Abstract: 【Abstract】 Objective To evaluate the diagnostic performance of 3 novel neurosyphilis biomarkers, including ubiquitin C-terminal hydrolase L1 （UCH-L1）, glial fibrillary acidic protein （GFAP）, and neurofilament light chain protein （NF-L）. Methods Data were retrospectively collected from 51 untreated, human immunodeficiency virus （HIV）-negative inpatients with neurosyphilis, who visited the Zhongshan Hospital of Xiamen University from December 2021 to November 2022. After adjustment for the age by propensity score matching, 51 untreated, HIV-negative, non-neurosyphilis inpatients with syphilis （named as patients without neurosyphilis） were included at the same time. Serum and cerebrospinal fluid （CSF） samples were collected from all patients, and enzyme-linked immunosorbent assay was performed to detect the levels of UCH-L1, GFAP, and NF-L in both serum and CSF samples. Spearman correlation coefficients were used to analyze correlations of serum and CSF levels of the 3 novel neurosyphilis biomarkers （UCH-L1, GFAP, and NF-L） with traditional neurosyphilis indicators such as rapid plasma reagin （RPR） test, Treponema pallidum particle agglutination assay （TPPA）, CSF white blood cell （WBC） counts, and CSF protein concentrations. The Hanley & McNeil method was used to compare the areas under the receiver operating characteristic curves （AUCs） of serum and CSF UCH-L1, GFAP, and NF-L levels versus the 4 traditional laboratory indicators for diagnosing neurosyphilis. The paired chi-square test was used to compare the sensitivity and specificity among the above neurosyphilis indicators. Results The 51 patients with neurosyphilis were aged 56.0 （48.0, 67.0） years, and included 33 males and 18 females; the 51 patients without neurosyphilis were aged 54.0 （44.0, 64.0） years, and included 30 males and 21 females. The patients with neurosyphilis showed significantly increased serum RPR titers and positive rates, CSF RPR and TPPA titers and positive rates, CSF WBC counts and proportions of patients with elevated WBC counts in CSF, and CSF protein concentrations and proportions of patients with elevated CSF protein concentrations compared with those without neurosyphilis （all P < 0.001）. Spearman correlation analysis showed that neither serum nor CSF levels of UCH-L1, GFAP, and NF-L were correlated with CSF TPPA titers, CSF RPR titers, CSF WBC counts, or CSF protein concentrations among the 51 patients with neurosyphilis （rs ranged from -0.22 to 0.74, all P > 0.05）. The AUC value of serum UCH-L1 levels （0.966） was significantly higher than those of CSF RPR titers, CSF TPPA titers, CSF WBC counts, and CSF protein concentrations （AUC = 0.745, 0.894, 0.845, 0.765, respectively, all P < 0.05）; the AUC value of serum GFAP levels （0.862） did not differ from those of the above 4 traditional laboratory indicators （all P > 0.05）; the AUC value of serum NF-L levels （0.903） was significantly higher than those of CSF RPR titers and CSF protein concentrations （both P < 0.01）, but did not differ from those of CSF TPPA titers and CSF WBC counts （both P > 0.05）. The AUC value of CSF UCH-L1 levels （0.958） was significantly higher than those of CSF RPR titers, CSF WBC counts, and CSF protein concentrations （all P < 0.01）, but did not differ from that of CSF TPPA titers （P = 0.070）; the AUC value of CSF GFAP levels （0.906） was significantly higher than those of CSF RPR titers and CSF protein concentrations （both P < 0.01）, but did not differ from those of CSF TPPA titers and CSF WBC counts （both P > 0.05）; there were no significant differences in the AUC values between CSF NF-L levels （0.828） and the 4 traditional laboratory indicators （all P > 0.05）. The diagnostic sensitivity of serum UCH-L1 levels was significantly higher than that of CSF RPR titers, CSF WBC counts, and CSF protein concentrations （all P < 0.05）, and the diagnostic specificity of serum UCH-L1 levels was significantly higher than that of CSF TPPA titers （P = 0.031）; the diagnostic sensitivity of serum GFAP and NF-L levels was significantly higher than that of CSF RPR titers and CSF protein concentrations （both P < 0.05）. The diagnostic sensitivity of CSF UCH-L1 levels was significantly higher than that of CSF RPR titers, CSF WBC counts, and CSF protein concentrations （all P < 0.05）, and the diagnostic specificity of CSF UCH-L1 levels was significantly higher than that of CSF TPPA titers （P = 0.049）; the diagnostic sensitivity of CSF GFAP levels was significantly higher than that of CSF RPR titers, CSF WBC counts, and CSF protein concentrations （all P < 0.05）, and the diagnostic sensitivity of CSF NF-L levels was significantly higher than that of CSF RPR titers （P < 0.001）. Conclusion The serum and CSF biomarkers UCH-L1, GFAP and NF-L all exhibited better performance for the diagnosis of neurosyphilis than traditional laboratory indicators, and may be of great value in the future application.

Key words: Neurosyphilis, Ubiquitin C-terminal hydrolase L1, Glial fibrillary acidic protein, Neurofilament light chain protein, Diagnostic markers, Diagnostic performance