AbstractBackgroundCurrently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS).AimsThis study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb‐onset ALS.Patients and methodsConsecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups.ResultsAmong 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. The frequency of HSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74% vs. 50%) in patients with upper limb‐onset (UL‐ALS), compared to patients with lower limb‐onset (LL‐ALS;p< .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL‐ALS, compared to UL‐ALS (p< .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS‐r sub‐score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS‐r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP.ConclusionsOur findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease