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.