Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia

Yanaika S. Hok-A-Hin; Lisa Vermunt; Carel F.W. Peeters; Emma L. van der Ende; Sterre C.M. de Boer; Lieke H. Meeter; Julie de Houwer; Harro Seelaar; John C. van Swieten; William T. Hu; Alberto Lleó; Daniel Alcolea; Sebastiaan Engelborghs; Anne Sieben; Alice Chen-Plotkin; David J. Irwin; Wiesje M. van der Flier; Yolande A.L. Pijnenburg; Charlotte E. Teunissen; Marta del Campo

doi:10.1186/s13024-025-00882-5

Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia

Yanaika S. Hok-A-Hin^*
, Lisa Vermunt
, Carel F.W. Peeters
, Emma L. van der Ende
, Sterre C.M. de Boer
, Lieke H. Meeter
, Julie de Houwer
, Harro Seelaar
, John C. van Swieten
, William T. Hu
, Alberto Lleó
, Daniel Alcolea
, Sebastiaan Engelborghs
, Anne Sieben
, Alice Chen-Plotkin
, David J. Irwin
, Wiesje M. van der Flier
, Yolande A.L. Pijnenburg
, Charlotte E. Teunissen
, Marta del Campo

^*Corresponding author for this work

Neurology

Amsterdam UMC
Vrije Universiteit Amsterdam
Wageningen University & Research
The University of Sydney
Emory University School of Medicine
Autonomous University of Barcelona
Instituto de Salud Carlos III
University of Antwerp
Vrije Universiteit Brussel
UPenn School of Medicine
Pasqual Maragall Foundation
CEU Universities

Research output: Contribution to journal › Article › Academic › peer-review

7 Citations (Scopus)

118 Downloads (Pure)

Abstract

Background:

Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy.

Methods:

We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included 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 = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55).

Results:

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 (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80).

Conclusions:

Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.

Original language	English
Article number	93
Journal	Molecular Neurodegeneration
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s13024-025-00882-5
Publication status	Published - 27 Aug 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Access to Document

10.1186/s13024-025-00882-5Licence: CC BY

Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementiaFinal published version, 4.86 MBLicence: CC BY

Cite this

Hok-A-Hin, Y. S., Vermunt, L., Peeters, C. F. W., van der Ende, E. L., de Boer, S. C. M., Meeter, L. H., de Houwer, J., Seelaar, H., van Swieten, J. C., Hu, W. T., Lleó, A., Alcolea, D., Engelborghs, S., Sieben, A., Chen-Plotkin, A., Irwin, D. J., van der Flier, W. M., Pijnenburg, Y. A. L., Teunissen, C. E., & del Campo, M. (2025). Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia. Molecular Neurodegeneration, 20(1), Article 93. https://doi.org/10.1186/s13024-025-00882-5

@article{ba3165ff1c1a49629fd83d1b3feb130d,

title = "Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia",

abstract = "Background: Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. Methods: We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer{\textquoteright}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 = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55).Results: 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 (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Conclusions: Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.",

author = "Hok-A-Hin, \{Yanaika S.\} and Lisa Vermunt and Peeters, \{Carel F.W.\} and \{van der Ende\}, \{Emma L.\} and \{de Boer\}, \{Sterre C.M.\} and Meeter, \{Lieke H.\} and \{de Houwer\}, Julie and Harro Seelaar and \{van Swieten\}, \{John C.\} and Hu, \{William T.\} and Alberto Lle{\'o} and Daniel Alcolea and Sebastiaan Engelborghs and Anne Sieben and Alice Chen-Plotkin and Irwin, \{David J.\} and \{van der Flier\}, \{Wiesje M.\} and Pijnenburg, \{Yolande A.L.\} and Teunissen, \{Charlotte E.\} and \{del Campo\}, Marta",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = aug,

day = "27",

doi = "10.1186/s13024-025-00882-5",

language = "English",

volume = "20",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central Ltd.",

number = "1",

}

Hok-A-Hin, YS, Vermunt, L, Peeters, CFW, van der Ende, EL, de Boer, SCM, Meeter, LH, de Houwer, J, Seelaar, H , van Swieten, JC, Hu, WT, Lleó, A, Alcolea, D, Engelborghs, S, Sieben, A, Chen-Plotkin, A, Irwin, DJ, van der Flier, WM, Pijnenburg, YAL, Teunissen, CE & del Campo, M 2025, 'Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia', Molecular Neurodegeneration, vol. 20, no. 1, 93. https://doi.org/10.1186/s13024-025-00882-5

TY - JOUR

T1 - Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia

AU - Hok-A-Hin, Yanaika S.

AU - Vermunt, Lisa

AU - Peeters, Carel F.W.

AU - van der Ende, Emma L.

AU - de Boer, Sterre C.M.

AU - Meeter, Lieke H.

AU - de Houwer, Julie

AU - Seelaar, Harro

AU - van Swieten, John C.

AU - Hu, William T.

AU - Lleó, Alberto

AU - Alcolea, Daniel

AU - Engelborghs, Sebastiaan

AU - Sieben, Anne

AU - Chen-Plotkin, Alice

AU - Irwin, David J.

AU - van der Flier, Wiesje M.

AU - Pijnenburg, Yolande A.L.

AU - Teunissen, Charlotte E.

AU - del Campo, Marta

PY - 2025/8/27

Y1 - 2025/8/27

N2 - Background: Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. Methods: We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included 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 = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55).Results: 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 (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Conclusions: Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.

AB - Background: Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. Methods: We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included 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 = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55).Results: 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 (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Conclusions: Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.

UR - https://www.scopus.com/pages/publications/105014139738

U2 - 10.1186/s13024-025-00882-5

DO - 10.1186/s13024-025-00882-5

M3 - Article

C2 - 40866991

AN - SCOPUS:105014139738

SN - 1750-1326

VL - 20

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

IS - 1

M1 - 93

ER -

Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this