Distinct proteomic CSF profiles in genetic frontotemporal lobar degeneration

Fluid biomarkers to diagnose frontotemporal lobar degeneration (FTLD) are currently lacking. In this study, we aimed to identify proteomic changes in cerebrospinal fluid (CSF) associated with FTLD pathogenesis, focusing on signatures unique to different genetic groups. Additionally, we sought proteins distinguishing FTLD-spectrum disorders from controls. To this end, we measured a comprehensive library of over 2900 proteins in CSF using proximity extension assay technology in two well-characterized FTLD cohorts. The discovery cohort, selected from the GENFI cohort, included 47 symptomatic pathogenic variant carriers (22 C9orf72, 14 GRN, 10 MAPT and 1 TARDBP), 124 presymptomatic pathogenic variant carriers (55 C9orf72, 44 GRN, 24 MAPT and 1 TARDBP) and 57 healthy non-carriers. The validation cohort comprised individuals clinically diagnosed with an FTLD-spectrum disorder (n = 132) and cognitively intact controls (n = 32). We assessed differentially abundant proteins using linear regression, adjusting for age and sex. Overrepresentation analysis was conducted for the three genetic groups using Gene Ontology Biological Processes as ontology source. To develop diagnostic tools, we applied a LASSO regression, establishing two types of panels: one to distinguish individuals with an FTLD-spectrum disorder from controls (FTLD panel) and another to differentiate individuals with underlying TDP pathology from controls (TDP panel). We observed 23 dysregulated proteins in symptomatic carriers. Of these, four were also significantly dysregulated (NEFL, TPM3, MSLN and DNM3) in the validation cohort. When focusing on genetic subgroups, 63 upregulated proteins were observed in symptomatic MAPT carriers, with enriched biological pathways linked to immune function. In symptomatic C9orf72 carriers, four proteins - related to energy metabolism - were upregulated. When limiting symptomatic carriers to GRN, six proteins were dysregulated, with enriched pathways involved in neuronal development and projection. Notably, NEFL and TPM3 were consistently significant in all comparisons across both cohorts. We developed two diagnostic panels: one for FTLD and one for FTLD-TDP. The FTLD panel consisted of six proteins (NEFL, RBFOX3, NPTX1, TFF1, ENTPD5, and CNP). The TDP panel was made up of seven proteins (NEFL, RBFOX3, CBLN4, ENTPD5, CCL25, CNP, and MMP1). Both panels were successfully replicated in the validation cohort (AUC of 0.94 and 0.96 respectively). This study highlights distinct proteomic signatures across FTLD genetic subgroups and their associated pathologies using a targeted proteomic approach. Additionally, we present two diagnostic panels-comprising both established and novel proteins-that effectively differentiate individuals with FTLD-spectrum disorders from healthy controls, offering promising avenues for improved clinical diagnosis.

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Journal
Brain
Published
2025-12-02
DOI
https://doi.org/10.1093/brain/awaf457
Citations
1
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
1.39

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article

Distinct proteomic CSF profiles in genetic frontotemporal lobar degeneration

John Cornelis Van Swieten, Elise G.P. Dopper, Renee van Buuren, Caroline Graff et al.
1 citations
Brain
Amyotrophic Lateral Sclerosis Research
1.39
article

Distinct proteomic CSF profiles in genetic frontotemporal lobar degeneration

John Cornelis Van Swieten, Elise G.P. Dopper, Renee van Buuren, Caroline Graff, Liset de Boer, Maria Carmela Tartaglia, James Benedict Rowe, Alexander Gerhard, Christopher Robert Butler, Betty Marije Tijms, Matthis Synofzik, Johannes Levin, Alexandre de Mendonça, Eve Ferry‐Bolder, Isabelle Le Ber, Raquel Sánchez‐Valle, Harro Seelaar, Aitana Sogorb‐Esteve, Pietro Tiraboschi, Ana Rajicic, Phoebe H. Foster, Arabella Bouzigues, Lize Corrine Jiskoot, Benedetta Nacmias, Lucy Louise Russell, Jonathan D. Rohrer, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Elizabeth C. Finger, Charlotte Elisabeth Teunissen, Henrik Zetterberg, Daniela Galimberti, Thibaud Lebouvier, Fermín Moreno, Barbara Borroni, Tine Swartenbroekx, Yolande A.L. Pijnenburg, Julie F. H. De Houwer, Mario Masellis, Robert Laforce, Simon Ducharme, Isabel Santana, Marijke E. Stokkel, Pam Boesjes
article en
1 citations

Abstract

Fluid biomarkers to diagnose frontotemporal lobar degeneration (FTLD) are currently lacking. In this study, we aimed to identify proteomic changes in cerebrospinal fluid (CSF) associated with FTLD pathogenesis, focusing on signatures unique to different genetic groups. Additionally, we sought proteins distinguishing FTLD-spectrum disorders from controls. To this end, we measured a comprehensive library of over 2900 proteins in CSF using proximity extension assay technology in two well-characterized FTLD cohorts. The discovery cohort, selected from the GENFI cohort, included 47 symptomatic pathogenic variant carriers (22 C9orf72, 14 GRN, 10 MAPT and 1 TARDBP), 124 presymptomatic pathogenic variant carriers (55 C9orf72, 44 GRN, 24 MAPT and 1 TARDBP) and 57 healthy non-carriers. The validation cohort comprised individuals clinically diagnosed with an FTLD-spectrum disorder (n = 132) and cognitively intact controls (n = 32). We assessed differentially abundant proteins using linear regression, adjusting for age and sex. Overrepresentation analysis was conducted for the three genetic groups using Gene Ontology Biological Processes as ontology source. To develop diagnostic tools, we applied a LASSO regression, establishing two types of panels: one to distinguish individuals with an FTLD-spectrum disorder from controls (FTLD panel) and another to differentiate individuals with underlying TDP pathology from controls (TDP panel). We observed 23 dysregulated proteins in symptomatic carriers. Of these, four were also significantly dysregulated (NEFL, TPM3, MSLN and DNM3) in the validation cohort. When focusing on genetic subgroups, 63 upregulated proteins were observed in symptomatic MAPT carriers, with enriched biological pathways linked to immune function. In symptomatic C9orf72 carriers, four proteins - related to energy metabolism - were upregulated. When limiting symptomatic carriers to GRN, six proteins were dysregulated, with enriched pathways involved in neuronal development and projection. Notably, NEFL and TPM3 were consistently significant in all comparisons across both cohorts. We developed two diagnostic panels: one for FTLD and one for FTLD-TDP. The FTLD panel consisted of six proteins (NEFL, RBFOX3, NPTX1, TFF1, ENTPD5, and CNP). The TDP panel was made up of seven proteins (NEFL, RBFOX3, CBLN4, ENTPD5, CCL25, CNP, and MMP1). Both panels were successfully replicated in the validation cohort (AUC of 0.94 and 0.96 respectively). This study highlights distinct proteomic signatures across FTLD genetic subgroups and their associated pathologies using a targeted proteomic approach. Additionally, we present two diagnostic panels-comprising both established and novel proteins-that effectively differentiate individuals with FTLD-spectrum disorders from healthy controls, offering promising avenues for improved clinical diagnosis.

Brain
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Allen Institute for Brain Science (US), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Wisconsin–Madison (US), University of Lisbon (PT), Inserm (FR), University of Toronto (CA), Neurosciences Institute (US), University of Milan (IT), Universität Ulm (DE), Hong Kong University of Science and Technology (HK), Université de Lille (FR), Douglas Mental Health University Institute (CA), Institut Pasteur de Lille (FR), Sahlgrenska University Hospital (SE), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Health Sciences Centre (CA), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Manchester (GB), Centre Hospitalier Universitaire de Lille (FR), Brescia University (US), Sorbonne Université (FR), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Ospedale Maggiore (IT), Madison Group (United States) (US), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), UK Green Building Council (GB), Biogipuzkoa Health Research Institute (ES), Amsterdam Neuroscience (NL), 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), Donostiako Unibertsitate Ospitalea (ES), 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), University Hospital Ulm (DE), 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), Indian Institute of Science Bangalore (IN), University of Duisburg-Essen (DE), Universitat de Barcelona (ES), University of Coimbra (PT), University of Brescia (IT), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Erasmus University Rotterdam (NL), KU Leuven (BE)
Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Wellcome Trust, Stiftelsen för Gamla Tjänarinnor, Weston Brain Institute, EU Joint Programme – Neurodegenerative Disease Research, Brain Research UK, National Institute for Health and Care Research, University of Cambridge, University College London, European Commission, Deutsche Forschungsgemeinschaft, ZonMw, Bundesministerium für Bildung und Forschung, Ministero della Salute, Hjärnfonden, Vetenskapsrådet, Stichting Dioraphte, Alzheimer Nederland, UK Dementia Research Institute, Bentham-Moxon Trust, HORIZON EUROPE Framework Programme, Medical Research Council, Instituto de Salud Carlos III, NIHR Cambridge Biomedical Research Centre
Openalex Percentile: Top 14%
Amyotrophic Lateral Sclerosis Research
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