An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers

Article type: Research Article

Authors: Premi, Enrico^{a; b; 1} | Costa, Tommaso^{c; d; e; 1} | Gazzina, Stefano^a | Benussi, Alberto^a | Cauda, Franco^{c; d; e} | Gasparotti, Roberto^f | Archetti, Silvana^g | Alberici, Antonella^a | van Swieten, John C.^h | Sanchez-Valle, Raquelⁱ | Moreno, Fermin^{j; k} | Santana, Isabel^{l; m; n} | Laforce, Robert^o | Ducharme, Simon^{p; q} | Graff, Caroline^{r; s} | Galimberti, Daniela^{t; u} | Masellis, Mario^v | Tartaglia, Carmela^w | Rowe, James B.^x | Finger, Elizabeth^y | Tagliavini, Fabrizio^z | de Mendonça, Alexandre^aa | Vandenberghe, Rik^{bb; cc; dd} | Gerhard, Alexander^{ee; ff} | Butler, Chris R.^gg | Danek, Adrian^hh | Synofzik, Matthis^{ii; jj} | Levin, Johannes^{hh; kk} | Otto, Markus^ll | Ghidoni, Roberta^mm | Frisoni, Giovanni^{nn; oo} | Sorbi, Sandro^{pp; qq} | Peakman, Georgia^rr | Todd, Emily^rr | Bocchetta, Martina^rr | Rohrer, Johnathan D.^rr | Borroni, Barbara^{a; *} | GENFI Consortium Members

Collaborators: Afonso, Sónia | Rosario Almeida, Maria | Anderl-Straub, Sarah | Andersson, Christin | Antonell, Anna | Arighi, Andrea | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robart | Bender, Benjamin | Benussi, Luisa | Bessi, Valentina | Binetti, Giuliano | Black, Sandra | Borrego-Ecija, Sergi | Bras, Jose | Bruffaerts, Rose | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Convery, Rhian | Cope, Thomas | de Arriba, María | Di Fede, Giuseppe | Díaz, Zigor | Duro, Diana | Fenoglio, Chiara | Ferrari, Camilla | B. Ferreira, Catarina | Fox, Nick | Freedman, Morris | Fumagalli, Giorgio | Gabilondo, Alazne | Gauthier, Serge | Giaccone, Giorgio | Gorostidi, Ana | Greaves, Caroline | Guerreiro, Rita | Heller, Carolin | Hoegen, Tobias | Indakoetxea, Begoña | Jelic, Vesna | Jiskoot, Lize | Karnath, Hans-Otto | Keren, Ron | Langheinrich, Tobias | João Leitão, Maria | Lladó, Albert | Lombardi, Gemma | Loosli, Sandra | Maruta, Carolina | Mead, Simon | Meeter, Lieke | Miltenberger, Gabriel | van Minkelen, Rick | Mitchell, Sara | Moore, Katrina | Nacmias, Benedetta | Nicholas, Jennifer | Öijerstedt, Linn | Olives, Jaume | Panman, Jessica | Papma, Janne | Pievani, Michela | Pijnenburg, Yolande | Polito, Cristina | Prioni, Sara | Prix, Catharina | Rademakers [as London Ontario geneticist], Rosa | Redaelli, Veronica | Rittman, Tim | Rogaeva, Ekaterina | Rosa-Neto, Pedro | Rossi, Giacomina | Rossor, Martin | Santiago, Beatriz | Scarpini, Elio | Schönecker, Sonja | Semler, Elisa | Shafei, Rachelle | Shoesmith, Christen | Tábuas-Pereira, Miguel | Tainta, Mikel | Taipa, Ricardo | Tang-Wai, David | L Thomas, David | Thompson, Paul | Thonberg, Hakan | Timberlake, Carolyn | Tiraboschi, Pietro | Van Damme, Philip | Vandenbulcke, Mathieu | Veldsman, Michele | Verdelho, Ana | Villanua, Jorge | Warren, Jason | Wilke, Carlo | Woollacott, Ione | Wlasich, Elisabeth | Zetterberg, Henrik | Zulaica, Miren

Affiliations: Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Department of Neurology, University of Ulm, Ulm, Germany; | Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain; | Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; | Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | CITA Alzheimer, San Sebastian, Gipuzkoa, Spain; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; | Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; | The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada; | Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; | Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; | Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London UK; | Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; | Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; | Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Department of Neurology, Erasmus Medical Center, Rotterdam; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands; | Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Department of Neurosciences, Mayo Clinic, Jacksonville, Florida, USA; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; | Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; | Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Department of Neurology, University of Ulm, Ulm; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; | Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto Hospital de Santo António, Oporto, Portugal; | The University Health Network, Krembil Research Institute, Toronto, Canada; | Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK; | Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; | Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; | Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium; | Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium; | Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK; | Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain. | [a] Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy | [b] Stroke Unit, Azienda Socio Sanitaria Territoriale Spedali Civili, Spedali Civili Hospital, Brescia, Italy | [c] Focus Lab, Department of Psychology, University of Turin, Turin, Italy | [d] GCS-FMRI, Koelliker Hospital and Department of Psychology, University of Turin, Turin, Italy | [e] Neuroscience Institute of Turin, University of Turin, Turin, Italy | [f] Neuroradiology Unit, University of Brescia, Brescia, Italy | [g] Biotechnology Laboratory, Department of Diagnostic, Spedali Civili Hospital, Brescia, Italy | [h] Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands | [i] Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain | [j] Department of Neurology, Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain | [k] Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain | [l] Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal | [m] Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [n] Centre of Neurosciences and Cell biology, Universidade de Coimbra, Coimbra, Portugal | [o] Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Faculté de Médecine, CHU de Québec-Université Laval, QC, Canada | [p] Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, QC, Canada | [q] McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada | [r] Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden | [s] Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden | [t] Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, University of Milan, Milan, Italy | [u] Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy | [v] Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON, Canada | [w] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada | [x] Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK | [y] Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada | [z] Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy | [aa] Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal | [bb] Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium | [cc] Neurology Service, University Hospitals Leuven, Belgium | [dd] Leuven Brain Institute, KU Leuven, Leuven, Belgium | [ee] Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK | [ff] Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Germany | [gg] Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK | [hh] Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany | [ii] Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany | [jj] German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany | [kk] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany | [ll] Department of Neurology, University Hospital Ulm, Ulm, Germany | [mm] Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [nn] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [oo] Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland | [pp] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy | [qq] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Don Gnocchi”, Florence, Italy | [rr] Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK | Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Department of Neurology, University of Ulm, Ulm, Germany; | Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain; | Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; | Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | CITA Alzheimer, San Sebastian, Gipuzkoa, Spain; | Faculty of Medicine, University of Coimbra, Coimbra, Portugal; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; | Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; | The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada; | Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; | Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; | Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London UK; | Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; | Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; | Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden; | Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; | Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; | Department of Neurology, Erasmus Medical Center, Rotterdam; | Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; | Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands; | Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Department of Neurosciences, Mayo Clinic, Jacksonville, Florida, USA; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; | Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; | Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; | Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Department of Neurology, University of Ulm, Ulm; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; | Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; | Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto Hospital de Santo António, Oporto, Portugal; | The University Health Network, Krembil Research Institute, Toronto, Canada; | Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK; | Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; | Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; | Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; | Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; | Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium; | Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium; | Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK; | Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal; | OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; | Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; | Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; | Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain.

Correspondence: [*] Barbara Borroni, MD, Centre for Neuro-degenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives:To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods:84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results:Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion:The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself.

Keywords: Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic

DOI: 10.3233/JAD-215447

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 205-218, 2022