拓扑结构和形态与特定的临床综合征和遗传突变相关，这表明存在尚未发现的不同病理机制；因此，TDP-43 的研究实际上才刚刚开始。在这篇综述中，我们描述了在过去的一个世纪中，FTLD-TDP 是如何在临床和神经病理学上被确立和定义的。
