Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes
Aitana Sogorb‐Esteve, Sophia Weiner, Joel Simrén, Imogen J. Swift, Martina Bocchetta, Emily Todd, David M. Cash, Arabella Bouzigues, Lucy L. Russell, Phoebe H. Foster, Eve Ferry‐Bolder, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Raquel Sánchez‐Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Alexander Gerhard, Johannes Levin, Sandro Sorbi, Markus Otto, Florence Pasquier, Simon Ducharme, Christopher Butler, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B. Rowe, Matthis Synofzik, Fermín Moreno, Barbara Borroni, Rhian S. Convery, Kaj Blennow, Henrik Zetterberg, Jonathan D. Rohrer, Johan Gobom, David L. Thomas, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Radaaelli, David F. Tang‐Wai, Ekaterina Rogaeva, Michel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie M. Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande A.L. Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Håkan Thonberg, Linn Öijerstedt, Vesna Jelić, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Núria Bargalló, Sergi Borrego‐Écija, Ana Verdelho, Carolina Maruta, Catarina B. Ferreira, Gabriel Miltenberger
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 C9orf72 , 38 GRN , and 25 MAPT ) and 55 symptomatic (27 C9orf72 , 17 GRN , and 11 MAPT ) 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 MAPT 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.