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Neurobiol Aging. 2019 May;77:169-177. doi: 10.1016/j.neurobiolaging.2018.12.009. Epub 2019 Jan 4.

Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia.

Author information

1
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. Electronic address: tr332@medschl.cam.ac.uk.
2
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
3
Alzheimercentrum, Erasmus Medical Center, Rotterdam, the Netherlands.
4
Department of Clinical and Experimental Sciences, University of Brescia, Italy.
5
Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
6
Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada.
7
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
8
Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
9
Istituto Neurologico Carlo Besta, Milan, Italy.
10
Department of Psychiatry, University Hospitals and University of Geneva, Geneva, Switzerland; Neuroimaging and Epidemiology Unit, IRCCS San Giovanni di Dio Fatebenefratelli Brescia, Brescia, Italy.
11
Faculty of Medicine, Université Laval, Quebec, Canada.
12
Department of Clinical Neurological Sciences, University of Western Ontario, Ontario, Canada.
13
Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
14
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy; IRCCS Don Gnocchi, Florence, Italy.
15
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
16
Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal.
17
Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
18
Department of Neurology, University of Ulm, Ulm, Germany.
19
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
20
Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain.
21
Biotechnology Laboratory, Department of Diagnostics, Spedali Civili Hospital, Brescia, Italy.
22
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy.
23
Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain.
24
Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain.
25
Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
26
Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany.
27
Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
28
Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy.
29
Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
30
Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
31
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
32
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
33
Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
34
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
35
Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain.
36
CITA Alzheimer, San Sebastian, Gipuzkoa, Spain.
37
Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
38
Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.
39
Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada.
40
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
41
Neuroradiology Unit, University of Brescia, Brescia, Italy.
42
Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada.
43
Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany.
44
Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
45
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
46
Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
47
The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada.
48
Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal.
49
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
50
Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
51
MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
52
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
53
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
54
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
55
Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
56
Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, the Netherlands.
57
London Ontario geneticist, Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
58
Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada.
59
Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal.
60
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
61
Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto - Hospital de Santo António, Oporto, Portugal.
62
The University Health Network, Krembil Research Institute, Toronto, Canada.
63
Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK.
64
Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
65
Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium.
66
Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium.
67
Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
68
Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte - Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
69
OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain.
70
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Abstract

The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions. Measures of topological efficiency of the brain's functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. We propose that maintaining the efficient organization of the brain's functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.

KEYWORDS:

Cognition; Connectivity; Frontotemporal dementia; Functional imaging; Genetics

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