Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia
Author:
Shafiei Golia1ORCID, Bazinet Vincent1, Dadar Mahsa12ORCID, Manera Ana L1, Collins D Louis1ORCID, Dagher Alain1ORCID, Borroni Barbara3, Sanchez-Valle Raquel4ORCID, Moreno Fermin56, Laforce Robert7, Graff Caroline89ORCID, Synofzik Matthis1011ORCID, Galimberti Daniela1213, Rowe James B14, Masellis Mario15ORCID, Tartaglia Maria Carmela16, Finger Elizabeth17, Vandenberghe Rik181920, de Mendonça Alexandre21, Tagliavini Fabrizio22, Santana Isabel2324, Butler Chris2526, Gerhard Alex2728, Danek Adrian29, Levin Johannes293031, Otto Markus32, Sorbi Sandro3334, Jiskoot Lize C35ORCID, Seelaar Harro35ORCID, van Swieten John C35, Rohrer Jonathan D36, Misic Bratislav1ORCID, Ducharme Simon137ORCID, Rosen Howard, Dickerson Bradford C, Domoto-Reilly Kimoko, Knopman David, Boeve Bradley F, Boxer Adam L, Kornak John, Miller Bruce L, Seeley William W, Gorno-Tempini Maria-Luisa, McGinnis Scott, Mandelli Maria Luisa, Esteve Aitana Sogorb, Nelson Annabel, Bouzigues Arabella, Heller Carolin, Greaves Caroline V, Cash David, Thomas David L, Todd Emily, Benotmane Hanya, Zetterberg Henrik, Swift Imogen J, Nicholas Jennifer, Samra Kiran, Russell Lucy L, Bocchetta Martina, Shafei Rachelle, Convery Rhian S, Timberlake Carolyn, Cope Thomas, Rittman Timothy, Benussi Alberto, Premi Enrico, Gasparotti Roberto, Archetti Silvana, Gazzina Stefano, Cantoni Valentina, Arighi Andrea, Fenoglio Chiara, Scarpini Elio, Fumagalli Giorgio, Borracci Vittoria, Rossi Giacomina, Giaccone Giorgio, Fede Giuseppe Di, Caroppo Paola, Tiraboschi Pietro, Prioni Sara, Redaelli Veronica, Tang-Wai David, Rogaeva Ekaterina, Castelo-Branco Miguel, Freedman Morris, Keren Ron, Black Sandra, Mitchell Sara, Shoesmith Christen, Bartha Robart, Rademakers Rosa, van der Ende Emma, Poos Jackie, Papma Janne M, Giannini Lucia, van Minkelen Rick, Pijnenburg Yolande, Nacmias Benedetta, Ferrari Camilla, Polito Cristina, Lombardi Gemma, Bessi Valentina, Veldsman Michele, Andersson Christin, Thonberg Hakan, Öijerstedt Linn, Jelic Vesna, Thompson Paul, Langheinrich Tobias, Lladó Albert, Antonell Anna, Olives Jaume, Balasa Mircea, Bargalló Nuria, Borrego-Ecija Sergi, Verdelho Ana, Maruta Carolina, Ferreira Catarina B, Miltenberger Gabriel, do Couto Frederico Simões, Gabilondo Alazne, Gorostidi Ana, Villanua Jorge, Cañada Marta, Tainta Mikel, Zulaica Miren, Barandiaran Myriam, Alves Patricia, Bender Benjamin, Wilke Carlo, Graf Lisa, Vogels Annick, Vandenbulcke Mathieu, Van Damme Philip, Bruffaerts Rose, Rosa-Neto Pedro, Gauthier Serge, Camuzat Agnès, Brice Alexis, Bertrand Anne, Funkiewiez Aurélie, Rinaldi Daisy, Saracino Dario, Colliot Olivier, Sayah Sabrina, Prix Catharina, Wlasich Elisabeth, Wagemann Olivia, Loosli Sandra, Schönecker Sonja, Hoegen Tobias, Lombardi Jolina, Anderl-Straub Sarah, Rollin Adeline, Kuchcinski Gregory, Bertoux Maxime, Lebouvier Thibaud, Deramecourt Vincent, Santiago Beatriz, Duro Diana, Leitão Maria João, Almeida Maria Rosario, Tábuas-Pereira Miguel, Afonso Sónia, Engel Annerose, Polyakova Maryna, ,
Affiliation:
1. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, QC , Canada 2. Radiology and Nuclear Medicine, Laval University , Quebec City, QC , Canada 3. Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia , Brescia , Italy 4. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona , Barcelona , Spain 5. Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital , San Sebastian, Gipuzkoa , Spain 6. Neuroscience Area, Biodonostia Health Research Institute , San Sebastian, Gipuzkoa , Spain 7. Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval , Quebec, QC , Canada 8. Department of Geriatric Medicine, Karolinska University Hospital-Huddinge , Stockholm , Sweden 9. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital , Solna , Sweden 10. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen , Tübingen , Germany 11. Center for Neurodegenerative Diseases (DZNE) , Tübingen , Germany 12. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit , Milan , Italy 13. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Dino Ferrari Center , Milan , Italy 14. University of Cambridge, Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, and MRC Cognition and Brain Sciences Unit , Cambridge , UK 15. Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto , Toronto, ON , Canada 16. Toronto Western Hospital, Tanz Centre for Research in Neurodegenerative Disease , Toronto, ON , Canada 17. Department of Clinical Neurological Sciences, University of Western Ontario , London, ON , Canada 18. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven , Leuven , Belgium 19. Neurology Service, University Hospitals Leuven , Leuven , Belgium 20. Leuven Brain Institute, KU Leuven , Leuven , Belgium 21. Faculty of Medicine, University of Lisbon , Lisbon , Portugal 22. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta , Milan , Italy 23. Neurology Department, Centro Hospitalar e Universitário de Coimbra , Coimbra , Portugal 24. Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra , Coimbra , Portugal 25. Department of Clinical Neurology, University of Oxford , Oxford , UK 26. Department of Brain Sciences, Imperial College London , London , UK 27. Division of Neuroscience and Experimental Psychology, Faculty of Medicine, Biology and Health, University of Manchester , Manchester , UK 28. Department of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen , Duisburg and Essen , Germany 29. Department of Neurology, Ludwig-Maximilians-Universität München , Munich , Germany 30. Clinical Research Unit, German Center for Neurodegenerative Diseases (DZNE) , Munich , Germany 31. Munich Cluster of Systems Neurology (SyNergy) , Munich , Germany 32. Department of Neurology, University Hospital Ulm , Ulm , Germany 33. Department of Neurofarba, University of Florence , Florence , Italy 34. IRCCS Fondazione Don Carlo Gnocchi , Florence , Italy 35. Department of Neurology, Erasmus University Medical Centre , Rotterdam , The Netherlands 36. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology , Queen Square, London , UK 37. Department of Psychiatry, Douglas Mental Health University Institute, McGill University , Montreal, QC , Canada
Abstract
Abstract
Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.
Funder
Natural Sciences and Engineering Research Council of Canada Canada Research Chairs Program Fonds de Recherche du Québec—Santé Fonds de recherche du Québec—Nature et Technologies Fonds de recherche du Québec Frontotemporal Lobar Degeneration Neuroimaging Initiative National Institutes of Health University of California, San Francisco University of Southern California
Publisher
Oxford University Press (OUP)
Subject
Neurology (clinical)
Cited by
28 articles.
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