Mapping the natural history of amyotrophic lateral sclerosis: time-to-event analysis of clinical milestones in the pan-European, population-based PRECISION-ALS cohort

Objective Map time to key clinical milestones in amyotrophic lateral sclerosis (ALS), highlighting underlying genotypic and phenotypic prognostic factors. Background 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. Methods 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. Results 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. Conclusion 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.