TY - JOUR
T1 - Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression
T2 - A Multidimensional Analysis
AU - Grassano, Maurizio
AU - Moglia, Cristina
AU - Palumbo, Francesca
AU - Koumantakis, Emanuele
AU - Cugnasco, Paolo
AU - Callegaro, Stefano
AU - Canosa, Antonio
AU - Manera, Umberto
AU - Vasta, Rosario
AU - De Mattei, Filippo
AU - Matteoni, Enrico
AU - Fuda, Giuseppe
AU - Salamone, Paolina
AU - Marchese, Giulia
AU - Casale, Federico
AU - De Marchi, Fabiola
AU - Mazzini, Letizia
AU - Mora, Gabriele
AU - Calvo, Andrea
AU - Chiò, Adriano
N1 - Publisher Copyright:
© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/7
Y1 - 2024/7
N2 - Objective: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Methods: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. Results: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00–1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09–1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07–0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (−4.2 forced vital capacity%/month, 95% CI −6.3 to −2.2, p < 0.0001) and faster weight loss (−0.15 kg/month, 95% CI −0.25 to −0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. Interpretation: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159–169.
AB - Objective: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Methods: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. Results: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00–1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09–1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07–0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (−4.2 forced vital capacity%/month, 95% CI −6.3 to −2.2, p < 0.0001) and faster weight loss (−0.15 kg/month, 95% CI −0.25 to −0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. Interpretation: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159–169.
UR - http://www.scopus.com/inward/record.url?scp=85189881947&partnerID=8YFLogxK
U2 - 10.1002/ana.26933
DO - 10.1002/ana.26933
M3 - Article
SN - 0364-5134
VL - 96
SP - 159
EP - 169
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -