A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study
Sofia Bergström, Linn Öijerstedt, Julia Remnestål, Jennie Olofsson, Abbe Ullgren, Harro Seelaar, John C. van Swieten, Matthis Synofzik, Raquel Sánchez‐Valle, Fermín Moreno, Elizabeth Finger, Mario Masellis, Maria Carmela Tartaglia, Rik Vandenberghe, Robert Laforce, Daniela Galimberti, Barbara Borroni, Christopher Butler, Alexander Gerhard, Simon Ducharme, Jonathan D. Rohrer, Anna Månberg, Caroline Graff, Peter Nilsson, on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI), Lize C. Jiskoot, James B. Rowe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Isabelle Le Ber, Johannes Levin, Adrian Danek, Markus Otto, Giovanni B. Frisoni, Roberta Ghidoni, Sandro Sorbi, Florence Pasquier, Vesna Jelić, Christin Andersson, Sónia Afonso, Maria Rosário Almeida, Sarah Anderl‐Straub, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiarán, Núria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Luisa Benussi, Valentina Bessi, Giuliano Binetti, Sandra E. Black, Martina Bocchetta, Sergi Borrego‐Écija, José Brás, Rose Bruffaerts, Marta Cañada, Valentina Cantoni, Paola Caroppo, David M. Cash, Miguel Castelo‐Branco, Rhian S. Convery, Thomas Cope, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick C. Fox, Morris Freedman, Giorgio Fumagalli, Alazne Gabilondo, Roberto Gasparotti, Serge Gauthier, Stefano Gazzina, Giorgio Giaccone, Ana Gorostidi, Caroline Greaves, Rita Guerreiro, Carolin Heller, Tobias Hoegen, Begoña Indakoetxea, Lize C. Jiskoot, Hans‐Otto Karnath, Ron Keren, Tobias Langheinrich, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli, Carolina Maruta, Simon Mead, Lieke Meeter, Gabriel Miltenberger, Rick van Minkelen
Abstract
BACKGROUND: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. METHODS: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. RESULTS: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). CONCLUSION: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.