Motor Phenotypes Identify Distinct Progression Patterns in ALS

Researchers classified 1,307 patients with ALS by region of onset, timing of spread to a vertically distant body region, and the balance of upper and lower motor neuron dysfunction. They compared phenotype associations with ALS progression rate (ALSPR), serum NfL, and survival, and assessed consistency across participating centers. Classification consistency was high, with Kendall’s W ranging from 0.75 to 0.89.

Onset phenotypes were associated with progression rate, NfL, and survival (p<0.001). Early propagation, defined as spread within 12 months, was the strongest marker of disease aggressiveness: it was associated with higher progression rates, elevated NfL, and reduced survival (hazard ratio 2.93; p<0.001). Balanced upper/lower motor neuron involvement and predominant lower motor neuron involvement were also associated with shorter survival (hazard ratio 2.51; p<0.001). Trunk-onset disease showed the lowest log(NfL/ALSPR), while early propagation showed a relative mismatch between NfL and functional decline.

The findings suggest that structured motor phenotyping may help refine prognostic models and trial stratification. The abstract provides no details on cohort recruitment, follow-up duration, or adjustment variables; these prognostic associations do not establish that phenotyping changes treatment or outcomes.