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Neuroimage. 2019 Apr 1;189:645-654. doi: 10.1016/j.neuroimage.2019.01.080. Epub 2019 Feb 1.

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint.

Author information

1
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; Stroke Unit, Azienda Socio Sanitaria Territoriale Spedali Civili, Spedali Civili Hospital, Brescia, Italy.
2
The Mind Research Network, Albuquerque, USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, USA.
3
Department of Psychology, University of Turin, Turin, Italy; Department of Medical and Clinical Psychology, CoRPS - Center of Research on Psychology in Somatic Diseases, Tilburg University, the Netherlands.
4
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
5
Biotechnology Laboratory, Department of Diagnostic, Spedali Civili Hospital, Brescia, Italy.
6
Neuroradiology Unit, University of Brescia, Italy.
7
Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
8
Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
9
Neurology Department, Hospital Clinic, Institut d'Investigacions Biomèdiques, Barcelona, Spain.
10
Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, Faculté de Médecine, Université Laval, QC, Canada.
11
Department of Neurology, Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain.
12
Department of Cognitive Neurology, Center for Neurology, Hertie-Institute for Clinical Brain Research, Tübingen, Germany.
13
Karolinska Institutet, Department NVS, Center for Alzheimer Research, Division of Neurogenetics, Sweden.
14
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Toronto, ON, Canada.
15
Toronto Western Hospital, Tanz Centre for Research in Neurodegenerative Disease, Toronto, ON, Canada.
16
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
17
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
18
Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
19
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy.
20
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
21
Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.
22
Department of Clinical Neurology, University of Oxford, Oxford, UK.
23
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
24
Institute of Brain, Behaviour and Mental Health, The University of Manchester, Withington, Manchester, UK.
25
Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
26
Department of Neurology, University Hospital Ulm, Ulm, Germany.
27
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 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.
28
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
29
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) "Don Gnocchi", Florence, Italy.
30
Dementia Research Centre, UCL Institute of Neurology, UK.
31
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. Electronic address: bborroni@inwind.it.
32
Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal.
33
Ulm University, Ulm, Germany.
34
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
35
Alzheimer's disease and Other Cognitive disorders Unit, Neurology Department, Hospital Clinic, Institut d'Investigacions Biomèdiques, Barcelona, Spain.
36
Neurology Unit, Department of Physiopathology and Transplantation, Fondazione Cà Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan, Italy.
37
Neuroscience Area, Biodonostia Health Research Institute, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain.
38
Radiology Department, Image Diagnosis Center, Hospital Clínic and Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain.
39
Department of Medical Biophysics, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
40
Department of Radiology, University of Tuebingen, Tuebingen, Germany.
41
Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
42
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Toronto, Canada.
43
Department of Neurodegenerative Disease, UCL Institute of Neurology, UK.
44
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milano, Italy.
45
Neurology Department, Centro Hospitalar e Universitário de Coimbra, Instituto de Ciências Nucleares Aplicadas à Saúde (ICNAS), Portugal.
46
University of Cambridge, UK.
47
ITA Alzheimer, San Sebastian, Spain.
48
Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.
49
Instituto Ciências Nucleares Aplicadas à Saúde, Universidade de Coimbra, Coimbra, Portugal.
50
Faculty of Medicine, University of Lisbon, Portugal.
51
University of Manchester, UK.
52
Division of Neurology, Baycrest Centre for Geriatric Care, University of Toronto, Canada.
53
Neurology Unit, Fondazione Cà Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico, Milan, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
54
Department of Neurology, Ludwig-Maximilians-University Munich, Germany.
55
Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, Paseo Dr Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain.
56
Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
57
Section of Neuropsychology, Department of Cognitive Neurology, Center for Neurology & Hertie-Institute for Clinical Brain Research, Tübingen, Germany.
58
University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Canada.
59
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
60
Lisbon Faculty of Medicine, Language Research Laboratory, Lisbon, Portugal.
61
MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
62
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
63
The London School of Hygiene and Tropical Medicine, London, UK.
64
Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
65
Department of Neuroradiology, Ludwig-Maximilians-University Munich, Germany.
66
Department of Neurosciences, Mayo Clinic, Jacksonville, FL, United States.
67
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
68
Translational Neuroimaging Laboratory, McGill University, Montreal, Quebec, Canada.
69
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
70
Neuroradiological Academic Unit, UCL Institute of Neurology, UK.
71
Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
72
Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium.
73
Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium.
74
University of Oxford, UK.
75
Department of Neurosciences, Santa Maria Hospital, University of Lisbon, Portugal.
76
OSATEK Unidad de Donostia, San Sebastian, Gipuzkoa, Spain.
77
Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.

Abstract

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials.

KEYWORDS:

C9orf72; Chronnectome; Dynamic brain functional connectivity; Frontotemporal dementia; Granulin; Microtuble associate protein tau; Mutation; resting-state fMRI

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