CSF peptidomics reveals an IGF2-derived peptide as a candidate biomarker for neurosyphilis diagnosis

Background Neurosyphilis (NS) diagnosis is challenging due to the cerebrospinal fluid-Venereal Disease Research Laboratory (CSF-VDRL) assay has limited sensitivity, whereas CSF abnormalities lack sufficient specificity. Methods To identify novel CSF peptide biomarkers for NS, we performed comparative peptidomic analysis of CSF samples from 51 individuals across four groups: NS, syphilis/non-NS (NNS), infectious brain diseases without syphilis (IBD), and non-infectious brain disorders without syphilis (NIBD). Peptides were profiled by high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatic analysis and machine learning identified candidate biomarkers, validated by parallel reaction monitoring (PRM) in an independent cohort ( n = 23). Results A total of 4,738 peptides were identified. The insulin-like growth factor 2 (IGF2)-derived peptide GHVLAKELE showed strong discriminative performance: area under the curve (AUC) values of 0.914 (NS vs. NNS), 0.964 (NS vs. IBD), and 0.878 (NS vs. NIBD). Conclusion This first systematic CSF peptidomic characterization of neurosyphilis identifies GHVLAKELE as a promising diagnostic biomarker.