CSF Beta-Synuclein, SNAP-25, and Neurogranin in Infectious and Autoimmune Inflammatory Neurologic Diseases

Beta-synuclein (beta-syn), synaptosomal-associated protein 25 (SNAP-25), and neurogranin are CSF biomarkers of synaptic damage, which have been poorly investigated in non-neurodegenerative neurologic diseases. In this study, we examined the diagnostic and prognostic role of these markers compared with the neuroaxonal damage marker neurofilament light chain protein (NfL) in infectious and autoimmune inflammatory neurologic diseases (IINDs and AINDs).

This cohort study included CSF samples from patients with different etiologies of IIND (varicella-zoster virus, herpes simplex virus, tick-borne meningoencephalitis, bacterial meningitis/(meningo)encephalitis, neuroborreliosis, or other/unknown etiology) or AIND (autoimmune encephalitis or other etiology) as well as controls.

A total of 123 patients with IINDs (mean age 55.23 ± 18.04 years, 43.2% female), 22 with AINDs (age 60.41 ± 16.03 years, 81.8% female), and 95 controls (age 52.39 ± 17.94 years, 56.9% female) were enrolled. Compared with the control group, participants with IINDs and AINDs showed higher concentrations of beta-syn (p < 0.001 and p = 0.038, respectively), neurogranin (p = 0.039 and p = 0.002, respectively), and NfL (p < 0.001 and p = 0.001, respectively), with no differences between the 2 latter groups. Overall, synaptic markers and NfL demonstrated poor-to-moderate diagnostic accuracy in discriminating between diagnostic groups (area under the curve 0.366-0.809). All synaptic biomarkers were elevated in participants with IINDs presenting with altered mental status (beta-syn, p < 0.001; SNAP-25, p = 0.002; and neurogranin, p = 0.008), seizures (beta-syn, p = 0.013; SNAP-25, p = 0.005; and neurogranin, p = 0.004), and inflammatory changes on neuroimaging (beta-syn, p = 0.016; SNAP-25, p = 0.029; and neurogranin, p = 0.007). Participants with AINDs requiring intensive care showed higher levels of beta-syn (p = 0.033) and NfL (p = 0.002). Participants with IINDs with a poor functional status (modified Rankin Scale [mRS] scores of 3-6) exhibited higher concentrations of beta-syn (p < 0.001), SNAP-25 (p = 0.022), neurogranin (p = 0.004), and NfL (p < 0.001) compared with those with mRS scores of 0-2. Accordingly, higher levels of synaptic markers were associated with poorer short-term outcomes in patients with IINDs, but not in those with AINDs.

Elevated CSF levels of beta-syn, neurogranin, and NfL may suggest a common pattern of synaptic and neuroaxonal damage in both IINDs and AINDs. Although these biomarkers have limited value in distinguishing between different diseases, they are associated with clinical severity and with short-term outcome, particularly in patients with IINDs.