Pathological Aging of Patients With Amyotrophic Lateral Sclerosis: A Preliminary Longitudinal Study

Objective

This longitudinal study investigated pathological brain aging in amyotrophic lateral sclerosis (ALS) by evaluating disparities between chronological age and deep learning-derived brain structure age (BSA) and exploring associations with cognitive and functional decline.

Methods

Ten limb-onset ALS patients (seven males) and 10 demographically matched healthy controls (HCs) underwent structural magnetic resonance imaging (sMRI) and cognitive assessments at baseline and follow-up. The BSA was estimated using the validated volBrain platform. Cognitive domains (language, verbal fluency, executive function, memory, and visuospatial skills) and global cognition (Persian adaptive Edinburgh Cognitive and Behavioral ALS Screen [ECAS] total score) were assessed along with functional status (ALSFRS-R).

Results

ALS patients exhibited significant BSA-chronological age disparities at baseline (Δ = +7.31 years, p = 0.009) and follow-up (Δ = +8.39 years, p = 0.003), with accelerated BSA progression over time (p = 0.004). The HCs showed no such disparities (p = 0.931). Longitudinal BSA increases were correlated with executive function decline (r = −0.651, p = 0.042). Higher education predicted preserved language (r = 0.831, p = 0.003) and verbal fluency (r = 0.738, p = 0.015). ALSFRS-R decline paralleled visuospatial (r = 0.642, p = 0.045) and global cognitive deterioration (r = 0.667, p = 0.035).

Conclusions

ALS is characterized by accelerated structural brain aging that progresses independently of chronological age and is correlated with executive dysfunction. Education may mitigate cognitive decline, while motor functional deterioration aligns with visuospatial and global cognitive impairments. BSA has emerged as a potential biomarker for tracking pathological aging trajectories in ALS, warranting validation using larger cohorts.