Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results

Maurice Pasternak; Saira S Mirza; Nicholas Luciw; Henri J M M Mutsaerts; Jan Petr; David Thomas; David Cash; Martina Bocchetta; Maria Carmela Tartaglia; Sara B Mitchell; Sandra E Black; Morris Freedman; David Tang-Wai; Ekaterina Rogaeva; Lucy L Russell; Arabella Bouzigues; John C van Swieten; Lize C Jiskoot; Harro Seelaar; Robert Laforce Jr; Pietro Tiraboschi; Barbara Borroni; Daniela Galimberti; James B Rowe; Caroline Graff; Elizabeth Finger; Sandro Sorbi; Alexandre de Mendonça; Chris Butler; Alex Gerhard; Raquel Sanchez-Valle; Fermin Moreno; Matthis Synofzik; Rik Vandenberghe; Simon Ducharme; Johannes Levin; Markus Otto; Isabel Santana; Antonio P Strafella; Bradley J MacIntosh; Jonathan D Rohrer; Mario Masellis; GENetic Frontotemporal dementia Initiative (GENFI)

doi:10.1002/alz.13750

Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results

Alzheimers Dement. 2024 May;20(5):3525-3542. doi: 10.1002/alz.13750. Epub 2024 Apr 16.

[Article in Italian]

Authors

Maurice Pasternak^{1

2}, Saira S Mirza¹, Nicholas Luciw^{1

3}, Henri J M M Mutsaerts⁴, Jan Petr⁵, David Thomas⁶, David Cash⁷, Martina Bocchetta⁷, Maria Carmela Tartaglia^{8

9

10}, Sara B Mitchell¹⁰, Sandra E Black^{10

11

12}, Morris Freedman^{10

11}, David Tang-Wai^{10

11

13}, Ekaterina Rogaeva⁸, Lucy L Russell⁷, Arabella Bouzigues⁶, John C van Swieten¹⁴, Lize C Jiskoot¹⁴, Harro Seelaar¹⁴, Robert Laforce Jr¹⁵, Pietro Tiraboschi¹⁶, Barbara Borroni¹⁷, Daniela Galimberti^{18

19}, James B Rowe^{20

21

22}, Caroline Graff^{23

24}, Elizabeth Finger²⁵, Sandro Sorbi^{26

27}, Alexandre de Mendonça²⁸, Chris Butler^{29

30}, Alex Gerhard^{31

32

33}, Raquel Sanchez-Valle³⁴, Fermin Moreno^{35

36}, Matthis Synofzik³⁷, Rik Vandenberghe³⁸, Simon Ducharme^{39

40}, Johannes Levin^{41

42}, Markus Otto⁴³, Isabel Santana⁴⁴, Antonio P Strafella^{13

45

46}, Bradley J MacIntosh^{1

3}, Jonathan D Rohrer⁷, Mario Masellis^{1

2

10

12

47}; GENetic Frontotemporal dementia Initiative (GENFI)

Collaborators

GENetic Frontotemporal dementia Initiative (GENFI):
Annabel Nelson⁴⁸, Martina Bocchetta⁴⁸, David Cash⁴⁸, David L Thomas⁴⁹, Emily Todd⁴⁸, Hanya Benotmane⁵⁰, Jennifer Nicholas⁵¹, Kiran Samra⁴⁸, Rachelle Shafei⁴⁸, Carolyn Timberlake²⁰, Thomas Cope²⁰, Timothy Rittman²⁰, Alberto Benussi⁵², Enrico Premi⁵³, Roberto Gasparotti⁵⁴, Silvana Archetti⁵⁵, Stefano Gazzina⁵⁶, Andrea Arighi^{57

58}, Chiara Fenoglio^{57

58}, Elio Scarpini^{57

58}, Giorgio Fumagalli^{57

58}, Vittoria Borracci^{57

58}, Giacomina Rossi⁵⁹, Giorgio Giaccone⁵⁹, Giuseppe Di Fede⁵⁹, Paola Caroppo⁵⁹, Pietro Tiraboschi⁵⁹, Sara Prioni⁵⁹, Veronica Redaelli⁵⁹, David Tang-Wai⁶⁰, Ekaterina Rogaeva⁶¹, Miguel Castelo-Branco⁶², Morris Freedman⁶³, Ron Keren⁶⁴, Sandra Black⁶⁵, Sara Mitchell⁶⁵, Christen Shoesmith⁶⁶, Robart Bartha^{67

68}, Rosa Rademakers⁶⁹, Jackie Poos¹⁴, Janne M Papma¹⁴, Lucia Giannini¹⁴, Rick van Minkelen⁷⁰, Yolande Pijnenburg⁷¹, Benedetta Nacmias⁷², Camilla Ferrari⁷², Cristina Polito⁷³, Gemma Lombardi⁷², Valentina Bessi⁷², Michele Veldsman²⁹, Christin Andersson⁷⁴, Hakan Thonberg⁷⁵, Linn Öijerstedt^{76

77}, Vesna Jelic⁷⁸, Paul Thompson⁷⁹, Tobias Langheinrich^{79

80}, Albert Lladó⁸¹, Anna Antonell⁸¹, Jaume Olives⁸¹, Mircea Balasa⁸¹, Nuria Bargalló⁸², Sergi Borrego-Ecija⁸¹, Ana Verdelho⁸³, Carolina Maruta⁸⁴, Catarina B Ferreira⁸⁵, Gabriel Miltenberger⁸⁶, Frederico Simões do Couto⁸⁷, Alazne Gabilondo^{88

89}, Ana Gorostidi⁸⁹, Jorge Villanua⁹⁰, Marta Cañada⁹¹, Mikel Tainta⁸⁹, Miren Zulaica⁸⁹, Myriam Barandiaran^{88

89}, Patricia Alves^{89

92}, Benjamin Bender⁹³, Carlo Wilke^{37

94}, Lisa Graf³⁷, Annick Vogels⁹⁵, Mathieu Vandenbulcke^{96

97}, Philip Van Damme^{98

99}, Rose Bruffaerts^{100

101}, Koen Poesen¹⁰², Pedro Rosa-Neto¹⁰³, Serge Gauthier¹⁰⁴, Agnès Camuzat¹⁰⁵, Alexis Brice^{105

106}, Anne Bertrand^{105

107}, Aurélie Funkiewiez^{105

108}, Daisy Rinaldi^{105

108

109}, Dario Saracino^{105

108}, Olivier Colliot^{105

107}, Sabrina Sayah¹⁰⁵, Catharina Prix¹¹⁰, Elisabeth Wlasich¹¹⁰, Olivia Wagemann¹¹⁰, Sandra Loosli¹¹⁰, Sonja Schönecker¹¹⁰, Tobias Hoegen¹¹⁰, Jolina Lombardi⁴³, Sarah Anderl-Straub⁴³, Adeline Rollin¹¹¹, Gregory Kuchcinski^{111

112

113}, Maxime Bertoux¹⁰⁶, Thibaud Lebouvier^{111

112

113}, Vincent Deramecourt^{111

112

113}, Beatriz Santiago¹¹⁴, Diana Duro⁶², Maria João Leitão¹¹⁵, Maria Rosario Almeida⁶², Miguel Tábuas-Pereira¹¹⁴, Sónia Afonso¹¹⁶

Affiliations

¹ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³ Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
⁴ Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, the Netherlands.
⁵ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
⁶ Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁹ Memory Clinic, University Health Network, Toronto, Ontario, Canada.
¹⁰ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹¹ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
¹² Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
¹⁴ Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁵ Clinique Interdisciplinaire de Mémoire, CHU de Québec, Département des Sciences Neurologiques, Université Laval, Quebec, Quebec, Canada.
¹⁶ Division of Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹⁷ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁸ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
¹⁹ Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
²¹ Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.
²² Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
²³ Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
²⁴ Unit for Hereditary Dementias, Karolinska University Hospital, Solna, Sweden.
²⁵ Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
²⁶ Department of Neurofarba, University of Florence, Florence, Italy.
²⁷ Fondazione Don Carlo Gnocchi, Istituto di Ricovero e Cura a Carattere Scientifico, Florence, Italy.
²⁸ Neurology Department, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²⁹ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
³⁰ Department of Brain Sciences, Imperial College London, London, UK.
³¹ Division of Psychology Communication and Human Neuroscience, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
³² Department of Geriatric Medicine, Klinikum Hochsauerland GmbH, Arnsberg, Germany.
³³ Department of Nuclear Medicine, Center for Translational Neuro- and Behavioral Sciences University Hospital Essen, Essen, Germany.
³⁴ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain.
³⁵ Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, Begiristain Doktorea Pasealekua, Donostia-San Sebastian, Gipuzkoa, Spain.
³⁶ Neuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastian, Gipuzkoa, Spain.
³⁷ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
³⁸ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
³⁹ Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
⁴⁰ McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
⁴¹ Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
⁴² Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
⁴³ Department of Neurology, University of Ulm, Ulm, Germany.
⁴⁴ Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁴⁵ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁴⁶ Edmond J. Safra Parkinson Disease Program & Morton and Gloria Shulman Movement Disorder Unit, Toronto Western Hospital UHN, Toronto, Ontario, Canada.
⁴⁷ Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
⁴⁸ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
⁴⁹ Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK.
⁵⁰ UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology, London, UK.
⁵¹ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
⁵² Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
⁵³ Stroke Unit, ASST Brescia Hospital, Brescia, Italy.
⁵⁴ Neuroradiology Unit, University of Brescia, Brescia, Italy.
⁵⁵ Biotechnology Laboratory, Department of Diagnostics, ASST Brescia Hospital, Brescia, Italy.
⁵⁶ Neurology, ASST Brescia Hospital, Brescia, Italy.
⁵⁷ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy.
⁵⁸ University of Milan, Centro Dino Ferrari, Milan, Italy.
⁵⁹ Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
⁶⁰ The University Health Network, Krembil Research Institute, Toronto, Canada.
⁶¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
⁶² Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁶³ Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada.
⁶⁴ The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada.
⁶⁵ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
⁶⁶ Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
⁶⁷ Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada.
⁶⁸ Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
⁶⁹ Center for Molecular Neurology, University of Antwerp.
⁷⁰ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands.
⁷¹ Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands.
⁷² Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
⁷³ Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Nuclear Medicine Unit, University of Florence, Florence, Italy.
⁷⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷⁵ Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden.
⁷⁷ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
⁷⁸ Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
⁷⁹ Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
⁸⁰ Manchester Centre for Clinical Neurosciences, Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK.
⁸¹ Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain.
⁸² Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain.
⁸³ Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte - Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁸⁴ Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁸⁵ Laboratory of Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁸⁶ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁸⁷ Faculdade de Medicina, Universidade Católica Portuguesa.
⁸⁸ Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain.
⁸⁹ Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain.
⁹⁰ OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain.
⁹¹ CITA Alzheimer, San Sebastian, Gipuzkoa, Spain.
⁹² Department of Educational Psychology and Psychobiology, Faculty of Education, International University of La Rioja, Logroño, Spain.
⁹³ Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany.
⁹⁴ Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁹⁵ Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁹⁶ Geriatric Psychiatry Service, University Hospitals Leuven, Leuven, Belgium.
⁹⁷ Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium.
⁹⁸ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
⁹⁹ Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium.
¹⁰⁰ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹⁰¹ Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
¹⁰² Laboratory for Molecular Neurobiomarker Research, KU Leuven, Leuven, Belgium.
¹⁰³ Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada.
¹⁰⁴ Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada.
¹⁰⁵ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
¹⁰⁶ Reference Network for Rare Neurological Diseases (ERN-RND).
¹⁰⁷ Centre pour l'Acquisition et le Traitement des Images, Institut du Cerveau et la Moelle, Paris, France.
¹⁰⁸ Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
¹⁰⁹ Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
¹¹⁰ Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany.
¹¹¹ CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, Lille, France.
¹¹² Univ Lille, Lille, France.
¹¹³ Inserm 1172, Lille, France.
¹¹⁴ Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal.
¹¹⁵ Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal.
¹¹⁶ Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal.

Abstract

Introduction: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers.

Methods: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment.

Results: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset.

Discussion: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset.

Highlights: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Keywords: arterial spin labeling; cerebral perfusion; frontotemporal dementia; presymptomatic biomarker.

Publication types

English Abstract
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Biomarkers
Brain / diagnostic imaging
C9orf72 Protein* / genetics
Cerebrovascular Circulation* / genetics
Cerebrovascular Circulation* / physiology
Disease Progression
Female
Frontotemporal Dementia* / diagnostic imaging
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / physiopathology
Gray Matter / diagnostic imaging
Gray Matter / pathology
Heterozygote
Humans
Longitudinal Studies
Magnetic Resonance Imaging*
Male
Middle Aged
Mutation
Progranulins / genetics
Spin Labels
tau Proteins* / genetics

Abstract

Publication types

MeSH terms

Grants and funding