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Cognitive neurology
Research paper
Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study
  1. Raphael Schneider1,2,
  2. Paul McKeever1,2,
  3. TaeHyung Kim3,4,
  4. Caroline Graff5,
  5. John Cornelis van Swieten6,
  6. Anna Karydas7,
  7. Adam Boxer7,
  8. Howie Rosen7,
  9. Bruce L Miller7,
  10. Robert Laforce Jr8,
  11. Daniela Galimberti9,
  12. Mario Masellis10,11,
  13. Barbara Borroni12,
  14. Zhaolei Zhang4,13,
  15. Lorne Zinman11,
  16. Jonathan Daniel Rohrer14,
  17. Maria Carmela Tartaglia2,15,
  18. Janice Robertson1,2
  19. on behalf of the Genetic FTD Initiative (GENFI)
    1. 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    2. 2Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
    3. 3Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
    4. 4The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
    5. 5Department of Neurobiology, Karolinska Institute, Stockholm, Sweden
    6. 6Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
    7. 7Department of Neurology, University of California, San Francisco, California, USA
    8. 8Département des Sciences Neurologiques, Université Laval, Quebec, Canada
    9. 9Centro Dino Ferrari, Fondazione Ca’ Granda IRCCS Ospedale Policlinico, University of Milan, Milan, Italy
    10. 10LC Campbell Cognitive Neurology Research Unit, University of Toronto, Toronto, Ontario, Canada
    11. 11Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
    12. 12Neurology Unit, Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Brescia, Italy
    13. 13Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
    14. 14Dementia Research Centre, University College London, London, UK
    15. 15Memory Clinic, University Health Network, Toronto, Ontario, Canada
    1. Correspondence to Dr Janice Robertson, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5T 2S8, Canada; jan.robertson{at}utoronto.ca

    Abstract

    Objective To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.

    Methods GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.

    Results In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).

    Conclusions Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

    This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

    https://doi.org/10.1136/jnnp-2017-317492

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      Footnotes

      • Contributors RS, MCT and JR wrote and revised the manuscript and contributed to study design, acquisition of data, analysis and interpretation of data. PM, TK, ZZ and LZ provided meaningful input to the manuscript and contributed to analysis and interpretation of data. CG, JCvS, AK, AB, HR, BLM, RL, DG, MM and BB provided meaningful input to the manuscript and contributed to acquisition of data. JDR provided meaningful input to the manuscript and contributed to study design, acquisition of data and interpretation of data. All authors approved the final version of the manuscript. The corresponding authors JR and MCT agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

      • Funding RS has received funding from the ALS Society of Canada (Clinical Research Fellowship) and the University of Toronto Eliot Phillipson Clinician-Scientist Training Program. PM has received funding from the Alzheimer Society of Canada (Doctoral Award). JCvS has received funding from the European Joint Program – Neurodegenerative Disease Research, The Netherlands Alzheimer Foundation (70-73305-98-105) and the Netherlands Organization for Health Research and Development. DG has received funding from the Italian Ministry of Health. JDR has received funding from the UK Medical Research Council through a Clinician Scientist Fellowship (MR/M008525/1) and the National Institute for Health Research – Rare Disease Translational Research Collaboration. AB has received funding from the US Department of Health and Human Services, National Institutes of Health NIH Clinical Center (R01AG038791 and U54NS092089) and the TAU consortium. MM and MCT have received funding from the Canadian Institutes of Health Research, Centres of Excellence in Neurodegeneration (Institute of Neurosciences, Mental Health and Addiction). JDR has received funding from the Government of Canada: Canadian Institutes of Health Research Centres of Excellence in Neurodegeneration grant (The TAR DNA-Binding Protein (TDP-43) and ALS) and the James Hunter Initiative.

      • Competing interests None declared.

      • Ethics approval Written informed consent and local research ethics boards’ approval was obtained at all participating centres (Six GENFI centres contributed CSF: Karolinska Institute, Department of Neurobiology, Stockholm, Sweden; Erasmus Medical Center, Department of Neurology, Rotterdam, The Netherlands; University College London, Dementia Research Centre, London, England; Université Laval, Département des Sciences Neurologiques, Quebec City, Canada; University of Milan, Centro Dino Ferrari, Fondazione Ca’ Granda IRCCS Ospedale Policlinico, Milan, Italy; and University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Canada).

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Data sharing statement Unpublished raw data files of PCR results are available to the corresponding authors.

      • Collaborators GENFI consortium members: Christin Andersson; Silvana Archetti; Andrea Arighi; Luisa Benussi; Giuliano Binetti; Sandra Black; Martina Bocchetta; David Cash; Maura Cosseddu; Katrina Dick; Marie Fallström; Carlos Ferreira; Chiara Fenoglio; Nick Fox; Morris Freedman; Giovanni Frisoni; Giorgio Fumagalli; Stefano Gazzina; Roberta Ghidoni; Marina Grisoli; Vesna Jelic; Lize Jiskoot; Ron Keren; Gemma Lombardi; Carolina Maruta; Lieke Meeter; Mendonça A Rick van Minkelen; Benedetta Nacmias; Linn Öijerstedt; Sebastien Ourselin; Alessandro Padovani; Jessica Panman; Michela Pievani; Cristina Polito; Enrico Premi; Sara Prioni; Rosa Rademakers, Veronica Redaelli; Ekaterina Rogaeva; Giacomina Rossi; Martin Rossor; James Row; Elio Scarpini; Fabrizio Tagliavini; Sandro Sorbi; David Tang-Wai; David Thomas; Hakan Thonberg; Pietro Tiraboschi; Ana Verdelho; Jason Warren.