Verde Federico, Del Tredici Kelly, Braak Heiko, Ludolph Albert
Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany - Email:
Arch Ital Biol. 2017 Dec 1;155(4):118-130. doi: 10.12871/00039829201746.
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.
肌萎缩侧索硬化症（ALS）传统上被认为是一种仅影响运动神经元的疾病。然而，大量证据表明，除运动系统外，脑的其他系统也会受到影响。多达一半的ALS患者存在认知行为障碍。相当一部分ALS病例与额颞叶痴呆（FTD）病例具有相同的神经病理学基础，即异常磷酸化的蛋白质TDP - 43（pTDP - 43）包涵体。与过去几十年为阿尔茨海默病（AD）和帕金森病（PD）制定的病理分期系统类似，最近有人提出了散发性ALS（sALS）中pTDP - 43病理的分期模型。据此，可以识别出4个阶段，其中在无颗粒运动皮质以及脑干和脊髓的α运动神经元中发现pTDP - 43包涵体（第1阶段），在前额叶新皮质（额中回）、网状结构和脑桥前核中发现（第2阶段），在前额叶新皮质的其他区域（直回和眶额回）、中央后回的感觉皮质和基底神经节中发现（第3阶段），在包括海马体在内的颞叶内侧前部发现（第4阶段）。基于这一分期研究，可以推测出一种病理扩散的皮质传出轴突模型，即病理始于初级运动皮质，然后通过轴突投射从那里扩散到下运动神经元和皮质下结构。最近的神经放射学证据似乎支持了所提出的分期系统。从临床角度来看，一部分ALS患者存在运动外缺陷（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受累情况相对应。本综述描述了sALS的神经病理学分期，并阐述了与此分期相对应的临床证据，指出ALS是一种多系统脑变性疾病，而非仅限于运动神经元的疾病。
