Focus on the heterogeneity of amyotrophic lateral sclerosis

Abstract

The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms. A variety of ALS animal models can be informative about the heterogeneity of the neuropathological or genetic aspects of the disease and can support the development of new therapeutic intervention. Evolving biomarkers can contribute to the identification of differing genotypes and phenotypes, and can be used to explore whether genotypic and phenotypic differences in animal models might help to provide a better definition of the heterogeneity of ALS in humans. These include neurofilaments, peripheral blood mononuclear cells, extracellular vesicles, microRNA and imaging findings. These biomarkers might predict not only the development of the disease, but also the variability in progression, although robust validation is required. A promising area of progress in modeling the heterogeneity of human ALS is represented by the use of human induced pluripotent stem cell (iPSCs)-derived motor neurons. Although the translational value of iPSCs remains unclear, this model is attractive in the perspective of replicating the heterogeneity of sporadic ALS as a first step toward a personalized medicine strategy.

Keywords:

• Risk factors
• genetic
• biomarkers
• animal models
• iPSC

Acknowledgement

We are grateful to the association “Io corro con Giovanni” for the generous support for the organization of the Workshop “Focus on the heterogeneity of amyotrophic lateral sclerosis” held in Milano. AAC acknowledges support through the following funding organizations under the egis of JPND – www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)), through the Motor Neurone Disease Association, the National Institute for Health Research (NIHR) Biomedical Research Center at South London and Maudsley NHS Foundation Trust and King’s College London, and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). FA is funded by the European Research Council (StG-2016_714388_NeuroTRACK).

Declaration of interest

C. Lunetta received compensation for consulting services from Neuraltus, Cytokinetics, Mitsubishi Tanabe Pharma Europe and Italfarmaco and has received funds from ARISLA and Italian Ministry of Health.

V. Silani is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology; received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, and Italfarmaco; and receives or has received research supports from the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call.

A. Chiò serves as a member of the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and of Neurological Sciences. He received compensation for consulting services from Cytokinetics, Mitsubishi Tanabe Pharma, Biogen, and Italfarmaco and has received funds from the Italian Ministry of Health and the Italian Ministry of Education, University and Research.

O. Hardiman is Editor in Chief of Amyotroph Lateral Sclerosis and Frontotemporal Degeneration and a member of the Editorial Board of Journal of Neurology Neurosurgery & Psychiatry. She has consulted for Cytokinetics, Mitsubishi Tanabe Pharma, Biogen, and Novartis and hold research grants from Science Foundation Ireland.

L. Greensmith serves as a member of the Editorial Board of Amyotroph Lateral Sclerosis and Frontotemporal Degeneration. She has consulted for Orphazyme ApS, Enterin Inc., Nido Biosciences and Immunoforge.

A. Al-Chalabi reports consultancies for GSK, Cytokinetics, Biogen Idec, Treeway Inc, Chronos Therapeutics, OrionPharma, and Mitsubishi-Tanabe Pharma, and was Chief Investigator for commercial clinical trials run by OrionPharma and Cytokinetics.

F. Agosta is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Biogen Idec, Novartis and Philips; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council.

All other authors declare no competing interests.

Additional information

Funding

This study was supported by the Italian Ministry of Health [GR-2016-02361552 to MB] and by the “Fondazione Regionale per la Ricerca Biomedica” (TRANS-ALS project).