Brain Folding Trajectories in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease, and neuroimaging markers offer a promising avenue to capture this variability. Cortical folding alterations in ALS remain largely unexplored despite growing interest in neuroimaging markers of the disease. This study is the first whole-brain investigation of sulcal morphometry in ALS. A total of 222 individuals diagnosed with ALS and 194 healthy controls (HC) were recruited through the Canadian ALS Neuroimaging Consortium (CALSNIC) for a longitudinal investigation. Using T1-weighted MRI processed with FreeSurfer and BrainVISA, we extracted cortical thickness and four sulcal features: width, mean depth, surface area, and length, across 123 sulci. We identified widespread alterations in ALS, with 19 sulci showing increased width and length alongside reduced depth and surface area, primarily in frontal and parietal regions surrounding the motor strip. The central sulcus (CS) emerged as the most consistently affected region, displaying bilateral widening and reduced depth, changes that closely tracked motor decline. Longitudinal analyses revealed progressive widening and reduced depth and surface area of the CS. These alterations closely tracked the progression of motor symptoms over the course of the disease and aligned with regional cortical thickness alterations. Our findings demonstrate that brain folding patterns, and in particular CS, are altered in ALS and correlate with clinical progression, resembling the neurodegenerative pattern of the disease. By revealing complementary and sensitive changes, sulcal-based metrics may offer promising neuroimaging biomarkers for early detection, prognosis, and patient stratification in ALS.