TY - JOUR
T1 - Mapping the natural history of amyotrophic lateral sclerosis
T2 - time-to-event analysis of clinical milestones in the pan-European, population-based PRECISION-ALS cohort
AU - Caravaca Puchades, Alejandro
AU - McDonough, Harry E
AU - Al-Chalabi, Ammar
AU - Chiò, Adriano
AU - Corcia, Philippe
AU - Galvin, Miriam
AU - Hardiman, Orla
AU - Heverin, Mark
AU - Hobin, Frederik
AU - Holmdahl, Oskar
AU - Ingre, Caroline
AU - Lamaire, Nikita
AU - Mac Domhnaill, Éanna
AU - Manera, Umberto
AU - McFarlane, Robert
AU - Mouzouri, Mohammed
AU - Ombelet, Fouke
AU - Opie-Martin, Sarah
AU - Sennfält, Stefan
AU - Terrafeta Pastor, Cristina
AU - Veldink, Jan H
AU - Van Damme, Philip
AU - van den Berg, Leonard
AU - van Eijk, Ruben P A
AU - Vasta, Rosario
AU - Weemering, Daphne N
AU - Shaw, Pamela
AU - McDermott, Christopher J
AU - Povedano Panadés, Mónica
N1 - Publisher Copyright:
© 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2025/5
Y1 - 2025/5
N2 - 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.
AB - 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.
KW - Adult
KW - Age of Onset
KW - Aged
KW - Amyotrophic Lateral Sclerosis/genetics
KW - C9orf72 Protein/genetics
KW - Cohort Studies
KW - Disease Progression
KW - Europe/epidemiology
KW - Female
KW - Gastrostomy
KW - Humans
KW - Male
KW - Middle Aged
KW - Noninvasive Ventilation
KW - Prognosis
KW - Superoxide Dismutase-1/genetics
U2 - 10.1080/21678421.2024.2448535
DO - 10.1080/21678421.2024.2448535
M3 - Article
C2 - 40326915
SN - 2167-8421
VL - 26
SP - 8
EP - 19
JO - Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration
IS - sup1
ER -