Jonathan D Rohrer1, Jennifer M Nicholas2, David M Cash3, John van Swieten4, Elise Dopper4, Lize Jiskoot4, Rick van Minkelen5, Serge A Rombouts6, M Jorge Cardoso3, Shona Clegg1, Miklos Espak3, Simon Mead7, David L Thomas8, Enrico De Vita9, Mario Masellis10, Sandra E Black10, Morris Freedman11, Ron Keren12, Bradley J MacIntosh10, Ekaterina Rogaeva13, David Tang-Wai12, Maria Carmela Tartaglia13, Robert Laforce14, Fabrizio Tagliavini15, Pietro Tiraboschi15, Veronica Redaelli15, Sara Prioni15, Marina Grisoli15, Barbara Borroni16, Alessandro Padovani16, Daniela Galimberti17, Elio Scarpini17, Andrea Arighi17, Giorgio Fumagalli17, James B Rowe18, Ian Coyle-Gilchrist18, Caroline Graff19, Marie Fallström20, Vesna Jelic21, Anne Kinhult Ståhlbom19, Christin Andersson22, Håkan Thonberg19, Lena Lilius23, Giovanni B Frisoni24, Michela Pievani25, Martina Bocchetta26, Luisa Benussi25, Roberta Ghidoni25, Elizabeth Finger27, Sandro Sorbi28, Benedetta Nacmias28, Gemma Lombardi28, Cristina Polito29, Jason D Warren1, Sebastien Ourselin3, Nick C Fox1, Martin N Rossor30, Giuliano Binetti. 1. Dementia Research Centre, University College London, London, UK. 2. Dementia Research Centre, University College London, London, UK; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK. 3. Dementia Research Centre, University College London, London, UK; Department of Neurodegenerative Disease, University College London Institute of Neurology, and Centre for Medical Image Computing, University College London, London, UK. 4. Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands. 5. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands. 6. Institute of Psychology, Leiden University, and Department of Radiology, Leiden University Medical Center, Leiden, Netherlands. 7. Medical Research Council Prion Unit, University College London, London, UK. 8. Dementia Research Centre, University College London, London, UK; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, University College London, London, UK. 9. Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, University College London, London, UK; Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK. 10. LC Campbell Cognitive Neurology Research Unit, Department of Medicine, Division of Neurology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. 11. Department of Medicine, Division of Neurology, Baycrest, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; Rotman Research Institute, Baycrest, Toronto, ON, Canada. 12. University Health Network Memory Clinic, Toronto Western Hospital, Toronto, ON, Canada. 13. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada. 14. Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Hôpital de l'Enfant-Jésus, and Faculté de Médecine, Université Laval, QC, Canada. 15. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy. 16. Neurology Unit, Department of Medical and Experimental Sciences, University of Brescia, Brescia, Italy. 17. Neurology Unit, Department of Physiopathology and Transplantation, University of Milan, Fondazione Cà Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan, Italy. 18. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 19. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden. 20. Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden. 21. Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden. 22. Department of Clinical Neuroscience, Karolinska Institutet, Huddinge, Sweden; Department of Psychology, Karolinska University Hospital-Huddinge, Stockholm, Sweden. 23. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden. 24. Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland. 25. Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 26. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. 27. Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada. 28. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. 29. Department of Clinical Pathophysiology, Nuclear Medicine Division, University of Florence, Florence, Italy. 30. Dementia Research Centre, University College London, London, UK. Electronic address: m.rossor@ucl.ac.uk.
Abstract
BACKGROUND: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING: Centres of Excellence in Neurodegeneration.
BACKGROUND: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING: Centres of Excellence in Neurodegeneration.
Authors: William W Seeley; Vinod Menon; Alan F Schatzberg; Jennifer Keller; Gary H Glover; Heather Kenna; Allan L Reiss; Michael D Greicius Journal: J Neurosci Date: 2007-02-28 Impact factor: 6.167
Authors: John C Morris; Sandra Weintraub; Helena C Chui; Jeffrey Cummings; Charles Decarli; Steven Ferris; Norman L Foster; Douglas Galasko; Neill Graff-Radford; Elaine R Peskind; Duane Beekly; Erin M Ramos; Walter A Kukull Journal: Alzheimer Dis Assoc Disord Date: 2006 Oct-Dec Impact factor: 2.703
Authors: Salvatore Spina; Martin R Farlow; Frederick W Unverzagt; David A Kareken; Jill R Murrell; Graham Fraser; Francine Epperson; R Anthony Crowther; Maria G Spillantini; Michel Goedert; Bernardino Ghetti Journal: Brain Date: 2007-12-07 Impact factor: 13.501
Authors: B Borroni; A Alberici; E Premi; S Archetti; V Garibotto; C Agosti; R Gasparotti; M Di Luca; D Perani; A Padovani Journal: Rejuvenation Res Date: 2008-06 Impact factor: 4.663
Authors: Carlos Cruchaga; Maria A Fernández-Seara; Manuel Seijo-Martínez; Lluis Samaranch; Elena Lorenzo; Anthony Hinrichs; Jaione Irigoyen; Cristina Maestro; Elena Prieto; Josep M Martí-Climent; Javier Arbizu; Maria A Pastor; Pau Pastor Journal: Cereb Cortex Date: 2008-11-19 Impact factor: 5.357
Authors: J C Janssen; J M Schott; L Cipolotti; N C Fox; R I Scahill; K A Josephs; J M Stevens; M N Rossor Journal: J Neurol Neurosurg Psychiatry Date: 2005-02 Impact factor: 10.154
Authors: Rachael I Scahill; Jonathan M Schott; John M Stevens; Martin N Rossor; Nick C Fox Journal: Proc Natl Acad Sci U S A Date: 2002-04-02 Impact factor: 11.205
Authors: Jonathan D Rohrer; Jason D Warren; Josephine Barnes; Simon Mead; Jonathan Beck; Tracey Pepple; Richard Boyes; Rohani Omar; John Collinge; John M Stevens; Elizabeth K Warrington; Martin N Rossor; Nick C Fox Journal: Nat Clin Pract Neurol Date: 2008-07-22
Authors: Mary K Floeter; Bryan J Traynor; Jennifer Farren; Laura E Braun; Michael Tierney; Edythe A Wiggs; Tianxia Wu Journal: Neurology Date: 2017-06-14 Impact factor: 9.910
Authors: Enrico Premi; Vince D Calhoun; Matteo Diano; Stefano Gazzina; Maura Cosseddu; Antonella Alberici; Silvana Archetti; Donata Paternicò; Roberto Gasparotti; John van Swieten; Daniela Galimberti; Raquel Sanchez-Valle; Robert Laforce; Fermin Moreno; Matthis Synofzik; Caroline Graff; Mario Masellis; Maria Carmela Tartaglia; James 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 Frisoni; Stefano Cappa; Sandro Sorbi; Alessandro Padovani; Jonathan D Rohrer; Barbara Borroni Journal: Neuroimage Date: 2019-02-01 Impact factor: 6.556
Authors: Adam M Staffaroni; Lynn Bajorek; Kaitlin B Casaletto; Yann Cobigo; Sheng-Yang M Goh; Amy Wolf; Hilary W Heuer; Fanny M Elahi; Peter A Ljubenkov; Reilly Dever; John Kornak; Brian Appleby; Jessica Bove; Yvette Bordelon; Patrick Brannelly; Danielle Brushaber; Christina Caso; Giovanni Coppola; Christina Dheel; Bradford C Dickerson; Susan Dickinson; Sophia Dominguez; Kimiko Domoto-Reilly; Kelly Faber; Jessica Ferrall; Julie A Fields; Ann Fishman; Jamie Fong; Tatiana Foroud; Leah K Forsberg; Ralitza Gavrilova; Debra Gearhart; Behnaz Ghazanfari; Nupur Ghoshal; Jill Goldman; Jonathan Graff-Radford; Neill Graff-Radford; Ian Grant; Murray Grossman; Dana Haley; Ging-Yuek Hsiung; Edward D Huey; David J Irwin; David T Jones; Lynne Jones; Kejal Kantarci; Anna Karydas; Daniel I Kaufer; Diana R Kerwin; David S Knopman; Ruth Kraft; Walter K Kremers; Walter A Kukull; Irene Litvan; Diane Lucente; Codrin Lungu; Ian R Mackenzie; Miranda Maldonado; Masood Manoochehri; Scott M McGinnis; Emily McKinley; Mario F Mendez; Bruce L Miller; Namita Multani; Chiadi Onyike; Jaya Padmanabhan; Alex Pantelyat; Rodney Pearlman; Len Petrucelli; Madeline Potter; Rosa Rademakers; Eliana Marisa Ramos; Katherine P Rankin; Katya Rascovsky; Erik D Roberson; Emily Rogalski; Pheth Sengdy; Leslie M Shaw; Jeremy Syrjanen; M Carmela Tartaglia; Nadine Tatton; Joanne Taylor; Arthur Toga; John Q Trojanowski; Sandra Weintraub; Ping Wang; Bonnie Wong; Zbigniew Wszolek; Adam L Boxer; Brad F Boeve; Joel H Kramer; Howard J Rosen Journal: Alzheimers Dement Date: 2019-05-11 Impact factor: 21.566
Authors: Stacey Li Hi Shing; Mary Clare McKenna; We Fong Siah; Rangariroyashe H Chipika; Orla Hardiman; Peter Bede Journal: Brain Imaging Behav Date: 2021-01-05 Impact factor: 3.978