Alberto Benussi1, Enrico Premi2, Stefano Gazzina3, Chiara Brattini1, Elisa Bonomi1, Antonella Alberici4, Lize Jiskoot5, John C van Swieten5, Raquel Sanchez-Valle6, Fermin Moreno7,8, Robert Laforce9, Caroline Graff10,11, Matthis Synofzik12,13, Daniela Galimberti14,15, Mario Masellis16, Carmela Tartaglia17, James B Rowe18, Elizabeth Finger19, Rik Vandenberghe20,21,22, Alexandre de Mendonça23, Fabrizio Tagliavini24, Isabel Santana25,26, Simon Ducharme27,28, Chris R Butler29,30, Alexander Gerhard31,32, Johannes Levin33,34,35, Adrian Danek33, Markus Otto36, Giovanni Frisoni37, Roberta Ghidoni38, Sandro Sorbi39,40, Isabelle Le Ber41,42,43,44, Florence Pasquier45,46,47, Georgia Peakman47, Emily Todd47, Martina Bocchetta47, Jonathan D Rohrer47, Barbara Borroni1. 1. Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. 2. Vascular Neurology Unit, Department of Neurological and Vision Sciences, ASST Spedali Civili, Brescia, Italy. 3. Neurophysiology Unit, Department of Neurological and Vision Sciences, ASST Spedali Civili, Brescia, Italy. 4. Neurology Unit, Department of Neurological and Vision Sciences, ASST Spedali Civili, Brescia, Italy. 5. Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands. 6. 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. 7. Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain. 8. Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain. 9. Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques du CHU de Québec, and Faculté de Médecine, Université Laval, Québec, Canada. 10. Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden. 11. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden. 12. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany. 13. Center for Neurodegenerative Diseases, Tübingen, Germany. 14. Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy. 15. University of Milan, Centro Dino Ferrari, Milan, Italy. 16. Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. 17. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada. 18. Department of Clinical Neurosciences, University of Cambridge, United Kingdom. 19. Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada. 20. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium. 21. Neurology Service, University Hospitals Leuven, Leuven, Belgium. 22. Leuven Brain Institute, KU Leuven, Leuven, Belgium. 23. Faculty of Medicine, University of Lisbon, Lisbon, Portugal. 24. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. 25. Neurology Service, Faculty of Medicine, University Hospital of Coimbra, University of Coimbra, Coimbra, Portugal. 26. Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 27. Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Québec, Canada. 28. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada. 29. Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom. 30. Department of Brain Sciences, Imperial College London, London, United Kingdom. 31. Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom. 32. Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany. 33. Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany. 34. German Center for Neurodegenerative Diseases, Munich, Germany. 35. Munich Cluster of Systems Neurology, Munich, Germany. 36. Department of Neurology, University of Ulm, Ulm, Germany. 37. IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 38. Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 39. Department of Neurofarba, University of Florence, Florence, Italy. 40. IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. 41. Institut National de la Santé et de la Recherche Medicale (INSERM) U1127, Paris, France. 42. Centre de National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 7225, Paris, France. 43. Unité Mixte de Recherche en Santé 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, Paris, France. 44. Institute du Cerveau et de la Moelle Epinière, Paris, France. 45. Inserm CHU Lille, Lille Neurosciences & Cognition UMR-S1172 Degenerative and Vascular Cognitive Disorders, Université de Lille, Lille, France. 46. CHU Lille, DistAlz Licend Memory Clinic, Lille, France. 47. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, United Kingdom.
Abstract
Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers. Conclusions and Relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.
Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers. Conclusions and Relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.
Authors: Tiffany W Chow; Jonathan D Fridhandler; Malcolm A Binns; Albert Lee; Jennifer Merrilees; Howie J Rosen; Robin Ketelle; Bruce L Miller Journal: J Alzheimers Dis Date: 2012 Impact factor: 4.472
Authors: S Agarwal; R M Ahmed; M D'Mello; D Foxe; C Kaizik; M C Kiernan; G M Halliday; O Piguet; J R Hodges Journal: Eur J Neurol Date: 2019-01-29 Impact factor: 6.089
Authors: Emma L van der Ende; Lieke H Meeter; Jackie M Poos; Jessica L Panman; Lize C Jiskoot; Elise G P Dopper; Janne M Papma; Frank Jan de Jong; Inge M W Verberk; Charlotte Teunissen; Dimitris Rizopoulos; Carolin Heller; Rhian S Convery; Katrina M Moore; Martina Bocchetta; Mollie Neason; David M Cash; Barbara Borroni; Daniela Galimberti; Raquel Sanchez-Valle; Robert Laforce; Fermin Moreno; Matthis Synofzik; Caroline Graff; Mario Masellis; Maria Carmela Tartaglia; James B Rowe; Rik Vandenberghe; Elizabeth Finger; Fabrizio Tagliavini; Alexandre de Mendonça; Isabel Santana; Chris Butler; Simon Ducharme; Alex Gerhard; Adrian Danek; Johannes Levin; Markus Otto; Giovanni B Frisoni; Stefano Cappa; Yolande A L Pijnenburg; Jonathan D Rohrer; John C van Swieten Journal: Lancet Neurol Date: 2019-12 Impact factor: 44.182
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Authors: Annabel Nelson; Lucy L Russell; Georgia Peakman; Rhian S Convery; Arabella Bouzigues; Caroline V Greaves; Martina Bocchetta; David M Cash; John C van Swieten; Lize Jiskoot; Fermin Moreno; Raquel Sanchez-Valle; Robert Laforce; Caroline Graff; Mario Masellis; Maria Carmela Tartaglia; James B Rowe; Barbara Borroni; Elizabeth Finger; Matthis Synofzik; Daniela Galimberti; Rik Vandenberghe; Alexandre de Mendonça; Chris R Butler; Alexander Gerhard; Simon Ducharme; Isabelle Le Ber; Isabel Santana; Florence Pasquier; Johannes Levin; Markus Otto; Sandro Sorbi; Jonathan D Rohrer Journal: Ann Clin Transl Neurol Date: 2022-03-26 Impact factor: 5.430
Authors: Jackie M Poos; Esther van den Berg; Janne M Papma; Fleur C van der Tholen; Harro Seelaar; Laura Donker Kaat; J Anneke Kievit; Aad Tibben; John C van Swieten; Lize C Jiskoot Journal: Front Psychiatry Date: 2022-04-27 Impact factor: 5.435
Authors: Megan S Barker; Reena T Gottesman; Masood Manoochehri; Silvia Chapman; Brian S Appleby; Danielle Brushaber; Katrina L Devick; Bradford C Dickerson; Kimiko Domoto-Reilly; Julie A Fields; Leah K Forsberg; Douglas R Galasko; Nupur Ghoshal; Jill Goldman; Neill R Graff-Radford; Murray Grossman; Hilary W Heuer; Ging-Yuek Hsiung; David S Knopman; John Kornak; Irene Litvan; Ian R Mackenzie; Joseph C Masdeu; Mario F Mendez; Belen Pascual; Adam M Staffaroni; Maria Carmela Tartaglia; Bradley F Boeve; Adam L Boxer; Howard J Rosen; Katherine P Rankin; Stephanie Cosentino; Katya Rascovsky; Edward D Huey Journal: Brain Date: 2022-04-29 Impact factor: 15.255
Authors: Alberto Benussi; Nicholas J Ashton; Thomas K Karikari; Antonella Alberici; Claudia Saraceno; Roberta Ghidoni; Luisa Benussi; Henrik Zetterberg; Kaj Blennow; Barbara Borroni Journal: Alzheimers Res Ther Date: 2021-11-15 Impact factor: 6.982
Authors: Georgia Peakman; Lucy L Russell; Rhian S Convery; Jennifer M Nicholas; John C Van Swieten; Lize C Jiskoot; Fermin Moreno; Raquel Sanchez-Valle; Robert Laforce; Caroline Graff; Mario Masellis; Maria Carmela Tartaglia; James B Rowe; Barbara Borroni; Elizabeth Finger; Matthis Synofzik; Daniela Galimberti; Rik Vandenberghe; Alexandre de Mendonça; Chris R Butler; Alex Gerhard; Simon Ducharme; Isabelle Le Ber; Fabrizio Tagliavini; Isabel Santana; Florence Pasquier; Johannes Levin; Adrian Danek; Markus Otto; Sandro Sorbi; Jonathan D Rohrer Journal: J Neurol Neurosurg Psychiatry Date: 2021-08-05 Impact factor: 10.154