Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia
Por:
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
Publicada:
27 ago 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.
Filiaciones:
Hok-A-Hin, YS:
Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam Neurosci,Amsterdam UMC,Med Ctr, Amsterdam, Netherlands
Vermunt, L:
Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam Neurosci,Amsterdam UMC,Med Ctr, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr, Dept Neurol, Amsterdam Neurosci,Med Ctr,Amsterdam UMC, Amsterdam, Netherlands
Peeters, CFW:
Wageningen Univ & Res, Math & Stat Methods Grp Biometris, Wageningen, Netherlands
van der Ende, EL:
Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam Neurosci,Amsterdam UMC,Med Ctr, Amsterdam, Netherlands
de Boer, SCM:
Vrije Univ Amsterdam, Alzheimer Ctr, Dept Neurol, Amsterdam Neurosci,Med Ctr,Amsterdam UMC, Amsterdam, Netherlands
Univ Sydney, Sch Psychol, Sydney, Australia
Univ Sydney, Brain & Mind Ctr, Sydney, Australia
Meeter, LH:
Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
de Houwer, J:
Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Seelaar, H:
Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
van Swieten, JC:
Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Hu, WT:
Emory Univ, Ctr Neurodegenerat Dis Res, Dept Neurol, Sch Med, Atlanta, GA USA
Lleó, A:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Invest Biomed St Pau IIB ST PAU, Hosp St Pau,Dept Neurol, Barcelona, Catalunya, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Alcolea, D:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Invest Biomed St Pau IIB ST PAU, Hosp St Pau,Dept Neurol, Barcelona, Catalunya, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Engelborghs, S:
Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Dept Biomed Sci, Antwerp, Belgium
Vrije Univ Brussel, Ctr Neurosci C4N, Neuroprotect & Neuromodulat Res Grp NEUR, Brussels, Belgium
Univ Ziekenhuis Brussel, Dept Neurol, Brussels, Belgium
Sieben, A:
Antwerp Univ, Inst Born Bunge, Lab Neuropathol, Neurobiobank, Edegem, Belgium
Chen-Plotkin, A:
Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA USA
Irwin, DJ:
Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA USA
van der Flier, WM:
Vrije Univ Amsterdam, Alzheimer Ctr, Dept Neurol, Amsterdam Neurosci,Med Ctr,Amsterdam UMC, Amsterdam, Netherlands
Pijnenburg, YAL:
Vrije Univ Amsterdam, Alzheimer Ctr, Dept Neurol, Amsterdam Neurosci,Med Ctr,Amsterdam UMC, Amsterdam, Netherlands
Teunissen, CE:
Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam Neurosci,Amsterdam UMC,Med Ctr, Amsterdam, Netherlands
del Campo, M:
Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam Neurosci,Amsterdam UMC,Med Ctr, Amsterdam, Netherlands
Pasqual Maragall Fdn, BarcelonaBeta Brain Res Ctr, Barcelona, Spain
CEU Univ, Univ San Pablo CEU, Fac Farm, Dept Ciencias Farmaceut & Salud, Madrid, Spain
Green Submitted, gold
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