Journal Article

DZNE-2026-00622

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Composite grey matter fingerprints for genetic frontotemporal dementia.

Bouzigues, A. ; Campana, G. ; Joulot, M. ; Gensollen, N. ; Russell, L. L. ; Foster, P. H. ; Ferry-Bolder, E. ; Van Swieten, J. C. ; Jiskoot, L. C. ; Seelaar, H. ; Sánchez-Valle, R. ; Laforce, R. ; Graff, C. ; Galimberti, D. ; Vandenberghe, R. ; de Mendonca, A. ; Tiraboschi, P. ; Santana, I. ; Gerhard, A. ; Levin, J.DZNE* ; Sorbi, S. ; Otto, M. ; Bertoux, M. ; Lebouvier, T. ; Ducharme, S. ; Butler, C. ; Finger, E. ; Tartaglia, M. C. ; Masellis, M. ; Rowe, J. B. ; Synofzik, M.DZNE* ; Moreno, F. ; Borroni, B. ; Leber, I. ; Zanusso, G. ; Rohrer, J. D. ; Migliaccio, R. ; Initiative, G. F. d. (Collaboration Author) ; Convery, R. (Contributor) ; Bocchetta, M. (Contributor) ; Cash, D. (Contributor) ; Goldsmith, S. (Contributor) ; Samra, K. (Contributor) ; Thomas, D. L. (Contributor) ; Cope, T. (Contributor) ; Malpetti, M. (Contributor) ; Alberici, A. (Contributor) ; Premi, E. (Contributor) ; Gasparotti, R. (Contributor) ; Buratti, E. (Contributor) ; Cantoni, V. (Contributor) ; Arighi, A. (Contributor) ; Fenoglio, C. (Contributor) ; Borracci, V. (Contributor) ; Serpente, M. (Contributor) ; Carandini, T. (Contributor) ; Rotondo, E. (Contributor) ; Rossi, G. (Contributor) ; Giorgio Giaccone, D. F. (Contributor) ; Caroppo, P. (Contributor) ; Prioni, S. (Contributor) ; Redaelli, V. (Contributor) ; Tang-Wai, D. (Contributor) ; Rogaeva, E. (Contributor) ; Krüger, J. (Contributor) ; Castelo-Branco, M. (Contributor) ; Freedman, M. (Contributor) ; Keren, R. (Contributor) ; Black, S. (Contributor) ; Mitchell, S. (Contributor) ; Shoesmith, C. (Contributor) ; Bartha, R. (Contributor) ; Rademakers, R. (Contributor) ; Poos, J. (Contributor) ; Papma, J. M. (Contributor) ; Giannini, L. (Contributor) ; Boer, L. d. (Contributor) ; Houwer, J. d. (Contributor) ; Minkelen, R. v. (Contributor) ; Pijnenburg, Y. (Contributor) ; Nacmias, B. (Contributor) ; Ferrari, C. (Contributor) ; Polito, C. (Contributor) ; Lombardi, G. (Contributor) ; Bessi, V. (Contributor) ; Fainardi, E. (Contributor) ; Chiti, S. (Contributor) ; Nilsson, M. (Contributor) ; Viklund, H. (Contributor) ; Rydell, M. T. (Contributor) ; Jelic, V. (Contributor) ; Ullgren, A. (Contributor) ; Rodriguez-Vieitez, E. (Contributor) ; Langheinrich, T. (Contributor) ; Lladó, A. (Contributor) ; Antonell, A. (Contributor) ; Olives, J. (Contributor) ; Balasa, M. (Contributor) ; Bargalló, N. (Contributor) ; Borrego-Ecija, S. (Contributor) ; Verdelho, A. (Contributor) ; Maruta, C. (Contributor) ; Costa-Coelho, T. (Contributor) ; Miltenberger, G. (Contributor) ; Couto, F. S. d. (Contributor) ; Gabilondo, A. (Contributor) ; Croitoru, I. (Contributor) ; Tainta, M. (Contributor) ; Barandiaran, M. (Contributor) ; Alves, P. (Contributor) ; Bender, B. (Contributor) ; Mengel, D. (Contributor)Extern* ; Graf, L. (Contributor)Extern* ; Vogels, A. (Contributor) ; Vandenbulcke, M. (Contributor) ; Damme, P. V. (Contributor) ; Bruffaerts, R. (Contributor) ; Poesen, K. (Contributor) ; Rosa-Neto, P. (Contributor) ; Montembault, M. (Contributor) ; Burgos, N. (Contributor) ; Rinaldi, D. (Contributor) ; Prix, C. (Contributor)Extern* ; Wlasich, E. (Contributor) ; Wagemann, O. (Contributor)Extern* ; Schönecker, S. (Contributor) ; Bernhardt, A. M. (Contributor)Extern* ; Stockbauer, A. (Contributor)Extern* ; Lombardi, J. (Contributor) ; Anderl-Straub, S. (Contributor) ; Rollin, A. (Contributor) ; Kuchcinski, G. (Contributor) ; Deramecourt, V. (Contributor) ; Durães, J. (Contributor) ; Lima, M. (Contributor) ; Leitão, M. J. (Contributor) ; Almeida, M. R. (Contributor) ; Tábuas-Pereira, M. (Contributor) ; Afonso, S. (Contributor) ; Lemos, J. (Contributor)

2026
BMJ Publishing Group London

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Please use a persistent id in citations: doi:10.1136/jnnp-2025-337186

Abstract: Brain structural changes in frontotemporal dementia (FTD) can occur decades before symptom onset. Precise characterisation of grey matter changes is necessary for developing models of biomarker progression, while better understanding the trajectory of the pathology is invaluable for prognosis and detecting treatment effects as we enter the era of clinical trials.Cortical and subcortical grey matter volume and thickness from structural MRI were assessed in a large cohort of 892 participants including presymptomatic and symptomatic carriers of mutations within the three main genetic causes of FTD (C9 open reading-frame 72 (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT)) compared with mutation-negative relatives (controls). We compared the distribution of grey matter changes of each metric at different stages of the disease cross sectionally. We aimed to identify grey matter composites for each genetic group which would show the earliest changes and which separated presymptomatic carriers from controls.While C9orf72 mutation carriers showed widespread presymptomatic grey matter changes, MAPT and particularly GRN mutation carriers showed changes more proximally to symptom onset. Our composite grey matter signatures, which discriminate asymptomatic/prodromal carriers from controls with high to very high areas under the curve, involved bilateral thalami volumes, precuneus and postcentral thickness in C9orf72; left caudal middle frontal thickness, frontal pole and pars orbitalis volumes in GRN; right temporal pole volume and left insula thickness in MAPT mutation carriers.We propose the use of cortical thickness and volume measurements combined from multiple regions into a composite region of interest for each FTD genetic group to identify the earliest changes and track disease progression. Our quasi-longitudinal design illustrates that these regions continue to evolve throughout the symptomatic stages. Investigating how our selected composites progress and validating these in longitudinal samples will be invaluable for future clinical trials.

Keyword(s): Humans (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: diagnostic imaging (MeSH) ; Progranulins: genetics (MeSH) ; tau Proteins: genetics (MeSH) ; Gray Matter: pathology (MeSH) ; Gray Matter: diagnostic imaging (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Female (MeSH) ; C9orf72 Protein: genetics (MeSH) ; Middle Aged (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Disease Progression (MeSH) ; Mutation (MeSH) ; Cross-Sectional Studies (MeSH) ; Adult (MeSH) ; DEMENTIA ; FRONTAL LOBE ; FRONTOTEMPORAL DEMENTIA ; IMAGE ANALYSIS ; NEUROANATOMY ; Progranulins ; tau Proteins ; MAPT protein, human ; C9orf72 Protein ; GRN protein, human ; C9orf72 protein, human

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Clinical Neurodegeneration (AG Levin)
3. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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