Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia
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.
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.
Referencia
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. Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia. Mol Neurodegener. 2025 Aug 27;20(1):93. doi: 10.1186/s13024-025-00882-5. PMID: 40866991; PMCID: PMC12392567.
