. 2022 Aug;269(8):4322-4332.

doi: 10.1007/s00415-022-11068-0. Epub 2022 Mar 29.

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Arabella Bouzigues¹, Lucy L Russell¹, Georgia Peakman¹, Martina Bocchetta¹, Caroline V Greaves¹, Rhian S Convery¹, Emily Todd¹, James B Rowe², Barbara Borroni³, Daniela Galimberti^{4

5}, Pietro Tiraboschi⁶, Mario Masellis⁷, Maria Carmela Tartaglia⁸, Elizabeth Finger⁹, John C van Swieten¹⁰, Harro Seelaar¹⁰, Lize Jiskoot¹⁰, Sandro Sorbi^{11

12}, Chris R Butler^{13

14}, Caroline Graff^{15

16}, Alexander Gerhard^{17

18}, Tobias Langheinrich^{17

19}, Robert Laforce²⁰, Raquel Sanchez-Valle²¹, Alexandre de Mendonça²², Fermin Moreno^{23

24}, Matthis Synofzik^{25

26}, Rik Vandenberghe^{27

28

29}, Simon Ducharme^{30

31}, Isabelle Le Ber^{32

33

34}, Johannes Levin^{35

36

37}, Adrian Danek³⁵, Markus Otto³⁸, Florence Pasquier^{39

40

41}, Isabel Santana^{42

43}, Jonathan D Rohrer⁴⁴; Genetic FTD Initiative, GENFI

Collaborators, Affiliations

Collaborators

Genetic FTD Initiative, GENFI:
Aitana Sogorb Esteve, Annabel Nelson, Arabella Bouzigues, Carolin Heller, Caroline V Greaves, David Cash, David L Thomas, Emily Todd, Hanya Benotmane, Henrik Zetterberg, Imogen J Swift, Jennifer Nicholas, Kiran Samra, Lucy L Russell, Martina Bocchetta, Rachelle Shafei, Rhian S Convery, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso, Annerose Engel, Maryna Polyakova

Affiliations

¹ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
² Trust and Medical Research Council Cognition and Brain Sciences Unit, Department of Clinical Neurosciences and Cambridge University Hospitals NHS, University of Cambridge, Cambridge, UK.
³ Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁴ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
⁵ Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
⁶ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
⁷ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
⁹ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
¹⁰ Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
¹¹ Department of Neurofarba, University of Florence, Florence, Italy.
¹² IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
¹³ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
¹⁴ Department of Brain Sciences, Imperial College London, London, UK.
¹⁵ Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Bioclinicum, Karolinska Institutet, Solna, Sweden.
¹⁶ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
¹⁷ Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
¹⁸ Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg, Essen, Germany.
¹⁹ Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.
²⁰ Département Des Sciences Neurologiques, Clinique Interdisciplinaire de Mémoire, CHU de Québec, and Faculté de Médecine, Université Laval, Québec, QC, Canada.
²¹ 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.
²² Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²³ Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain.
²⁴ Neuroscience Area, Biodonostia Health Research Institute, Gipuzkoa, San Sebastian, Spain.
²⁵ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
²⁶ Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²⁷ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
²⁸ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
²⁹ Leuven Brain Institute, KU Leuven, Leuven, Belgium.
³⁰ Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³¹ Department of Neurology & Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
³² Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³³ Centre de Référence Des Démences Rares Ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁴ Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁵ Neurologische Klinik Und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany.
³⁶ Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
³⁷ Munich Cluster of Systems Neurology, Munich, Germany.
³⁸ Department of Neurology, University of Ulm, Ulm, Germany.
³⁹ Univ Lille, Lille, France.
⁴⁰ Inserm 1172, Lille, France.
⁴¹ CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, Lille, France.
⁴² Neurology Service, Faculty of Medicine, University Hospital of Coimbra (HUC), University of Coimbra, Coimbra, Portugal.
⁴³ Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁴⁴ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. j.rohrer@ucl.ac.uk.

PMID: 35348856
PMCID: PMC9294015
DOI: 10.1007/s00415-022-11068-0

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Arabella Bouzigues et al. J Neurol. 2022 Aug.

. 2022 Aug;269(8):4322-4332.

doi: 10.1007/s00415-022-11068-0. Epub 2022 Mar 29.

Authors

Collaborators

Genetic FTD Initiative, GENFI:
Aitana Sogorb Esteve, Annabel Nelson, Arabella Bouzigues, Carolin Heller, Caroline V Greaves, David Cash, David L Thomas, Emily Todd, Hanya Benotmane, Henrik Zetterberg, Imogen J Swift, Jennifer Nicholas, Kiran Samra, Lucy L Russell, Martina Bocchetta, Rachelle Shafei, Rhian S Convery, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso, Annerose Engel, Maryna Polyakova

Affiliations

¹ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
² Trust and Medical Research Council Cognition and Brain Sciences Unit, Department of Clinical Neurosciences and Cambridge University Hospitals NHS, University of Cambridge, Cambridge, UK.
³ Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁴ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
⁵ Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
⁶ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
⁷ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
⁹ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
¹⁰ Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
¹¹ Department of Neurofarba, University of Florence, Florence, Italy.
¹² IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
¹³ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
¹⁴ Department of Brain Sciences, Imperial College London, London, UK.
¹⁵ Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Bioclinicum, Karolinska Institutet, Solna, Sweden.
¹⁶ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
¹⁷ Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
¹⁸ Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg, Essen, Germany.
¹⁹ Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.
²⁰ Département Des Sciences Neurologiques, Clinique Interdisciplinaire de Mémoire, CHU de Québec, and Faculté de Médecine, Université Laval, Québec, QC, Canada.
²¹ 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.
²² Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²³ Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain.
²⁴ Neuroscience Area, Biodonostia Health Research Institute, Gipuzkoa, San Sebastian, Spain.
²⁵ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
²⁶ Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²⁷ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
²⁸ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
²⁹ Leuven Brain Institute, KU Leuven, Leuven, Belgium.
³⁰ Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³¹ Department of Neurology & Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada.
³² Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³³ Centre de Référence Des Démences Rares Ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁴ Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁵ Neurologische Klinik Und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany.
³⁶ Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
³⁷ Munich Cluster of Systems Neurology, Munich, Germany.
³⁸ Department of Neurology, University of Ulm, Ulm, Germany.
³⁹ Univ Lille, Lille, France.
⁴⁰ Inserm 1172, Lille, France.
⁴¹ CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, Lille, France.
⁴² Neurology Service, Faculty of Medicine, University Hospital of Coimbra (HUC), University of Coimbra, Coimbra, Portugal.
⁴³ Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁴⁴ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. j.rohrer@ucl.ac.uk.

PMID: 35348856
PMCID: PMC9294015
DOI: 10.1007/s00415-022-11068-0

Abstract

Introduction: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail.

Methods: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis.

Results: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions.

Conclusion: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.

Keywords: C9orf72; Cognition; Frontotemporal dementia; Naming; Progranulin; Tau.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest. Johannes Levin reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG, outside the submitted work.

Figures

**Fig. 1**
Mean scores and standard error on the BNT for each group. Significantly worse performance compared with controls is shown with a star in the bar. Only differences between disease groups and controls, and within each genetic group are shown on the graph. Additional between genetic group differences were seen between MAPT 1 + and both GRN and C9orf72 1 + , between MAPT 0.5 and C9orf72 0.5, and between both MAPT 0 and C9orf72 0 and GRN 0

**Fig. 2**
Neural correlates of naming in C9orf72, MAPT and GRN mutation carriers. Results are shown on a study-specific T1-weighted MRI template in MNI space and at p < 0.05 for Family-Wise error. Colour bars represent T-values

**Fig. 3**
Overlapping neural correlates of naming across the three genetic groups. Comparative results are shown on a study-specific T1-weighted MRI template in MNI space and at p < 0.05 for Family-Wise error. The C9orf72 group are shown in green, the GRN group are shown in red and the MAPT group are shown in yellow

See this image and copyright information in PMC

References

1. Snowden JS. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry. 2001;70(3):323–332. doi: 10.1136/jnnp.70.3.323. - DOI - PMC - PubMed
1. Rohrer JD, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009;73(18):1451–1456. doi: 10.1212/WNL.0b013e3181bf997a. - DOI - PMC - PubMed
1. Hardy CJD, et al. The language profile of behavioral variant frontotemporal dementia. J Alzheimers Dis. 2016;50(2):359–371. doi: 10.3233/JAD-150806. - DOI - PMC - PubMed
1. Rohrer JD, et al. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol. 2015;14(3):291–301. doi: 10.1016/S1474-4422(14)70233-9. - DOI - PubMed
1. Snowden JS, et al. Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotroph Lateral Scler Front Degener. 2015;16(7–8):497–505. doi: 10.3109/21678421.2015.1074700. - DOI - PubMed

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Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Collaborators

Affiliations

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Authors

Collaborators

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Abstract

Conflict of interest statement

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