Amyotrophic lateral sclerosis regional progression intervals change according to time of involvement of different body regions

The prediction of the disease course is one of the main targets of ALS research, particularly considering its wide phenotypic heterogeneity. Despite many attempts to classify patients in prognostic categories according to the different spreading patterns at diagnosis, a precise regional progression rate and the time of involvement of each region has yet to be clarified.In a population-based dataset of ALS patients, we analyse the functional decline in different body regions according to time and order of regional involvement. We calculated the regional progression intervals (RPIs) from the initial involvement (Inv) to the severe functional impairment (SevI), using the ALS Functional Rating Scale revised (ALSFRS-r) subscores of bulbar, upper limbs, lower limbs and respiratory/thoracic regions. Time-to-event analyses, adjusted for age, sex, ALSFRS-r pre-slope (ΔALSFRS-R), cognitive and mutational status were performed.RPI duration differed significantly among ALS phenotypes, being the RPI of first region involved significantly longer than RPIs of regions involved later. Cox proportional hazard models showed that the time between disease onset and initial regional involvement is invariably related to a reduced RPI duration in each different body region (bulbar region, HR 1.11, 95% CI 1.06-1.16, p0.001; upper limbs region, HR 1.16, 95% CI 1.06-1.28, p=0.002; lower limbs region, HR 1.11, 95% CI 1.03-1.19, p=0.009; respiratory/thoracic region, HR 1.10, 95% CI 1.06-1.14, p=0.005).We found that the progression of functional decline accelerates in regions involved later during disease course. Our findings can be useful in patients' management and prognosis prediction.