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Lancet Neurol. 2015 Mar;14(3):253-62. doi: 10.1016/S1474-4422(14)70324-2. Epub 2015 Feb 4.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.

Author information

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.

Erratum in

  • Lancet Neurol. 2015 Dec;14(12):1151. Binetti, Giuliano [added].

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.

PMID:
25662776
DOI:
10.1016/S1474-4422(14)70324-2
[Indexed for MEDLINE]
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