Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia
Authors: Shafiei Golia , Bazinet Vincent , Dadar Mahsa , Manera Ana L , Collins D Louis , Dagher Alain , Borroni Barbara , Sanchez-Valle Raquel , Moreno Fermin , Laforce Robert , Graff Caroline , Synofzik Matthis , Galimberti Daniela , Rowe James B , Masellis Mario , Tartaglia Maria Carmela , Finger Elizabeth , Vandenberghe Rik , de Mendonça Alexandre , Tagliavini Fabrizio , Santana Isabel , Butler Chris , Gerhard Alex , Danek Adrian , Levin Johannes , Otto Markus , Sorbi Sandro , Jiskoot Lize C , Seelaar Harro , van Swieten John C , Rohrer Jonathan D , Misic Bratislav , Ducharme Simon ,   Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI), 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 ,   GENetic Frontotemporal dementia Initiative (GENFI), 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 
Published: February 2022

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.