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Research paper
Education modulates brain maintenance in presymptomatic frontotemporal dementia
  1. Stefano Gazzina1,
  2. Mario Grassi2,
  3. Enrico Premi3,
  4. Maura Cosseddu4,
  5. Antonella Alberici1,
  6. Silvana Archetti5,
  7. Roberto Gasparotti6,
  8. John Van Swieten7,
  9. Daniela Galimberti8,9,
  10. Raquel Sanchez-Valle10,
  11. Robert Jr Laforce11,
  12. Fermin Moreno12,
  13. Matthis Synofzik13,14,
  14. Caroline Graff15,
  15. Mario Masellis16,
  16. Maria Carmela Tartaglia17,
  17. James B Rowe18,
  18. Rik Vandenberghe19,
  19. Elizabeth Finger20,
  20. Fabrizio Tagliavini21,
  21. Alexandre de Mendonça22,
  22. Isabel Santana23,
  23. Christopher R Butler24,
  24. Simon Ducharme25,26,
  25. Alex Gerhard27,
  26. Adrian Danek28,
  27. Johannes Levin28,
  28. Markus Otto29,
  29. Giovanni Frisoni30,31,
  30. Sandro Sorbi32,33,
  31. Alessandro Padovani1,
  32. Jonathan D Rohrer34,
  33. Barbara Borroni1
  34. on behalf of the Genetic FTD Initiative, GENFI
    1. 1Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
    2. 2Department of Brain and Behavioral Science, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy
    3. 3Stroke Unit, Neurology Unit, Spedali Civili Hospital, Brescia, Italy
    4. 4Neurology Unit, Spedali Civili Hospital, Brescia, Italy
    5. 5Biotechnology Laboratory, Department of Diagnostics, Spedali Civili Hospital, Brescia, Italy
    6. 6Neuroradiology Unit, University of Brescia, Brescia, Italy
    7. 7Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands
    8. 8Centro Dino Ferrari, University of Milan, Milan, Italy
    9. 9Neurodegenerative Diseases Unit, Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
    10. 10Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain
    11. 11Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Québec, Quebec, Canada
    12. 12Department of Neurology, Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain
    13. 13Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany
    14. 14German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
    15. 15Karolinska Institutet, Department NVS, Center for Alzheimer Research, Division of Neurogenetics, Stockholm, Sweden
    16. 16LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Toronto, Ontario, Canada
    17. 17Toronto Western Hospital, Tanz Centre for Research in Neurodegenerative Disease, Toronto, Ontario, Canada
    18. 18Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    19. 19Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium
    20. 20Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
    21. 21Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy
    22. 22Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    23. 23Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
    24. 24Department of Clinical Neurology, University of Oxford, Oxford, United Kingdom
    25. 25Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
    26. 26McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
    27. 27Institute of Brain, Behaviour and Mental Health, The University of Manchester, Withington, Manchester, United Kingdom
    28. 28Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    29. 29Department of Neurology, University Hospital Ulm, Ulm, Germany
    30. 30Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
    31. 31Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland
    32. 32Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
    33. 33Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Don Gnocchi”, Florence, Italy
    34. 34Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom
    1. Correspondence to Professor Barbara Borroni, Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; bborroni{at}inwind.it

    Abstract

    Objective Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.

    Methods Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.

    Results Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.

    Conclusions This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

    • frontotemporal dementia (FTD)
    • brain reserve
    • brain maintenance
    • graph theory
    • magnetic resonance imaging (MRI)
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    • Collaborators List of other GENFI consortium members: Maria Rosario Almeida - Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portuga; Sarah Anderl-Straub - 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; 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 Radiology, University of Tuebingen, Tuebingen, Germany; Luisa Benussi - Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Thomas Cope - University of Cambridge, Cambridge, UK; 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 - ITA Alzheimer, San Sebastian, Spain; Katrina M Dick - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Diana Duro - Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal; Chiara Fenoglio - University of Milan, Centro Dino Ferrari, Milan, 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 - University of Manchester, Manchester, UK; Nick Fox - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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; Serge Gauthier - Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada; Roberta Ghidoni - Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Rita Guerreiro - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Carolin Heller - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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; Benedetta Nacmias - Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Mollie Neason - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Jennifer Nicholas - The London School of Hygiene and Tropical Medicine, London, UK; Linn Öijerstedt - Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Jaume Olives - Alzheimer’s disease and other cognitive disorders unit, Neurology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques, Barcelona, Spain; Jessica Panman – Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Janne Papma - Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Maximilian Patzig - Department of Neuroradiology, Ludwig-Maximilians-University Munich, Germany; 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; 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 - 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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; Elisa Semler - Ulm University, Ulm, Germany; Rachelle Shafei - Department of Neurodegenerative Disease, UCL Institute of Neurology, 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; 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 - University of Cambridge, Cambridge, UK; Pietro Tiraboschi - Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy; 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 - 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 - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Carlo Wilke - Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, 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 SG planned the study, conducted the statistical analyses, contributed to interpretation of the results and drafted the initial version of the manuscript; MG carried out the statistical analyses and contributed to interpretation of the results; EP, MC, AA, SA, RG, JvS, DG, RS-V, RL Jr, FM, MS, CG, MM, MCT, JBR, RV, EF, FT, AdeM, IS, CB, SD, AG, AD, JL, MO, GF, SS, AP and JDR contributed to acquisition of data; Barbara Borroni planned the study, contributed to interpretation of the results, drafted the initial version of the manuscript and is responsible for the overall content as guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by Brescia Hospital Ethics Committee (NP2224). Local ethics committees approved the study at each site.

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

    • Data sharing statement Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information.

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