Sex-related Differences in ALS Survival and Progression: Insights from a Population-based Study
Maurizio Grassano1, Francesca Palumbo1, Cristina Moglia1, Paolina Salamone1, Giuseppe Fuda1, Rosario Vasta1, Umberto Manera1, Antonio Canosa1, Federico Casale1, Letizia Mazzini2, Andrea Calvo1, Adriano Chio1
1Dept. of Neuroscience, University of Turin, 2University of Oriental Piedmont
Objective:
This study aimed to investigate sex-related differences in Amyotrophic Lateral Sclerosis (ALS) prognosis and identify potential contributing factors.
Background:
ALS is a neurodegenerative disease characterized by known disparities in prevalence rates and differences in the age and site of disease onset between males and females. However, the intricate relationship between sex, disease progression, and underlying mechanisms in ALS remains incompletely understood.
Design/Methods:
We obtained data from the population-based Piemonte and Valle d'Aosta Register for ALS (PARALS) and used the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database as a replication cohort. Survival analyses, stratified by the site of disease onset, were conducted to assess sex-related differences in survival. Disease progression was evaluated using the multidomain ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Additionally, we explored the roles of Forced Vital Capacity (FVC) and weight decline through causal mediation analysis.
Results:
Males exhibited shorter survival when stratified by disease onset site (spinal onset: HR 1.143, 95%CI 1.04-1.257, P=0.0057; bulbar onset: HR 1.15, 95%CI 1.015-1.303, P=0.0284). Intriguingly, males did not experience faster disease progression; instead, women showed a more pronounced functional decline (+0.05 ALSFRS-R points per month, 95%CI 0.04-0.06, P<0.0001). Conversely, men exhibited worse respiratory decline (FVC% -4.2, 95%CI -6.3 to -2.2, P<0.0001) and faster weight loss (Kg lost per month -0.15, 95%CI -0.25 to -0.05, P=0.0030) already at diagnosis. Causal mediation analysis demonstrated that respiratory function and weight loss played pivotal roles in sex-related survival disparities. Analysis of the PRO-ACT cohort confirmed these trends.
Conclusions:
This comprehensive study reveals the interplay between sex, survival, and disease progression in ALS. The observed shorter survival in males is not directly linked to faster disease progression but is instead associated with respiratory function and weight loss. These findings underscore the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies for this devastating disease.