Year: 2026
Type: preprint
Study design: Observational Study
Abstract: C9orf72 encodes a protein that is important for both typical neurodevelopment and homeostatic processes across the lifespan. Pathogenic C9orf72 repeat expansions constitute the most common genetic cause of frontotemporal lobar degeneration (FTLD). Collectively, preclinical models and clinical neuroimaging studies have observed smaller thalamic volumes in C9orf72 -associated FTLD, including in asymptomatic young adult C9orf72 repeat expansion carriers across 18 to 30 years old, supportive of potential neurodevelopmental origins. However, it is unknown whether asymptomatic young adult C9orf72 expansion carriers demonstrate volume differences in specific thalamic nuclei, as reported in older asymptomatic carriers and symptomatic patients; if so, normative transcriptomic patterns could reveal relevant neurodevelopmental and/or FTLD-related neurodegenerative processes. This study investigated volumetric MRI differences of the thalamic nuclei in asymptomatic young adult C9orf72 expansion carriers compared to non-carriers, and examined spatial associations with normative thalamic transcriptomics from 8 weeks post-conception through middle age. Young adult C9orf72 expansion carriers ( n =72) and non-carriers ( n =48) were enrolled in the Frontotemporal Dementia Prevention Initiative across Europe, Canada, and the USA (ages: 18-30 years; sex: 57% female). Spatial associations between young adult thalamic nuclei volumes and normative transcriptomics from the Allen Human Brain Atlas were examined using complementary data-driven and hypothesis-driven approaches. Spatial expression patterns of transcripts of interest were characterized across prenatal and postnatal neurodevelopment using BrainSpan data. Smaller volumes of the pulvinar, mediodorsal, and lateral nuclei were observed in young adult C9orf72 expansion carriers compared to non-carriers. These nuclei showed higher normative expression of transcripts involved concurrently in neurodevelopmental and C9orf72 -associated FTLD neurodegenerative processes (including lysosomal, autophagic, and small GTPase functions), and lower normative expression of CALB1 , a marker of prenatal human thalamic development. Normative expression of CALB2 (another human thalamic development marker) yielded positive correlations with C9orf72 across prenatal development to adulthood. These findings identify candidate transcripts that may provide insight into the molecular architecture leading to smaller thalamic nuclei volumes in C9orf72 -associated FTLD.
Source: medRxiv
Authors: Isis So, Arabella Bouzigues, Eve Ferry-Bolder, Eva Cullen, Lucy L. Russell, Phoebe H. Foster, Sophie Farley, Rhian Convery, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Daniela Galimberti, Rik Vandenberghe, Robert Laforce, Rose Bruffaerts, Maxime Bertoux, Thibaud Lebouvier, Eino Solje, Johannes Levin, Giuseppe di Fede, Alexander Thompson, Isabelle Le Ber, Raffaella Lara Migliaccio, Peter Körtvélyessy, Matthias L. Schroeter, Giancarlo Logroscino, Markus Otto, Zeljko Uzelac, Ignacio Illán-Gala, Johanna Krüger, Benedetta Nacmias, Alexander Gerhard, Tobias Langheinrich, Simon Ducharme, Isabel Santana, Maria Carmela Tartaglia, Mario Masellis, Alexandre de Mendonça, James B. Rowe, Caroline Graff, Fermin Moreno, Matthis Synofzik, Barbara Borroni, Raquel Sanchez-Valle, Rosa Rademakers, Danielle Brushaber, Leah K. Forsberg, Hilary W. Heuer, Kejal Kantarci, Tyler Kolander, Carly Mester, Bradley F. Boeve, Adam L. Boxer, Howard J. Rosen, Suzee E. Lee, Jonathan D. Rohrer, Tallulah S. Andrews, Elizabeth C. Finger
Institutions: Western University, UCL Queen Square Institute of Neurology, University College London, Erasmus MC, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, KU Leuven, Centre hospitalier universitaire de Québec, Université Laval, University of Antwerp, Hasselt University, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, Lille Neurosciences & Cognition, University of Eastern Finland, Kuopio University Hospital, Ludwig-Maximilians-Universität München, Fondazione IRCCS Istituto Neurologico Carlo Besta, University of Oxford, Centre National de la Recherche Scientifique, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Charité – Universitätsmedizin Berlin, University Hospital Leipzig, Max Planck Institute for Human Cognitive and Brain Sciences, University of Bari Aldo Moro, Universität Ulm, Hospital de Sant Pau, Institut de Recerca Sant Pau, University of Oulu, University of Florence, University of Manchester, Douglas Mental Health University Institute, McGill University, Unidade Local de Saúde de Coimbra, University of Coimbra, University of Toronto, Sunnybrook Health Science Centre, University of Lisbon, MRC Cognition and Brain Sciences Unit, University of Cambridge, Karolinska Institutet, Donostiako Unibertsitate Ospitalea, Hertie Institute for Clinical Brain Research, University of Tübingen, Centro San Giovanni di Dio Fatebenefratelli, University of Brescia, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, VIB-UAntwerp Center for Molecular Neurology, Mayo Clinic in Florida, Mayo Clinic, University of California, San Francisco, UCSF Edward and Pearl Fein Memory and Aging Center
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, Weston Brain Institute, National Institute for Health and Care Research, University College London, Deutsche Forschungsgemeinschaft, ZonMw, Bundesministerium für Bildung und Forschung, Ministero della Salute, Jane ja Aatos Erkon Säätiö, Karolinska Institutet, Vetenskapsrådet, Stichting Dioraphte, Canada First Research Excellence Fund, Alzheimer Nederland, Canadian Institutes of Health Research, Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre
Awards: G1076890169, G1426422999, G1789099517, G2588154941, G2951265004, G3691030594, Diseño de biomarcadores para Demencia Fronto-temporal asociada a mutaciones en GRN, G3765210622, G3836382391, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G4665392370, G4692761294, Demencias genéticas (enfermedad de Alzheimer, demencia frontotemporal y enfermedades priónicas genéticas): cambios longitudinales y diferencias en expresión y epigenéticas con formas esporádicas, G6745503199, G730080581, G7624737488, G7643512016, G784856114
OpenAlex ID: W7221649232