Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study

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.

Authors

Institutions

Publication Details

Journal
Molecular Psychiatry
Published
2025-10-09
DOI
https://doi.org/10.1038/s41380-025-03280-x
Citations
2
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
2.33

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study

Juan Fortea, Sandro Sorbi, Caroline Graff, Maria Carmela Tartaglia et al.
2 citations
Molecular Psychiatry
Alzheimer's disease research and treatments
2.33
article

Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study

Juan Fortea, Sandro Sorbi, Caroline Graff, Maria Carmela Tartaglia, James Benedict Rowe, Alexander Gerhard, Christopher Robert Butler, Matthis Synofzik, Víctor Montal, Abbe Ullgren, Vesna Jelić, Johannes Levin, Alexandre de Mendonça, Eve Ferry‐Bolder, Isabelle Le Ber, Raquel Sánchez‐Valle, Ignacio Illán‐Gala, Harro Seelaar, Pietro Tiraboschi, Phoebe H. Foster, Florence Pasquier, Arabella Bouzigues, Isabel Santana, Lize Corrine Jiskoot, Lucy Louise Russell, Markus Otto, Rik R. Vandenberghe, Elizabeth C. Finger, Elena Rodriguez‐Vieitez, Melissa Taheri Rydell, Daniela Galimberti, Eric Westman, Mario Masellis, Fermín Moreno, Robert Laforce, Barbara Borroni, Simon Ducharme, Jonathan D. Rohrer
article en
2 citations

Abstract

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.

Molecular PsychiatryVol. 30(12)
Universitat Autònoma de Barcelona (ES), Western University (CA), Montreal Neurological Institute and Hospital (CA), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), The George Institute for Global Health (GB), University of Toronto (CA), University of Milan (IT), MRC Cognition and Brain Sciences Unit (GB), Université de Lille (FR), University of Cambridge (GB), Douglas Mental Health University Institute (CA), Barcelona Supercomputing Center (ES), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Biogipuzkoa Health Research Institute (ES), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Hospital Clínic de Barcelona (ES), Don Carlo Gnocchi Foundation (IT), Essen University Hospital (DE), UK Dementia Research Institute (GB), Klinikum Arnsberg (DE), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), VIB-KU Leuven Center for Brain & Disease Research (BE), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), University of Florence (IT), University College London (GB), Imperial College London (GB), McGill University (CA), Martin Luther University Halle-Wittenberg (DE), University of Coimbra (PT), University of Brescia (IT), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Medical Research Council (GB), Erasmus University Rotterdam (NL), Universitat Politècnica de Catalunya (ES), KU Leuven (BE)
Alzheimer's Association, Université Laval, McGill University, Gun och Bertil Stohnes Stiftelse, Stiftelsen för Gamla Tjänarinnor, Sunnybrook Research Institute, Università degli Studi di Milano, Weston Brain Institute, EU Joint Programme – Neurodegenerative Disease Research, Global Brain Health Institute, Université de Lille, Alzheimer Society, National Institute for Health and Care Research, University of Cambridge, Imperial College London, Institut National de la Santé et de la Recherche Médicale, ZonMw, Eberhard Karls Universität Tübingen, Bundesministerium für Bildung und Forschung, Cambridge University Hospitals, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Toronto, KU Leuven, Karolinska Institutet, Stockholms Läns Landsting, Vetenskapsrådet, Università degli Studi di Firenze, Deutsches Zentrum für Neurodegenerative Erkrankungen, Universidade de Coimbra, Universidade de Lisboa, Universitat de Barcelona, Barcelona Supercomputing Center, Università degli Studi di Brescia, Neuroförbundet, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Alzheimerfonden, Stichting Dioraphte, Alzheimer Nederland, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Sorbonne Université, George Institute for Global Health, Demensfonden, Faculté de Médecine, Université Laval, Canadian Institutes of Health Research, Medical Research Council, Instituto de Salud Carlos III, European Regional Development Fund, NIHR Cambridge Biomedical Research Centre
Openalex Percentile: Top 10%
Alzheimer's disease research and treatments
2.33
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.