Thalamus involvement in genetic frontotemporal dementia assessed using structural and diffusion MRI: a GENFI study

Thalamic subregions are commonly, but variably, affected by different forms of frontotemporal dementia. We aimed to better characterize thalamic subregional involvement in genetic frontotemporal dementia with a recently published thalamus segmentation tool that utilizes structural and diffusion MRI, offering additional assessment of mean diffusivity and a more fine-grained analysis of the pulvinar specifically compared to previous studies. Using this tool, we performed thalamus segmentations in MRI scans from <i>C9orf72</i>, <i>GRN</i> and <i>MAPT</i> mutation carriers and mutation non-carriers with suitable 3-Tesla MRI cross-sectional data from the GENetic Frontotemporal dementia Initiative. Mutation carriers were divided according to their genetic group and Clinical Dementia Rating® Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behaviour and Language Domains global score (0 or 0.5: presymptomatic/prodromal stage, 1 or higher: symptomatic stage). Following stringent quality control and harmonization across sites and scanners, we compared volumes and mean diffusivity values of thalamic subregions in <i>C9orf72</i> (47 presymptomatic, 10 symptomatic), <i>GRN</i> (57 presymptomatic, 11 symptomatic) and <i>MAPT</i> (31 presymptomatic, 12 symptomatic) mutation carriers to those in 109 mutation non-carriers with analyses of covariance including age and sex (and total intracranial volume for volumetric comparisons) as covariates. Presymptomatic <i>C9orf72</i> expansion carriers showed smaller volumes (3-8% difference from non-carriers) and higher mean diffusivity (2-5% difference from non-carriers) for several thalamic subregions, including all pulvinar subdivisions. We found subtly larger volumes of the ventral anterior subregion and the non-medial pulvinar (3% difference from non-carriers for both) in presymptomatic <i>GRN</i> mutation carriers, and of the anteroventral subregion (5% difference from non-carriers) in presymptomatic <i>MAPT</i> mutation carriers. Symptomatic mutation carriers in all three genetic groups showed significantly smaller volumes and widespread higher mean diffusivity of thalamic subregions compared with non-carriers, which were overall most prominent in subregions involved in associative and limbic functions (the midline, medial pulvinar, anteroventral, mediodorsal, laterodorsal and lateral posterior subregions). Notably smaller volume (12-23% difference from non-carriers) and higher mean diffusivity (16-23% difference from non-carriers) of the most medial part of the medial pulvinar was a shared feature across the three genetic groups at the symptomatic stage. Overall, our study confirms that thalamic subregions are affected in genetic frontotemporal dementia and identifies prominent involvement of the most medial part of the medial pulvinar as a potential unifying feature in the variable pattern of thalamic subregional involvement across the main genetic groups.

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Journal
Brain Communications
Published
2025-01-01
DOI
https://doi.org/10.1093/braincomms/fcaf420
Primary Topic
Advanced Neuroimaging Techniques and Applications
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Thalamus involvement in genetic frontotemporal dementia assessed using structural and diffusion MRI: a GENFI study

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai et al.
Brain Communications
Advanced Neuroimaging Techniques and Applications
article

Thalamus involvement in genetic frontotemporal dementia assessed using structural and diffusion MRI: a GENFI study

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai, Ron Keren, Kiran Samra, Koen Poesen, Maura Malpetti, Alexander Bernhardt, Robert Bartha, Stefano Chiti, Rick van Minkelen, Carolina Maruta, Emily Todd, Caroline Graff, Ekaterina Rogaeva, Philip Van Damme, Alazne Gabilondo, Andrea Arighi, Liset de Boer, Valentina Bessi, Henry F. J. Tregidgo, Raffaella Migliaccio, Maria Carmela Tartaglia, Jaume Olives, Tobias Langheinrich, Enrico Premi, James B. Rowe, Albert Lladó, Giorgio Giaccone, Alexander Gerhard, Lucia Giannini, Christopher Butler, Roberto Gasparotti, María Serpente, Matthis Synofzik, Emanuele Buratti, Abbe Ullgren, Daniel C. Alexander, Vesna Jelić, Lisa Graf, Johannes Levin, Johanna Krüger, Gemma Lombardi, Alexandre de Mendonça, Jolina Lombardi, Eve Ferry‐Bolder, Mircea Balasa, Sonja Soskic, Anna Stockbauer, David M. Cash, Isabelle Le Ber, João Durães, David Mengel, Camilla Ferrari, Thomas Cope, Sara Prioni, Raquel Sánchez‐Valle, Sonja Schönecker, Veronica Redaelli, Rosa Rademakers, Núria Bargalló, Harro Seelaar, Jackie M. Poos, Sergi Borrego‐Écija, Pietro Tiraboschi, Frederico Simões do Couto, Ninon Burgos, Grégory Kuchcinski, Juan Eugenio Iglesias, Phoebe H. Foster, Benjamin Bender, Tiago Costa-Coelho, Arabella Bouzigues, Isabel Santana, Lize C. Jiskoot, Daisy Rinaldi, Enrico Fainardi, Cristina Polito, Martina Bocchetta, Annick Vogels, Antonella Alberici, Vittoria Borracci, Lucy L. Russell, Jonathan D. Rohrer, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Jan De Houwer, Elizabeth Finger, Patricia Alves, Ian B. Malone, Valentina Cantoni, Mathieu Vandenbulcke, Ioana Croitoru, Adeline Rollin, Chiara Fenoglio, Melissa Taheri Rydell, Ana Verdelho, Henrik Viklund, Catharina Prix, Miguel Tábuas‐Pereira, Marisa Lima, Vincent Deramecourt, Daniela Galimberti, Maria João Leitão, Maria Rosário Almeida, Thibaud Lebouvier, Emanuela Rotondo, Fermín Moreno, Robert Laforce, David L. Thomas, Olivia Wagemann, Rhian S. Convery, Tiziana Carandini, Giuseppe Di Fede, João M. Lemos, Barbara Borroni, Pedro Rosa‐Neto, Sarah Anderl‐Straub, Miguel Castelo-Branco, Myriam Barandiarán, Yolande A.L. Pijnenburg, Mikel Tainta, Mario Masellis, Sara Mitchell, Rose Bruffaerts, Simon Ducharme, Giacomina Rossi, Gabriel Miltenberger, Sònia Afonso, Anna Antonell, Christen Shoesmith, Sophie Goldsmith, John C. van Swieten, Paola Caroppo, Janne M. Papma, Sandra Black, Benedetta Nacmias, Maxime Montembault
article en

Abstract

Thalamic subregions are commonly, but variably, affected by different forms of frontotemporal dementia. We aimed to better characterize thalamic subregional involvement in genetic frontotemporal dementia with a recently published thalamus segmentation tool that utilizes structural and diffusion MRI, offering additional assessment of mean diffusivity and a more fine-grained analysis of the pulvinar specifically compared to previous studies. Using this tool, we performed thalamus segmentations in MRI scans from <i>C9orf72</i>, <i>GRN</i> and <i>MAPT</i> mutation carriers and mutation non-carriers with suitable 3-Tesla MRI cross-sectional data from the GENetic Frontotemporal dementia Initiative. Mutation carriers were divided according to their genetic group and Clinical Dementia Rating® Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behaviour and Language Domains global score (0 or 0.5: presymptomatic/prodromal stage, 1 or higher: symptomatic stage). Following stringent quality control and harmonization across sites and scanners, we compared volumes and mean diffusivity values of thalamic subregions in <i>C9orf72</i> (47 presymptomatic, 10 symptomatic), <i>GRN</i> (57 presymptomatic, 11 symptomatic) and <i>MAPT</i> (31 presymptomatic, 12 symptomatic) mutation carriers to those in 109 mutation non-carriers with analyses of covariance including age and sex (and total intracranial volume for volumetric comparisons) as covariates. Presymptomatic <i>C9orf72</i> expansion carriers showed smaller volumes (3-8% difference from non-carriers) and higher mean diffusivity (2-5% difference from non-carriers) for several thalamic subregions, including all pulvinar subdivisions. We found subtly larger volumes of the ventral anterior subregion and the non-medial pulvinar (3% difference from non-carriers for both) in presymptomatic <i>GRN</i> mutation carriers, and of the anteroventral subregion (5% difference from non-carriers) in presymptomatic <i>MAPT</i> mutation carriers. Symptomatic mutation carriers in all three genetic groups showed significantly smaller volumes and widespread higher mean diffusivity of thalamic subregions compared with non-carriers, which were overall most prominent in subregions involved in associative and limbic functions (the midline, medial pulvinar, anteroventral, mediodorsal, laterodorsal and lateral posterior subregions). Notably smaller volume (12-23% difference from non-carriers) and higher mean diffusivity (16-23% difference from non-carriers) of the most medial part of the medial pulvinar was a shared feature across the three genetic groups at the symptomatic stage. Overall, our study confirms that thalamic subregions are affected in genetic frontotemporal dementia and identifies prominent involvement of the most medial part of the medial pulvinar as a potential unifying feature in the variable pattern of thalamic subregional involvement across the main genetic groups.

Brain CommunicationsVol. 7(6)
Western University (CA), Montreal Neurological Institute and Hospital (CA), Allen Institute for Brain Science (US), Sunnybrook Health Science Centre (CA), Energy Institute (GB), Karolinska University Hospital (SE), Harvard University (US), University of Lisbon (PT), Inserm (FR), University of Toronto (CA), Neurosciences Institute (US), University of Milan (IT), Universität Ulm (DE), Université de Lille (FR), University of Cambridge (GB), Douglas Mental Health University Institute (CA), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Health Sciences Centre (CA), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Massachusetts General Hospital (US), Centro Cardiologico Monzino (IT), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Don Carlo Gnocchi Foundation (IT), Essen University Hospital (DE), Pitié-Salpêtrière Hospital (FR), BioClinicum (Russia) (RU), UK Dementia Research Institute (GB), Athinoula A. Martinos Center for Biomedical Imaging (US), Klinikum Arnsberg (DE), UCL Biomedical Research Centre (GB), Donostiako Unibertsitate Ospitalea (ES), Hertie Institute for Clinical Brain Research (DE), The London College (GB), Oxford BioMedica (United Kingdom) (GB), National Hospital for Neurology and Neurosurgery (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), University Hospital Ulm (DE), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Ferrari (Italy) (IT), Technische Hochschule Ulm (DE), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), University of Florence (IT), University College London (GB), Imperial College London (GB), Brunel University of London (GB), University of Duisburg-Essen (DE), Massachusetts Institute of Technology (US), University of Coimbra (PT), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
Alzheimer's Association, Nvidia, Wellcome Trust, Weston Brain Institute, Brain Research UK, Alzheimer's Society, National Institute for Health and Care Research, Department of Health and Social Care, University of Cambridge, University College London, Deutsche Forschungsgemeinschaft, ZonMw, Bundesministerium für Bildung und Forschung, Ministero della Salute, Vetenskapsrådet, Stichting Dioraphte, Alzheimer Nederland, UK Dementia Research Institute, Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre
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