Caravaca Puchades Alejandro, McDonough Harry E, Al-Chalabi Ammar, Chiò Adriano, Corcia Philippe, Galvin Miriam, Hardiman Orla, Heverin Mark, Hobin Frederik, Holmdahl Oskar, Ingre Caroline, Lamaire Nikita, Mac Domhnaill Éanna, Manera Umberto, McFarlane Robert, Mouzouri Mohammed, Ombelet Fouke, Opie-Martin Sarah, Sennfält Stefan, Terrafeta Pastor Cristina, Veldink Jan H, Van Damme Philip, van den Berg Leonard, van Eijk Ruben P A, Vasta Rosario, Weemering Daphne N, Shaw Pamela, McDermott Christopher J, Povedano Panadés Mónica
Hospital Universitari de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Amyotroph Lateral Scler Frontotemporal Degener. 2025;26(sup1):8-19. doi: 10.1080/21678421.2024.2448535. Epub 2025 May 6.
Map time to key clinical milestones in amyotrophic lateral sclerosis (ALS), highlighting underlying genotypic and phenotypic prognostic factors.
Understanding the ALS disease trajectory and factors influencing the heterogeneous disease course is important to guide clinical care and stratify individuals to effectively assess therapeutics in clinical trials.
Population-based datasets from nine European ALS care centers were collated. Time-to-event analysis was conducted for key clinical milestones: symptom onset, diagnosis, gastrostomy insertion, noninvasive ventilation (NIV) initiation, and survival. Independent prognostic factors were determined.
21,820 people with ALS from nine ALS centers were included. Median age of symptom onset was 63.9 years. Median diagnostic delay was 1.0 years, with median survival of 33.7 months from onset. Prognostic factors for survival included age at onset, baseline vital capacity, progression rate, diagnostic delay, site of onset, and C9orf72-positive status. SOD1 variants D91A and G94C had protective prognostic effects in the whole cohort. Median time from diagnosis to gastrostomy insertion in bulbar-onset disease was 2.34 years. Median time from diagnosis to NIV initiation in those diagnosed between 2010 and 2019 was 3.61 years. Significant differences between ALS clinical center cohorts were seen in time to gastrostomy insertion, time to NIV initiation, and in overall survival time.
Our analysis of a large, well-defined, population-based European cohort provides detailed insight into the natural history of ALS, highlighting phenotypic and genetic factors affecting time to key clinical milestones. Further study is needed to determine the drivers in observed differences between ALS clinical center cohorts in time to clinical interventions and overall survival.
绘制肌萎缩侧索硬化症（ALS）关键临床里程碑的时间线，突出潜在的基因型和表型预后因素。
了解ALS疾病轨迹以及影响异质性病程的因素对于指导临床护理和对个体进行分层，以在临床试验中有效评估治疗方法非常重要。
整理了来自九个欧洲ALS护理中心的基于人群的数据集。对关键临床里程碑进行了事件发生时间分析：症状发作、诊断、胃造口术插入、无创通气（NIV）开始和生存。确定了独立的预后因素。
纳入了来自九个ALS中心的21,820例ALS患者。症状发作的中位年龄为63.9岁。中位诊断延迟为1.0年，从发作开始的中位生存期为33.7个月。生存的预后因素包括发病年龄、基线肺活量、进展率、诊断延迟、发病部位和C9orf72阳性状态。SOD1变体D91A和G94C在整个队列中具有保护性预后作用。延髓发病型疾病从诊断到胃造口术插入的中位时间为2.34年。在2010年至2019年期间确诊的患者中，从诊断到开始NIV的中位时间为3.61年。在ALS临床中心队列之间，在胃造口术插入时间、NIV开始时间和总生存时间方面存在显著差异。
我们对一个大型、明确的欧洲人群队列的分析提供了对ALS自然史的详细洞察，突出了影响关键临床里程碑时间的表型和遗传因素。需要进一步研究以确定在ALS临床中心队列之间观察到的临床干预时间和总生存差异的驱动因素。
