
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.19.24312100
preprint
1
Article
Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of Frontotemporal Dementia
Hok-A-Hin Yanaika S. http://orcid.org/0000-0001-9713-116X

Vermunt Lisa http://orcid.org/0000-0001-7420-6384

Peeters Carel F.W. http://orcid.org/0000-0001-5766-9969

van der Ende Emma L.
de Boer Sterre C.M. http://orcid.org/0000-0002-9595-7221

Meeter Lieke H. http://orcid.org/0000-0003-4277-0815

van Swieten John C. http://orcid.org/0000-0001-6278-6844

Hu William T. http://orcid.org/0000-0003-4862-6777

Lleó Alberto http://orcid.org/0000-0002-2568-5478

Alcolea Daniel http://orcid.org/0000-0002-3819-3245

Engelborghs Sebastiaan http://orcid.org/0000-0003-0304-9785

Sieben Anne http://orcid.org/0000-0003-1278-6605

Chen-Plotkin Alice
Irwin David J.
van der Flier Wiesje M. http://orcid.org/0000-0001-8766-6224

Pijnenburg Yolande A.L. http://orcid.org/0000-0003-2464-1905

Teunissen Charlotte E. http://orcid.org/0000-0002-4061-0837

del Campo Marta http://orcid.org/0000-0003-2808-3699

20 8 2024
2024.08.19.24312100https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.08.19.24312100
nihpp-2024.08.19.24312100.pdf
Abstract

Diagnosis of Frontotemporal dementia (FTD) and the specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) is challenging, and thus fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort including patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 68). Forty three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (AUC: 0.96) or AD (AUC: 0.91). Custom multiplex panels confirmed the highly accurate discrimination between FTD and controls (AUCs > 0.96) or AD (AUCs > 0.88) in three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau, but no reproducible classification model could be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic setting.
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pmc
