{
  "abstract": "Background Brain structural changes in frontotemporal dementia (FTD) can occur decades before symptom onset. Precise characterisation of grey matter changes is necessary for developing models of biomarker progression, while better understanding the trajectory of the pathology is invaluable for prognosis and detecting treatment effects as we enter the era of clinical trials.Methods Cortical and subcortical grey matter volume and thickness from structural MRI were assessed in a large cohort of 892 participants including presymptomatic and symptomatic carriers of mutations within the three main genetic causes of FTD (C9 open reading-frame 72 (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT)) compared with mutation-negative relatives (controls). We compared the distribution of grey matter changes of each metric at different stages of the disease cross sectionally. We aimed to identify grey matter composites for each genetic group which would show the earliest changes and which separated presymptomatic carriers from controls.Results While C9orf72 mutation carriers showed widespread presymptomatic grey matter changes, MAPT and particularly GRN mutation carriers showed changes more proximally to symptom onset. Our composite grey matter signatures, which discriminate asymptomatic/prodromal carriers from controls with high to very high areas under the curve, involved bilateral thalami volumes, precuneus and postcentral thickness in C9orf72; left caudal middle frontal thickness, frontal pole and pars orbitalis volumes in GRN; right temporal pole volume and left insula thickness in MAPT mutation carriers.Conclusion We propose the use of cortical thickness and volume measurements combined from multiple regions into a composite region of interest for each FTD genetic group to identify the earliest changes and track disease progression. Our quasi-longitudinal design illustrates that these regions continue to evolve throughout the symptomatic stages. Investigating how our selected composites progress and validating these in longitudinal samples will be invaluable for future clinical trials.",
  "authors": [
    {
      "affiliations": [
        "Hôpital Pitié-Salpêtrière, Paris Brain Institute, Paris, France",
        "Queen Square Institute of Neurology, University College London Dementia Research Centre, London, UK"
      ],
      "name": "Arabella Bouzigues"
    },
    {
      "affiliations": [
        "Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy"
      ],
      "name": "Giulia Campana"
    },
    {
      "affiliations": [
        "Hôpital Pitié-Salpêtrière, Paris Brain Institute, Paris, France"
      ],
      "name": "Matthieu Joulot"
    },
    {
      "affiliations": [
        "Hôpital Pitié-Salpêtrière, Paris Brain Institute, Paris, France"
      ],
      "name": "Nicolas Gensollen"
    },
    {
      "affiliations": [
        "Queen Square Institute of Neurology, University College London Dementia Research Centre, London, UK"
      ],
      "name": "Lucy L Russell"
    },
    {
      "affiliations": [
        "Queen Square Institute of Neurology, University College London Dementia Research Centre, London, UK"
      ],
      "name": "Phoebe H Foster"
    },
    {
      "affiliations": [
        "Queen Square Institute of Neurology, University College London Dementia Research Centre, London, UK"
      ],
      "name": "Eve Ferry-Bolder"
    },
    {
      "affiliations": [
        "Neurology, Erasmus MC, Rotterdam, The Netherlands"
      ],
      "name": "John Cornelis Van Swieten"
    },
    {
      "affiliations": [
        "Neurology, Erasmus MC, Rotterdam, The Netherlands"
      ],
      "name": "Lize C Jiskoot"
    },
    {
      "affiliations": [
        "Neurology, Erasmus MC, Rotterdam, The Netherlands"
      ],
      "name": "Harro Seelaar"
    },
    {
      "affiliations": [
        "Department of Neurology, Hospital Clinic de Barcelona, Barcelona, Spain",
        "Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain"
      ],
      "name": "Raquel Sánchez-Valle"
    },
    {
      "affiliations": [
        "Clinique Interdisciplinaire de Mémoire du CHU de Québec, Laval University, Québec City, Quebec, Canada"
      ],
      "name": "Robert Laforce"
    },
    {
      "affiliations": [
        "Department of Neurobiology, Care Sciences and Society, KI-ADRC, KASPAC, Novum, Karolinska Universitetssjukhuset, Stockholm, Sweden",
        "Unit for Hereditary Dementias, Theme Inflammation and Aging, Karolinska Institute, Stockholm, Sweden"
      ],
      "name": "Caroline Graff"
    },
    {
      "affiliations": [
        "Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy",
        "Centro Dino Ferrari, University of Milan, Milan, Italy"
      ],
      "name": "Daniela Galimberti"
    },
    {
      "affiliations": [
        "Neurology Service, University Hospitals Leuven, Leuven, Belgium",
        "Leuven Brain Institute, KU Leuven, Leuven, Belgium",
        "Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium"
      ],
      "name": "Rik Vandenberghe"
    },
    {
      "affiliations": [
        "Faculty of Medicine, University of Lisbon, Lisbon, Portugal"
      ],
      "name": "Alexandre de Mendonca"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Pietro Tiraboschi"
    },
    {
      "affiliations": [
        "Neurology Service, Faculty of Medicine, Coimbra University Hospital Centre, Coimbra, Portugal",
        "Faculty of Medicine, University of Coimbra Center for Neuroscience and Cell Biology, Coimbra, Portugal"
      ],
      "name": "Isabel Santana"
    },
    {
      "affiliations": [
        "Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK",
        "Department of Nuclear Medicine, Center for Translational Neuro- and Behavioral Sciences, University of Duisburg-Essen Faculty of Medicine, Essen, Germany",
        "Department of Geriatric Medicine, Klinikum Hochsauerland, Arnsberg, Germany"
      ],
      "name": "Alexander Gerhard"
    },
    {
      "affiliations": [
        "Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany",
        "German Centre for Neurodegenerative Diseases, Munich, Germany",
        "Munich Cluster of Systems Neurology (SyNergy), Munich, Germany"
      ],
      "name": "Johannes Levin"
    },
    {
      "affiliations": [
        "Department of Neurofarba, University of Florence, Firenze, Italy",
        "IRCCS Firenze, Fondazione Don Carlo Gnocchi, Firenze, Italy"
      ],
      "name": "Sandro Sorbi"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany",
        "Neurology, Martin-Luther-Universitat Halle-Wittenberg, Halle (Saale), Germany"
      ],
      "name": "Markus Otto"
    },
    {
      "affiliations": [
        "Lille Neurosciences & Cognition U1172, Inserm, Université de Lille, CHU Lille, Lille, France"
      ],
      "name": "Maxime Bertoux"
    },
    {
      "affiliations": [
        "Lille Neurosciences & Cognition U1172, Inserm, Université de Lille, CHU Lille, Lille, France"
      ],
      "name": "Thibaud Lebouvier"
    },
    {
      "affiliations": [
        "Department of Psychiatry, Douglas Mental Health University Institute, Montreal, Quebec, Canada",
        "McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada"
      ],
      "name": "Simon Ducharme"
    },
    {
      "affiliations": [
        "Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK",
        "Department of Brain Sciences, Imperial College London, London, UK"
      ],
      "name": "Chris Butler"
    },
    {
      "affiliations": [
        "Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada"
      ],
      "name": "Elizabeth Finger"
    },
    {
      "affiliations": [
        "Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Maria Carmela Tartaglia"
    },
    {
      "affiliations": [
        "Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Mario Masellis"
    },
    {
      "affiliations": [
        "Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK"
      ],
      "name": "James Benedict Rowe"
    },
    {
      "affiliations": [
        "Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany",
        "Center for Neurodegenerative Diseases, DZNE, Tubingen, Germany"
      ],
      "name": "Matthis Synofzik"
    },
    {
      "affiliations": [
        "Cognitive Disorders Unit, Department of Neurology, University Hospital of Donostia, San Sebastián, Spain",
        "Group of Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, San Sebastián, Spain"
      ],
      "name": "Fermin Moreno"
    },
    {
      "affiliations": [
        "Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy",
        "Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy"
      ],
      "name": "Barbara Borroni"
    },
    {
      "affiliations": [
        "Hôpital Pitié-Salpêtrière, Paris Brain Institute, Paris, France",
        "Groupe Hospitalier Pitié-Salpêtrière, Department of Neurology, IM2A, AP-HP, Paris, France"
      ],
      "name": "Isabelle Leber"
    },
    {
      "affiliations": [
        "Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy"
      ],
      "name": "Gianluigi Zanusso"
    },
    {
      "affiliations": [
        "Queen Square Institute of Neurology, University College London Dementia Research Centre, London, UK"
      ],
      "name": "Jonathan Daniel Rohrer"
    },
    {
      "affiliations": [
        "Hôpital Pitié-Salpêtrière, Paris Brain Institute, Paris, France",
        "Groupe Hospitalier Pitié-Salpêtrière, Department of Neurology, IM2A, AP-HP, Paris, France"
      ],
      "name": "Raffaella Migliaccio"
    },
    {
      "affiliations": [],
      "name": "on behalf of the GENetic Frontotemporal dementia Initiative (GENFI)"
    }
  ],
  "title": "Composite grey matter fingerprints for genetic frontotemporal dementia",
  "uid": "cc7c93eb-37f6-5e1e-99c0-65bcbb6e6fec"
}