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Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort
  1. Rhian S Convery1,
  2. Martina Bocchetta1,
  3. Caroline V Greaves1,
  4. Katrina M Moore1,
  5. David M Cash1,2,
  6. John Van Swieten3,
  7. Fermin Moreno4,
  8. Raquel Sánchez-Valle5,
  9. Barbara Borroni6,
  10. Robert Laforce Jr7,
  11. Mario Masellis8,
  12. Maria Carmela Tartaglia9,
  13. Caroline Graff10,
  14. Daniela Galimberti11,12,
  15. James B Rowe13,
  16. Elizabeth Finger14,
  17. Matthis Synofzik15,16,
  18. Rik Vandenberghe17,18,
  19. Alexandre de Mendonca19,
  20. Fabrizio Tagliavini20,
  21. Isabel Santana21,22,
  22. Simon Ducharme23,24,
  23. Christopher Butler25,
  24. Alex Gerhard26,27,
  25. Johannes Levin28,29,
  26. Adrian Danek29,
  27. Markus Otto30,
  28. Jason D Warren1,
  29. Jonathan D Rohrer1
  30. on behalf of the Genetic FTD Initiative (GENFI)
    1. 1 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
    2. 2 Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, UK
    3. 3 Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
    4. 4 Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, San Sebastian, Spain
    5. 5 Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain
    6. 6 Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
    7. 7 Clinique Interdisciplinaire de Mémoire (CIME), Département des Sciences Neurologiques du CHU de Québec, Laval University, Quebec, Quebec City, Canada
    8. 8 Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
    9. 9 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
    10. 10 Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden
    11. 11 La Fondazione IRCCS Ospedale Maggiore Policlinico, Milano, Italy
    12. 12 Centro Dino Ferrari, University of Milan, Milano, Italy
    13. 13 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
    14. 14 Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
    15. 15 Hertie-Institute for Clinical Brain Research and Center of Neurology, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
    16. 16 German Centre for Neurodegenerative Diseases, Tübingen, Germany
    17. 17 Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
    18. 18 Leuven Brain Institute, KU Leuven, Leuven, Belgium
    19. 19 Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisboa, Portugal
    20. 20 Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy
    21. 21 Faculty of Medicine, University of Coimbra, Coimbra, Portugal
    22. 22 Centre of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
    23. 23 Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
    24. 24 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
    25. 25 Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK
    26. 26 Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK
    27. 27 Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany
    28. 28 German Centre for Neurodegenerative Diseases Site Munich, Munchen, Germany
    29. 29 Neurologische Klinik, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany
    30. 30 Department of Neurology, University of Ulm, Ulm, Germany
    1. Correspondence to Dr Jonathan D Rohrer, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; j.rohrer{at}


    Objective Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).

    Methods Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.

    Results Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.

    Conclusion Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

    • frontotemporal dementia
    • pain

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    • Collaborators Martin N. Rossor, Nick C. Fox, Ione O.C. Woollacott, Rachelle Shafei, Carolin Heller, Georgia Peakman, Imogen J. Swift, Emily Todd, Rita Guerreiro, Jose Bras, David L. Thomas, Jennifer Nicholas, Simon Mead, Lize Jiskoot Lieke Meeter, Jessica Panman, Janne Papma, Rick van Minkelen, Yolande Pijnenburg, Myriam Barandiaran, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, Maria de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanua, Zigor Diaz, Sergi Borrego-Ecija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Nuria Bargallo, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David Tang-Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelic, Hakan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, Hans-Otto Karnarth, Benjamin Bender, Rose Bruffaerts, Philip Vandamme, Mathieu Vandenbulcke, Catarina B. Ferreira, Gabriel Miltenberger, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Duro, Maria Rosario Almeida, Miguel Castelo-Branco, Maria João Leitão, Miguel Tabuas-Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa-Neto, Michele Veldsman, Toby Flanagan, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schonecker, Elisa Semler, Sarah Anderl-Straub.

    • Contributors RC, MB and JR contributed to the study design, acquisition, analysis and interpretation of the data as well as drafting and revising the manuscript. All other authors (CVG, KM, DMc, JCVS, FM, RS-V, BB, RJrL, MM, MCT, CG, DG, JBR, EF, MS, RV, AdeM, FT, IS, SD, CRB, AG, JL, AD, MO, JW) contributed to the acquisition of data and study coordination as well as helping to critically review and revise the manuscript.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the local ethics committees and all participants gave their consent to take part.

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