Cerebral Function Unit, Manchester Centre for Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.
Division of Neuroscience & Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
J Neuropsychol. 2023 Jun;17(2):211-234. doi: 10.1111/jnp.12297. Epub 2022 Oct 31.
This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP-43 or more rarely fused-in-sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP-43 pathology, and speech or limb apraxia tau pathology. The co-occurrence of MND predicts TDP-43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non-fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub-variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies.
这篇文章考察了在过去四十年中人们对额颞叶痴呆（FTD）的认识的演变。一个核心主题是认识到异质性。FTD 最初被认为是一种行为和执行功能障碍的疾病，但现在也与语言、概念知识和实践的改变有关。许多 FTD 患者没有神经系统体征，但也与运动神经元病（MND）、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）有明确的关联。FTD 通常被定义为早发性痴呆，但约四分之一的患者在 65 岁后出现。潜在的病理蛋白是tau、TDP-43 或更罕见的融合肉瘤（FUS）。家族性 FTD 中已确定了特定的遗传突变。临床表型、病理基础和遗传突变之间存在可预测的关系。例如，局限性语义障碍预测 TDP-43 病理学，言语或肢体失用症预测 tau 病理学。MND 的共同发生预测 TDP-43 病理学，PSP 和 CBD 预测 tau 病理学。FUS 病理学与非常年轻的发病、刻板行为和尾状核萎缩有关。非流利性失语症与颗粒蛋白（GRN）突变和 MND 有关，精神症状与 C9orf72 基因的重复扩展有关。尽管在发现方面存在着全球范围内的惊人共识，但仍存在一些争议问题，主要与 FTD 的分类及其亚型有关。了解 FTD 的多样性对于有效的诊断、管理和靶向治疗的发展至关重要。
