Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia : a GENFI study
Rodriguez-Vieitez, Elena (Karolinska University Hospital)
Rydell, Melissa T. (Karolinska University Hospital)
Ullgren, Abbe (Karolinska University Hospital)
Montal, Victor (Barcelona Supercomputing Center)
Illán-Gala, Ignacio (Institut de Recerca Sant Pau)
Fortea, Juan (Institut de Recerca Sant Pau)
Jelic, Vesna (Karolinska University Hospital)
Bouzigues, Arabella (Sorbonne Université)
Russell, Lucy L. (University College London. Institute of Neurology)
Foster, Phoebe H. (University College London. Institute of Neurology)
Ferry-Bolder, Eve (University College London. Institute of Neurology)
van Swieten, John C. (Erasmus Medical Centre (Rotterdam, Països Baixos))
Jiskoot, Lize C. (Erasmus Medical Centre (Rotterdam, Països Baixos))
Seelaar, Harro (Erasmus Medical Centre (Rotterdam, Països Baixos))
Sanchez-Valle, Raquel (Hospital Clínic i Provincial de Barcelona)
Laforce, Robert (Université Laval)
Galimberti, Daniela (University of Milan)
Vandenberghe, Rik (Katholieke Universiteit te Leuven (1970- ))
de Mendonça, Alexandre (University of Lisbon)
Tiraboschi, Pietro (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Santana, Isabel (University of Coimbra (Coïmbra, Portugal))
Gerhard, Alexander (University Hospital Essen (Alemanya))
Levin, Johannes (German Center for Neurodegenerative Diseases (DZNE))
Sorbi, Sandro (Istituto di Ricovero e Cura A Carattere Scientifico (IRCCS))
Otto, M. (Martin-Luther University Halle-Wittenberg)
Pasquier, Florence (University of Lille and INSERM 1172)
Ducharme, Simon (McConnell Brain Imaging Centre)
Butler, Chris R. (Imperial College London)
Le Ber, Isabelle (Sorbonne Université)
Finger, Elizabeth (University of Western Ontario)
Tartaglia, Maria Carmela (University of Toronto)
Masellis, Mario (University of Toronto)
Rowe, James B. (University of Cambridge)
Synofzik, Matthis (Center for Neurodegenerative Diseases (DZNE))
Moreno, Fermin (Instituto de Salud Carlos III)
Borroni, Barbara (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Rohrer, Jonathan D. (University College London. Institute of Neurology)
Westman, Eric (Karolinska Institutet)
Graff, Caroline (Karolinska University Hospital. Unit for Hereditary Dementias, Theme Inflammation and Aging)
Universitat Autònoma de Barcelona. Departament de Medicina

Data:	2025
Resum:	The study of genetic frontotemporal dementia (FTD) allows investigating its earliest presymptomatic stages. Using cross-sectional T1-weighted and diffusion-weighted MRI, we test the hypothesis that cortical microstructural alterations, quantified as cortical mean diffusivity (cMD), are detectable earlier and are more strongly associated with clinical progression than cortical thickness (CTh). The sample comprised n = 710 individuals (47. 8 ± 13. 5 years, 56. 6% female, 14. 1 ± 3. 3 years of education), including 118 symptomatic carriers and 305 presymptomatic carriers with mutations in C9orf72, GRN or MAPT genes, and 287 non-carriers, collected from 24 GENFI sites. A subset of n = 453 individuals (289 carriers, 164 non-carriers) were investigated across Clinical Dementia Rating (CDR) = 0, 0. 5 and ≥1 stages. Two subsets had longitudinal clinical outcome measures, including n = 403 individuals (239 carriers, 164 non-carriers) with Cambridge Behavioural Inventory-Revised scores during 2. 8 ± 1. 6 years, and n = 261 individuals (164 carriers, 97 non-carriers) with CDR Sum-of-Boxes scores during 2. 0 ± 0. 8 years. Regional cMD and CTh were entered into linear mixed-effects models incorporating age, sex and education as covariates; site, and individual nested within site were random intercepts. The results demonstrated that cMD is more sensitive than CTh to track early cortical injury, with elevated cMD first observed at CDR = 0 in C9orf72 carriers, followed by MAPT carriers (from CDR = 0. 5 stage), and by GRN carriers (beginning at CDR ≥ 1). At all stages, cortical microstructural injury had stronger effect size and was more widespread than cortical thinning. In all mutation carrier types, cMD was more strongly associated than CTh with subsequent clinical progression. Cortical microstructure is a promising biomarker to identify at-risk individuals before atrophy and clinical progression, with utility in therapeutic trials.
Ajuts:	Instituto de Salud Carlos III PI21/00791 Instituto de Salud Carlos III PI19/01637
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Prognostic markers ; Diseases ; Psychology ; Genetics ; Neuroscience
Publicat a:	Molecular psychiatry, Vol. 30 (October 2025) , p. 5800-5812, ISSN 1476-5578

DOI: 10.1038/s41380-025-03280-x
PMID: 41068257

13 p, 4.3 MB

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