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Original research
MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia
  1. Ana L Manera1,
  2. Mahsa Dadar1,2,
  3. John Cornelis Van Swieten3,
  4. Barbara Borroni4,
  5. Raquel Sanchez-Valle5,
  6. Fermin Moreno6,
  7. Robert Laforce Jr7,
  8. Caroline Graff8,
  9. Matthis Synofzik9,
  10. Daniela Galimberti10,11,
  11. James Benedict Rowe12,
  12. Mario Masellis13,
  13. Maria Carmela Tartaglia14,
  14. Elizabeth Finger15,
  15. Rik Vandenberghe16,
  16. Alexandre de Mendonca17,
  17. Fabrizio Tagliavini18,
  18. Isabel Santana19,
  19. Christopher R Butler20,
  20. Alex Gerhard21,
  21. Adrian Danek22,23,
  22. Johannes Levin22,23,
  23. Markus Otto24,
  24. Giovanni Frisoni11,25,
  25. Roberta Ghidoni26,
  26. Sandro Sorbi27,
  27. Jonathan Daniel Rohrer28,
  28. Simon Ducharme1,29,
  29. D Louis Collins1,
  30. FTLDNI investigators
  31. GENFI Consortium
      1. 1McConnell Brain Imaging Center, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
      2. 2Radiology and Nuclear Medicine, Laval University, Quebec City, Quebec, Canada
      3. 3Neurology, Erasmus MC, Rotterdam, The Netherlands
      4. 4Department of Clinical and Experimental Sciences, Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Brescia, Italy
      5. 5Alzheimer’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. 6Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain
      7. 7Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Quebec City, Quebec, Canada
      8. 8Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden
      9. 9Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
      10. 10Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
      11. 11LANE - Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
      12. 12Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
      13. 13Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
      14. 14Tanz Centre for Research in Neurodegenerative Disease, Toronto Western Hospital, Toronto, Ontario, Canada
      15. 15Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
      16. 16Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
      17. 17Faculty of Medicine, University of Lisbon, Lisbon, Portugal
      18. 18Neurology and Neuropathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy
      19. 19Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
      20. 20Department of Clinical Neurology, University of Oxford, Oxford, UK
      21. 21Institute of Brain, Behaviour and Mental Health, The University of Manchester, Manchester, UK
      22. 22Neurologische Klinik und Poliklinik, Ludwig-Maximilians Universitat, Munich, Germany
      23. 23German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
      24. 24Department of Neurology, University Hospital Ulm, Ulm, Germany
      25. 25Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland
      26. 26Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
      27. 27Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
      28. 28Dementia Research Centre, UCL Institute of Neurology, London, UK
      29. 29Department of Psychiatry, Douglas Mental Health University Institute, Montreal, Quebec, Canada
      1. Correspondence to Dr Ana L Manera, Montreal Neurological Institute and Hospital, Montreal, QC H3A 2B4, Canada; ana.manera{at}mcgill.ca

      Abstract

      Introduction Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.

      Methods A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation.

      Results Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores.

      Conclusion Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.

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      Footnotes

      • SD and DLC are joint senior authors.

      • Twitter @anitamanera, @sducharme66

      • SD and DLC contributed equally.

      • Collaborators Data used in preparation of this article were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database (http://4rtni-ftldni.ini.usc.edu/). The investigators at NIFD/FTLDNI contributed to the design and implementation of FTLDNI and/or provided data but did not participate in analysis or writing of this report (unless otherwise listed). The FTLDNI investigators included the following individuals: Howard Rosen, University of California, San Francisco (PI); Bradford C. Dickerson, Harvard Medical School and Massachusetts General Hospital; Kimoko Domoto-Reilly, University of Washington School of Medicine; David Knopman, Mayo Clinic, Rochester; Bradley F. Boeve, Mayo Clinic Rochester; Adam L. Boxer, University of California, San Francisco; John Kornak, University of California, San Francisco; Bruce L. Miller, University of California, San Francisco; William W. Seeley, University of California, San Francisco; Maria-Luisa Gorno-Tempini, University of California, San Francisco; Scott McGinnis, University of California, San Francisco; Maria Luisa Mandelli, University of California, San Francisco. GENFI Consortium Members: Sónia Afonso - Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal; Maria Rosario Almeida - Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; Sarah Anderl-Straub - Department of Neurology, Ulm University, Ulm, Germany; Christin Andersson - Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Anna Antonell - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Silvana Archetti - Biotechnology Laboratory, Department of Diagnostics, ASST Brescia Hospital, Brescia, Italy; Andrea Arighi - Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; Mircea Balasa - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Myriam Barandiaran - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Nuria Bargalló - Radiology Department, Image Diagnosis Center, Hospital Clínic and Magnetic Resonance Image core facility, IDIBAPS, Barcelona, Spain; Robart Bartha - Department of Medical Biophysics, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; Benjamin Bender - Department of Diagnostic and Interventional Neuroradiology, University of Tuebingen, Tuebingen, Germany; Alberto Benussi - Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Luisa Benussi - Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Valentina Bessi - Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; Giuliano Binetti - Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sandra Black - LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Toronto, Canada; Martina Bocchetta - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square London, UK; Sergi Borrego-Ecija - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Jose Bras - Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Rose Bruffaerts - Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; Paola Caroppo - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; David Cash - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Miguel Castelo-Branco - Neurology Department, Centro Hospitalar e Universitário de Coimbra, Instituto de Ciências Nucleares Aplicadas à Saúde (ICNAS), Coimbra, Portugal; Rhian Convery - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Thomas Cope - Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; Maura Cosseddu - Neurology, ASST Brescia Hospital, Brescia, Italy; María de Arriba - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Giuseppe Di Fede - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; Zigor Díaz - CITA Alzheimer, San Sebastian, Spain; Diana Duro - Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal; Chiara Fenoglio - University of Milan, Centro Dino Ferrari, Milan, Italy; Camilla Ferrari - Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; Carlos Ferreira - Instituto Ciências Nucleares Aplicadas à Saúde, Universidade de Coimbra, Coimbra, Portugal; Catarina B. Ferreira - Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Toby Flanagan - Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK; Nick Fox - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Morris Freedman - Division of Neurology, Baycrest Centre for Geriatric Care, University of Toronto, Toronto, Canada; Giorgio Fumagalli - Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Alazne Gabilondo - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Roberto Gasparotti - Neuroradiology Unit, University of Brescia, Brescia, Italy; Serge Gauthier - Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada; Stefano Gazzina - Neurology, ASST Brescia Hospital, Brescia, Italy; Giorgio Giaccone - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; Ana Gorostidi - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Caroline Greaves – Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square London, UK; Rita Guerreiro - Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Carolin Heller - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Tobias Hoegen - Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany; Begoña Indakoetxea - Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Vesna Jelic - Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Lize Jiskoot - Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Hans-Otto Karnath - Section of Neuropsychology, Department of Cognitive Neurology, Center for Neurology & Hertie-Institute for Clinical Brain Research, Tübingen, Germany; Ron Keren - University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Canada; Maria João Leitão - Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; Albert Lladó - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Gemma Lombardi - Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Sandra Loosli - Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany; Carolina Maruta - Lisbon Faculty of Medicine, Language Research Laboratory, Lisbon, Portugal; Simon Mead - MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Lieke Meeter - Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; Gabriel Miltenberger - Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Rick van Minkelen - Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Sara Mitchell - LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Toronto, Canada; Katrina M Moore - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Benedetta Nacmias - Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Mollie Neason - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Jennifer Nicholas - Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; Linn Öijerstedt - Department of Geriatric Medicine, Karolinska Institutet, Stockholm, Sweden; Jaume Olives - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Sebastien Ourselin - School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK; Alessandro Padovani - Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Jessica Panman – Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Janne Papma - Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Georgia Peakman - Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Irene Piaceri - Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence; Michela Pievani - Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Yolande Pijnenburg - VUMC, Amsterdam, The Netherlands; Cristina Polito - Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy; Enrico Premi - Stroke Unit, ASST Brescia Hospital, Brescia, Italy; Sara Prioni - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; Catharina Prix - Department of Neurology, Ludwig-Maximilians-University Munich, Germany; Rosa Rademakers - Department of Neurosciences, Mayo Clinic, Jacksonville, Florida, USA; Veronica Redaelli - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; Tim Rittman - Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Ekaterina Rogaeva - Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Pedro Rosa-Neto - Translational Neuroimaging Laboratory, McGill University Montreal, Québec, Canada; Giacomina Rossi - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy; Martin Rossor - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Beatriz Santiago - Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Elio Scarpini - University of Milan, Centro Dino Ferrari, Milan, Italy; Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; Sonja Schönecker - Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Elisa Semler - Department of Neurology, Ulm University, Ulm, Germany; Rachelle Shafei - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Christen Shoesmith - Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; Miguel Tábuas-Pereira - Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; Mikel Tainta - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain; Ricardo Taipa - Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto - Hospital de Santo António, Oporto, Portugal; David Tang-Wai - University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Canada; David L Thomas - Neuroradiological Academic Unit, UCL Institute of Neurology, London, UK; Hakan Thonberg - Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Carolyn Timberlake - Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Pietro Tiraboschi - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy; Emily Todd - Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Philip Vandamme - Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium; Mathieu Vandenbulcke - Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium; Michele Veldsman - Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, UK ; Ana Verdelho - Department of Neurosciences, Santa Maria Hospital, University of Lisbon, Portugal; Jorge Villanua - OSATEK Unidad de Donostia, San Sebastian, Gipuzkoa, Spain; Jason Warren - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Carlo Wilke - Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; Ione Woollacott - Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Elisabeth Wlasich - Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Henrik Zetterberg - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Miren Zulaica - Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain.

      • Contributors ALM, MD, SD, DLC, JCVS, BB, RS-V, FM, RL, CG, MS, DG, JBR, MM, MCT, EF, RV, AM, FT, IS, CRB, AG, AD, JL, MO, GF, RG, SS and JDR contributed to study concept and design as well as data collection. ALM, MD, SD and DLC contributed to data analysis and interpretation. ALM and MD drafted the manuscript and figures.

      • Funding Data collection and sharing for this project was funded by the Frontotemporal Lobar Degeneration Neuroimaging Initiative (National Institutes of Health Grant R01 AG032306). The study is coordinated through the University of California, San Francisco, Memory and Aging Center. FTLDNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Brain scan acquisition at the McConnell Brain Imaging was supported by the Brain Canada Foundation with support from Health Canada and the Canada Foundation for Innovation (CFI Project 34874). This work was supported by Italian Ministry of Health (CoEN015 and Ricerca Corrente).

      • Competing interests Dr Collins receives funding from the Canadian Institutes of Health Research (MOP-111169), les Fonds de Research Santé Quebec Pfizer Innovation fund, and an NSERC CREATE grant (4140438-2012). We would like to acknowledge funding from the Famille Louise & André Charron. Dr Ducharme receives salary funding from the Fonds de Recherche du Québec-Santé. Dr Collins is co-founder of True Positive Medical Devices. Dr Ducharme is the co-founder of Arctic Fox AI.

      • Patient consent for publication Not required.

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

      • Data availability statement Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. The data that support the findings of this study were obtained from the FTLDNI and GENFI2 datasets. FTLDNI data are openly available at https://ida.loni.usc.edu. GENFI2 data can be shared according to the GENFI data sharing agreement, after review by the GENFI data access committee with final approval granted by the GENFI steering committee.

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