Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia
Hok-A-Hin, Yanaika S. (Amsterdam UMC)
Vermunt, Lisa (Amsterdam UMC)
Peeters, Carel F.W. (Wageningen University & Research)
van der Ende, Emma L. (VU University Medical Center.)
de Boer, Sterre C.M. (The University of Sydney (Sydney, Austràlia))
Meeter, Lieke H. (Erasmus Medical Center)
de Houwer, Julie (Alzheimer Center and Department of Neurology. Erasmus Medical Center)
Seelaar, Harro (Erasmus Medical Center)
van Swieten, John C. (Erasmus Medical Center)
Hu, William T. (Emory University School of Medicine)
Lleó, Alberto (Institut de Recerca Sant Pau)
Alcolea, Daniel (Institut de Recerca Sant Pau)
Engelborghs, Sebastiaan (Universitair Ziekenhuis Brussel. Department of Neurology)
Sieben, Anne (Antwerp University)
Chen-Plotkin, Alice (University of Pennsylvania)
Irwin, David J. (University of Pennsylvania)
van der Flier, Wiesje M. (Amsterdam UMC)
Pijnenburg, Yolande (Amsterdam UMC)
Teunissen, Charlotte E. (Amsterdam UMC)
Campo Milán, Marta del (Universidad CEU San Pablo)
Universitat Autònoma de Barcelona. Departament de Medicina

Fecha:	2025
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Biomarkers ; CSF ; FTD ; FTLD ; Proteomics ; TDP43 ; Tau
Publicado en:	Molecular neurodegeneration, Vol. 20, Num. 1 (December 2025) , p. 93, ISSN 1750-1326

DOI: 10.1186/s13024-025-00882-5
PMID: 40866991

18 p, 4.8 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
Artículos > Artículos de investigación
Artículos > Artículos publicados