Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 <i>C9orf72</i>, 38 <i>GRN</i>, and 25 <i>MAPT</i>) and 55 symptomatic (27 <i>C9orf72</i>, 17 <i>GRN</i>, and 11 <i>MAPT</i>) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in <i>MAPT</i> carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

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Journal
Science Translational Medicine
Published
2025-02-05
DOI
https://doi.org/10.1126/scitranslmed.adm9654
Citations
11
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
12.81

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article

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes

Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai, Ron Keren et al.
11 citations
Science Translational Medicine
Alzheimer's disease research and treatments
12.81
article

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes

Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai, Ron Keren, Serge Gauthier, Johan Gobom, Koen Poesen, Olivier Colliot, Tobias Hoegen, Sandro Sorbi, Robert Bartha, Rick van Minkelen, Carolina Maruta, Emily Todd, Caroline Graff, Ekaterina A. Rogaeva, Joel Simrén, Giacomina Rossi, Alazne Gabilondo, Andrea Arighi, Sandra Loosli, Valentina Bessi, Maria Carmela Tartaglia, Jaume Olives, Tobias Christoph Langheinrich, Catarina B. Ferreira, Stefano Gazzina, Elio Scarpini, Enrico Premi, James Benedict Rowe, Albert Lladó, Timothy Rittman, Giorgio Giaccone, Kaj Blennow, Alexander Gerhard, Lucia Giannini, Alexis Brice, Christopher Robert Butler, Roberto Gasparotti, Matthis Synofzik, Giorgio Fumagalli, Vesna Jelić, Linn Öijerstedt, Imogen J. Swift, Lisa H. Graf, Johannes Levin, Beatriz Santiago, Sophia Weiner, Gemma Lombardi, Aurélie Funkiewiez, Alexandre de Mendonça, Jolina Lombardi, Eve Ferry‐Bolder, Mircea Balasa, David M. Cash, Marta Cañada, Camilla Ferrari, Thomas Cope, Sara Prioni, Raquel Sánchez‐Valle, Sonja Schönecker, Núria Bargalló, Harro Seelaar, Jackie M. Poos, Aitana Sogorb‐Esteve, Sergi Borrego‐Écija, Diana Duro, Pietro Tiraboschi, Frederico Simões do Couto, Michele Veldsman, Grégory Kuchcinski, Phoebe H. Foster, Benjamin Bender, Anne Bertrand, Arabella Bouzigues, Pollianna Muniz Alves, Alberto Benussi, Isabel Santana, Lize Corrine Jiskoot, Daisy Rinaldi, Dario Saracino, Cristina Polito, Martina Bocchetta, Annick Vogels, Vittoria Borracci, Lucy Louise Russell, Jonathan D. Rohrer, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Elizabeth C. Finger, Valentina Cantoni, Mathieu Vandenbulcke, Carlo Wilke, Adeline Rollin, Michael A. van Es, Chiara Fenoglio, Ana Verdelho, Catharina Prix, Miguel Tábuas‐Pereira, Henrik Zetterberg, Vincent Deramecourt, Daniela Galimberti, Rose Buffaerts, Maria Rosário Almeida, Maria João Leitão, Thibaud Lebouvier, Paul Thompson, Miren Zulaica, Mario Masellis, Fermín Moreno, David Lee Thomas, Olivia Wagemann, Rhian S. Convery, Giuseppe Di Fede, Barbara Borroni, Miguel Castelo‐Branco, Pedro Rosa‐Neto, Sarah Anderl‐Straub, Myriam Barandiarán, Yolande A.L. Pijnenburg, Janne M. Papma, Jorge Villanúa, Mikel Tainta, Sara Berman Mitchell, Robert Laforce, Simon Ducharme, Gabriel Miltenberger, Silvana Archetti, Sònia Afonso, Isabelle Le Ber, Anna Antonell, Håkan Thonberg, Christen Shoesmith, Rosa Rademakers, Agnès Camuzat, Sabrina Sayah, John C. van Swieten, Christin Andersson, Paola Caroppo, Sandra Black, Florence Pasquier, Benedetta Nacmias, Veronica Radaaelli
article en
11 citations

Abstract

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 <i>C9orf72</i>, 38 <i>GRN</i>, and 25 <i>MAPT</i>) and 55 symptomatic (27 <i>C9orf72</i>, 17 <i>GRN</i>, and 11 <i>MAPT</i>) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in <i>MAPT</i> carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Science Translational MedicineVol. 17(784)
Western University (CA), University of Science and Technology of China (CN), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Wisconsin–Madison (US), University of Lisbon (PT), Inserm (FR), University of Toronto (CA), University of Milan (IT), Universität Ulm (DE), Université de Lille (FR), University of Cambridge (GB), Sahlgrenska University Hospital (SE), German Center for Neurodegenerative Diseases (DE), McGill University Health Centre (CA), Erasmus MC (NL), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), Sorbonne Université (FR), University of Oxford (GB), Centro Cardiologico Monzino (IT), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Don Carlo Gnocchi Foundation (IT), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), MRC Prion Unit (GB), Hertie Institute for Clinical Brain Research (DE), 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), Brunel University of London (GB), University of Duisburg-Essen (DE), Martin Luther University Halle-Wittenberg (DE), University of Coimbra (PT), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE), Erasmus University Rotterdam (NL), KU Leuven (BE)
Medical Research Council
Good health and well-being
Openalex Percentile: Top 1%
Alzheimer's disease research and treatments
12.81
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