title: Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Centres of Excellence in Neurodegeneration.
authors: Dementia Research Centre, University College London, London, UK.
authors: Jonathan D
authors: JD
authors: Rohrer
authors: Dementia Research Centre, University College London, London, UK; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
authors: Jennifer M
authors: JM
authors: Nicholas
authors: 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.
authors: David M
authors: DM
authors: Cash
authors: Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
authors: John
authors: J
authors: van Swieten
authors: Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Elise
authors: E
authors: Dopper
authors: Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Lize
authors: L
authors: Jiskoot
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Rick
authors: R
authors: van Minkelen
authors: Institute of Psychology, Leiden University, and Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
authors: Serge A
authors: SA
authors: Rombouts
authors: 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.
authors: M Jorge
authors: MJ
authors: Cardoso
authors: Dementia Research Centre, University College London, London, UK.
authors: Shona
authors: S
authors: Clegg
authors: 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.
authors: Miklos
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authors: Espak
authors: Medical Research Council Prion Unit, University College London, London, UK.
authors: Simon
authors: S
authors: Mead
authors: Dementia Research Centre, University College London, London, UK; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, University College London, London, UK.
authors: David L
authors: DL
authors: Thomas
authors: 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.
authors: Enrico
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authors: De Vita
authors: 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.
authors: Mario
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authors: Masellis
authors: 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.
authors: Sandra E
authors: SE
authors: Black
authors: Department of Medicine, Division of Neurology, Baycrest, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; Rotman Research Institute, Baycrest, Toronto, ON, Canada.
authors: Morris
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authors: Freedman
authors: University Health Network Memory Clinic, Toronto Western Hospital, Toronto, ON, Canada.
authors: Ron
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authors: Keren
authors: 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.
authors: Bradley J
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authors: MacIntosh
authors: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
authors: Ekaterina
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authors: Rogaeva
authors: University Health Network Memory Clinic, Toronto Western Hospital, Toronto, ON, Canada.
authors: David
authors: D
authors: Tang-Wai
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authors: Maria Carmela
authors: MC
authors: Tartaglia
authors: Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Hôpital de l'Enfant-Jésus, and Faculté de Médecine, Université Laval, QC, Canada.
authors: Robert
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authors: Laforce
authors: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
authors: Fabrizio
authors: F
authors: Tagliavini
authors: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
authors: Pietro
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authors: Tiraboschi
authors: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
authors: Veronica
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authors: Redaelli
authors: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
authors: Sara
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authors: Prioni
authors: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
authors: Marina
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authors: Grisoli
authors: Neurology Unit, Department of Medical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors: Barbara
authors: B
authors: Borroni
authors: Neurology Unit, Department of Medical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors: Alessandro
authors: A
authors: Padovani
authors: 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.
authors: Daniela
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authors: Galimberti
authors: 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.
authors: Elio
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authors: Scarpini
authors: 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.
authors: Andrea
authors: A
authors: Arighi
authors: 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.
authors: Giorgio
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authors: Fumagalli
authors: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors: James B
authors: JB
authors: Rowe
authors: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors: Ian
authors: I
authors: Coyle-Gilchrist
authors: 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.
authors: Caroline
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authors: Graff
authors: Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors: Marie
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authors: Fallström
authors: Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors: Vesna
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authors: Jelic
authors: 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.
authors: Anne Kinhult
authors: AK
authors: Ståhlbom
authors: Department of Clinical Neuroscience, Karolinska Institutet, Huddinge, Sweden; Department of Psychology, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors: Christin
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authors: Andersson
authors: 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.
authors: Håkan
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authors: Thonberg
authors: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors: Lena
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authors: Lilius
authors: 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.
authors: Giovanni B
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authors: Frisoni
authors: Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Michela
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authors: Pievani
authors: 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.
authors: Martina
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authors: Bocchetta
authors: Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Luisa
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authors: Benussi
authors: Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors: Roberta
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authors: Ghidoni
authors: Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
authors: Elizabeth
authors: E
authors: Finger
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors: Sandro
authors: S
authors: Sorbi
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors: Benedetta
authors: B
authors: Nacmias
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors: Gemma
authors: G
authors: Lombardi
authors: Department of Clinical Pathophysiology, Nuclear Medicine Division, University of Florence, Florence, Italy.
authors: Cristina
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authors: Polito
authors: Dementia Research Centre, University College London, London, UK.
authors: Jason D
authors: JD
authors: Warren
authors: 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.
authors: Sebastien
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authors: Ourselin
authors: Dementia Research Centre, University College London, London, UK.
authors: Nick C
authors: NC
authors: Fox
authors: Dementia Research Centre, University College London, London, UK. Electronic address: m.rossor@ucl.ac.uk.
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mesh_terms: D000328:Adult; D058070:Asymptomatic Diseases; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D003430:Cross-Sectional Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests