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Since its first description by Charcot, amyotrophic lateral sclerosis (ALS) has been classified as a single neurodegenerative disease involving motor neurons. More recently, however, it has become clear that ALS is pleiotropic and its phenotype could vary depending on several factors: age of onset, prevalent damage to the upper (UMN) or the lower motor neuron, body region mostly affected, progression rate and presence of non-motor symptoms, the most frequent being cognitive impairment.1 As a consequence, different phenotypes have been described.2 It remains unclear whether these presentations should be considered as distinct clinical entities or as variants of the same disease.3 More importantly, we do not know if different aetiologies justify this variability.3 Despite these uncertainties, we approach clinical trials by administering the same treatment to all patients with ALS.3
Spatial epidemiology could give some clues on aetiology by identifying clusters and subsequently seeking for causative genetic or environmental factors. Previously, we analysed the spatial distribution of a large ALS cohort in Northwestern Italy. Patients resulted to be homogeneously distributed, suggesting either that a single environmental factor was evenly distributed or that multiple factors acted on distinct subgroups, the latter being the more likely.4
Moving from the hypothesis that aetiology could vary according to phenotypes, here we performed a spatial analysis of ALS cases stratified according to their clinical presentation.
Materials and methods
Data from the Piemonte and Valle d’Aosta ALS Register were used.4 All patients with ALS diagnosed between 2007 and 2014 and who were resident in Piemonte at the time of diagnosis were included.
The cluster analysis was conducted considering …
Contributors RV participated in study conception and design, data collection, data analysis, interpretation of results and writing of the manuscript. AC and UM participated in data collection, study design, interpretation of results and revision of the manuscript. FDP, SC, LM and FDM participated in data collection and revision of the manuscript. AC, CM and ACh participated in study design, interpretation of results and revision of the manuscript.
Funding This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405), the European Commission’s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Italian Ministry of Education, University and Research (Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN, grant 2017SNW5MB), the Joint Programme–Neurodegenerative Disease Research (ALS-Care, Strength and Brain-Mend projects), granted by the Italian Ministry of Education, University and Research and the Susa and Val Susa Rotary Club. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the ’Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Italy.
Competing interests RV, AC, UM, FDP, SC, FDM and LM have no disclosures. AC has received research support from the Italian Ministry of Health (Ricerca Finalizzata). CM has received research support from the Italian Ministry of Health (Ricerca Finalizzata). ACh serves on the editorial advisory board of Amyotrophic Lateral Sclerosis and Neurological Sciences and has received research support from the Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Turin and the European Commission (Health Seventh Framework Programme) and serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denai, and Cytokinetics.
Provenance and peer review Not commissioned; externally peer reviewed.