Swash Michael, de Carvalho Mamede
Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, UK.
Department of Neurosciences and Mental Health, Centro Hospitalar Universitário Lisboa Norte, 1649-035 Lisboa, Portugal.
Brain Sci. 2025 Jun 3;15(6):601. doi: 10.3390/brainsci15060601.
This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease's pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised.
本综述聚焦于肌萎缩侧索硬化症（ALS）发病的复杂性，突出该疾病隐匿的本质以及在确定其确切起源和早期致病机制方面所面临的挑战。ALS的临床表现以进行性肌肉无力和萎缩为特征，常伴有广泛的肌束震颤，反映出下运动神经元的兴奋性增高。该疾病的发病机制涉及神经元蛋白病的漫长临床前期阶段，尤其是TDP - 43的积累，最终导致运动神经元死亡和明显的ALS。本综述讨论了检测这种转变的困难以及对早期治疗干预的影响。它还阐述了上、下运动神经元系统的受累情况，以及对有基因突变的症状前患者进行随访的重要性。强调了在开发有效治疗方法时理解TDP - 43沉积和随后神经元变性的不同过程的重要性。
