Journal Article

DZNE-2026-00857

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Distinct proteomic CSF profiles in genetic frontotemporal lobar degeneration.

De Houwer, J. F. H. ; Dopper, E. G. ; van Buuren, R. ; Stokkel, M. ; de Boer, L. ; Swartenbroekx, T. ; Boesjes, P. A. ; Rajicic, A. ; Sogorb-Esteve, A. ; Bouzigues, A. ; Russell, L. L. ; Foster, P. H. ; Ferry-Bolder, E. ; van Swieten, J. C. ; Jiskoot, L. C. ; Sanchez-Valle, R. ; Laforce, R. ; Graff, C. ; Galimberti, D. ; Vandenberghe, R. ; de Mendonça, A. ; Tiraboschi, P. ; Santana, I. ; Gerhard, A. ; Levin, J.DZNE* ; Nacmias, B. ; Otto, M. ; Bertoux, M. ; Lebouvier, T. ; Ducharme, S. ; Butler, C. R. ; Le Ber, I. ; Finger, E. ; Tartaglia, M. C. ; Masellis, M. ; Rowe, J. B. ; Synofzik, M.DZNE* ; Moreno, F. ; Borroni, B. ; Zetterberg, H. ; Rohrer, J. D. ; Tijms, B. M. ; Pijnenburg, Y. A. L. ; Teunissen, C. ; Seelaar, H. ; Members, G. C. (Collaboration Author) ; Convery, R. (Contributor) ; Bocchetta, M. (Contributor) ; Cash, D. (Contributor) ; Goldsmith, S. (Contributor) ; Samra, K. (Contributor) ; Thomas, D. L. (Contributor) ; Cope, T. (Contributor) ; Malpetti, M. (Contributor) ; Alberici, A. (Contributor) ; Premi, E. (Contributor) ; Gasparotti, R. (Contributor) ; Buratti, E. (Contributor) ; Cantoni, V. (Contributor) ; Arighi, A. (Contributor) ; Fenoglio, C. (Contributor) ; Borracci, V. (Contributor) ; Serpente, M. (Contributor) ; Carandini, T. (Contributor) ; Rotondo, E. (Contributor) ; Rossi, G. (Contributor) ; Giaccone, G. (Contributor) ; Fede, G. D. (Contributor) ; Caroppo, P. (Contributor) ; Prioni, S. (Contributor) ; Redaelli, V. (Contributor) ; Tang-Wai, D. (Contributor) ; Rogaeva, E. (Contributor) ; Krüger, J. (Contributor) ; Castelo-Branco, M. (Contributor) ; Freedman, M. (Contributor) ; Keren, R. (Contributor) ; Black, S. (Contributor) ; Mitchell, S. (Contributor) ; Shoesmith, C. (Contributor) ; Bartha, R. (Contributor) ; Rademakers, R. (Contributor) ; Poos, J. (Contributor) ; Papma, J. M. (Contributor) ; van Minkelen, R. (Contributor) ; Pijnenburg, Y. (Contributor) ; Nacmias, B. (Contributor) ; Ferrari, C. (Contributor) ; Polito, C. (Contributor) ; Lombardi, G. (Contributor) ; Bessi, V. (Contributor) ; Fainardi, E. (Contributor) ; Chiti, S. (Contributor) ; Nilsson, M. (Contributor) ; Viklund, H. (Contributor) ; Rydell, M. T. (Contributor) ; Jelic, V. (Contributor) ; Ullgren, A. (Contributor) ; Rodriguez-Vieitez, E. (Contributor) ; Langheinrich, T. (Contributor) ; Lladó, A. (Contributor) ; Antonell, A. (Contributor) ; Olives, J. (Contributor) ; Balasa, M. (Contributor) ; Bargalló, N. (Contributor) ; Borrego-Ecija, S. (Contributor) ; Verdelho, A. (Contributor) ; Maruta, C. (Contributor) ; Costa-Coelho, T. (Contributor) ; Miltenberger, G. (Contributor) ; Couto, F. S. d. (Contributor) ; Gabilondo, A. (Contributor) ; Croitoru, I. (Contributor) ; Tainta, M. (Contributor) ; Barandiaran, M. (Contributor) ; Alves, P. (Contributor) ; Bender, B. (Contributor) ; Mengel, D. (Contributor)Extern* ; Graf, L. (Contributor)Extern* ; Vogels, A. (Contributor) ; Vandenbulcke, M. (Contributor) ; Van Damme, P. (Contributor) ; Bruffaerts, R. (Contributor) ; Poesen, K. (Contributor) ; Rosa-Neto, P. (Contributor) ; Montembault, M. (Contributor) ; Migliaccio, R. L. (Contributor) ; Burgos, N. (Contributor) ; Rinaldi, D. (Contributor) ; Prix, C. (Contributor)Extern* ; Wlasich, E. (Contributor) ; Wagemann, O. (Contributor)Extern* ; Schönecker, S. (Contributor) ; Bernhardt, A. M. (Contributor)Extern* ; Stockbauer, A. (Contributor)Extern* ; Lombardi, J. (Contributor) ; Anderl-Straub, S. (Contributor) ; Rollin, A. (Contributor) ; Kuchcinski, G. (Contributor) ; Deramecourt, V. (Contributor) ; Durães, J. (Contributor) ; Lima, M. (Contributor) ; Leitão, M. J. (Contributor) ; Almeida, M. R. (Contributor) ; Tábuas-Pereira, M. (Contributor) ; Afonso, S. (Contributor) ; Lemos, J. (Contributor)

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf457

Abstract: Fluid biomarkers to diagnose frontotemporal lobar degeneration (FTLD) are currently lacking. In this study, we aimed to identify proteomic changes in 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. Over-representation analysis was conducted for the three genetic groups using Gene Ontology Biological Processes as the 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.

Keyword(s): Humans (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: cerebrospinal fluid (MeSH) ; Female (MeSH) ; Male (MeSH) ; Proteomics: methods (MeSH) ; Middle Aged (MeSH) ; Aged (MeSH) ; Progranulins: genetics (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Cohort Studies (MeSH) ; C9orf72 Protein: genetics (MeSH) ; dementia ; familial ; frontotemporal dementia ; olink ; proteome ; proximity extension-based assay ; Progranulins ; tau Proteins ; Biomarkers ; C9orf72 Protein ; C9orf72 protein, human ; MAPT protein, human ; GRN protein, human

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Clinical Neurodegeneration (AG Levin)
3. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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