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The multisystem degeneration amyotrophic lateral sclerosis - neuropathological staging and clinical translation.
Archives Italiennes De Biologie ( IF 1 ) Pub Date : 2018-2-7 , DOI: 10.12871/00039829201746
Federico Verde 1 , Kelly Del Tredici , Heiko Braak , Albert Ludolph
Affiliation  

Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP-43 pathology in sporadic ALS (sALS) has been recently proposed. According to it, 4 stages can be recognized, where pTDP-43 inclusions are found in the agranular motor cortex and α-motor neurons of the brain stem and spinal cord (stage 1), in prefrontal neocortex (middle frontal gyrus), reticular formation, and precerebellar nuclei (stage 2), in further areas of the prefrontal neocortex (gyrus rectus and orbitofrontal gyri), postcentrally located sensory cortex, and basal ganglia (stage 3), and in the anteromedial temporal lobe including the hippocampus (stage 4). Based on this staging effort, a corticofugal axonal model for spreading of pathology can be hypothesized, whereby pathology starts in the primary motor cortex and spreads from there via axonal projections to lower motor neurons and to subcortical structures. Recent neuroradiological evidence seems to support the proposed staging system. From the clinical standpoint, a proportion of ALS patients display extramotor deficits (namely cognitive-behavioural disturbances, impaired ocular movements, and extrapyramidal alterations), which seem to correspond to the pathological involvement of the relevant cerebral structures. This review describes neuropathological sALS staging and addresses clinical evidence corresponding to this staging, pointing towards the concept of ALS as a multisystem brain degeneration disorder instead of a disease confined to motor neurons.

中文翻译:

多系统变性肌萎缩性侧索硬化症-神经病理分期和临床翻译。

肌萎缩性侧索硬化症(ALS)传统上被视为仅影响运动神经元的疾病。但是,许多证据表明,除了运动以外,大脑系统还会有更多的参与。多达一半的ALS患者表现出认知行为障碍。ALS与​​相当一部分FTD病例共享相同的神经病理学底物,即包含异常磷酸化的蛋白TDP-43(pTDP-43)。与过去几十年来针对阿尔茨海默氏病(AD)和帕金森氏病(PD)阐述的病理分期系统类似,最近提出了散发性ALS(sALS)中pTDP-43病理分期的模型。据此可以识别4个阶段,pTDP-43夹杂物在大脑干和脊髓的非运动性皮层和α运动神经元(第1阶段),额前新皮层(中额回),网状结构和小脑前核(第2阶段)中被发现前额新皮层的其他区域(直肌回和眶额回),位于中心位置的感觉皮层和基底神经节(第3阶段),以及包括海马在内的颞上颞叶(第4阶段)。基于这一分阶段的努力,可以假设一个用于传播病理学的皮质耻骨轴突模型,由此病理学从初级运动皮层开始,并通过轴突投射从那里扩散到下运动神经元和皮层下结构。最近的神经放射学证据似乎支持拟议的分期系统。从临床的角度来看,一部分ALS患者表现出运动外功能障碍(即认知行为障碍,眼球运动受损和锥体外系改变),这似乎与相关脑结构的病理学病变相对应。这篇综述描述了神经病理学的sALS分期,并提出了与该分期相对应的临床证据,指出了ALS是一种多系统性大脑退行性疾病的概念,而不是局限于运动神经元的疾病。
更新日期:2020-08-21
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