ORIGINAL RESEARCH published: 15 April 2019 doi: 10.3389/fnins.2019.00344 Edited by: Grant Thomas Corbett, Harvard Medical School, United States Reviewed by: Bradley Turner, The Florey Institute of Neuroscience and Mental Health, Australia Gérard Lizard, Université de Bourgogne, France *Correspondence: Cristina Cereda cristina.cereda@mondino.it † These authors have contributed equally to this work Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience Received: 20 December 2018 Accepted: 25 March 2019 Published: 15 April 2019 Citation: Sproviero D, La Salvia S, Colombo F, Zucca S, Pansarasa O, Diamanti L, Costa A, Lova L, Giannini M, Gagliardi S, Lauranzano E, Matteoli M, Ceroni M, Malaspina A and Cereda C (2019) Leukocyte Derived Microvesicles as Disease Progression Biomarkers in Slow Progressing Amyotrophic Lateral Sclerosis Patients. Front. Neurosci. 13:344. doi: 10.3389/fnins.2019.00344 Leukocyte Derived Microvesicles as Disease Progression Biomarkers in Slow Progressing Amyotrophic Lateral Sclerosis Patients Daisy Sproviero 1† , Sabrina La Salvia 1† , Federico Colombo 2 , Susanna Zucca 1 , Orietta Pansarasa 1 , Luca Diamanti 3,4 , Alfredo Costa 3,4 , Luca Lova 3,5 , Marta Giannini 1,3 , Stella Gagliardi 1 , Eliana Lauranzano 6 , Michela Matteoli 6,7 , Mauro Ceroni 3,4 , Andrea Malaspina 8† and Cristina Cereda 1 * † 1 Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy, 2 Flow Cytometry and Cell Sorting Unit, Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy, 3 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy, 4 Division of General Neurology, IRCCS Mondino Foundation, Pavia, Italy, 5 Becton Dickinson Italia S.p.A., Milan, Italy, 6 Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy, 7 IN-CNR, Milan, Italy, 8 Neurodegeneration Group, Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, United Kingdom The lack of biomarkers in Amyotrophic Lateral Sclerosis (ALS) makes it difficult to determine the stage of the disease in patients and, therefore, it delays therapeutic trials. Microvesicles (MVs) are possible biomarkers implicated in physiological and pathological functions, however, their role in ALS remains unclear. We investigated whether plasma derived microvesicles could be overrepresented in a group of 40 patients affected by ALS compared to 28 Alzheimer’s Disease (AD) patients and 36 healthy volunteers. Leukocyte derived MVs (LMVs) compared to endothelial, platelet, erythrocyte derived MVs, were mostly present in ALS patients compared to AD patients and healthy donors. Correlation analysis corrected for the presence of confounding variables (riluzole, age at onset, site of onset, gender) was tested between PRL (Progression Rate at the Last visit) and LMVs, and a statistically significant value was found (Pearson partial correlation r = 0.407, p = 0.006). We also investigated SOD1, TDP-43 intravesicular protein level in LMVs. Misfolded SOD1 was selectively transported by LMVs and its protein level was associated with the percentage of LMVs in slow progressing patients (r = 0.545, p = 0.033). Our preliminary findings suggest that LMVs are upregulated in ALS patients and they can be considered possible markers of disease progression. Keywords: amyotrophic lateral sclerosis, biomarkers, disease progression, microvesicles, SOD1, TDP-43 INTRODUCTION The discovery of disease biomarkers for prognostic purposes, clinical monitoring, and evaluation of treatment response is a major research endeavor in Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease caused by selective motor neuron death (Al-Chalabi and Hardiman, 2013; Al-Chalabi et al., 2016). Microvesicles (MVs), a subclass of Abbreviations: ALS, amyotrophic lateral sclerosis; EVs, extracellular vesicles; LMVs leukocyte derived microvesicles; MVs, microvesicles. Frontiers in Neuroscience | www.frontiersin.org 1 April 2019 | Volume 13 | Article 344