Bi-compartmental CSF–Serum Analysis of NfL and GFAP Differentiates Central and Peripheral Pathology in Neuroinfectious Diseases
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Background
Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), established biomarkers of neuroaxonal injury and astroglial pathology, are frequently only assessed in blood, which limits conclusions regarding their origin. Bi-compartmental analyses of CSF and serum may help differentiate central or peripheral origin of biomarker elevation. Moreover, studies on NfL and GFAP in distinct neuroinfectious disease (NID) phenotypes are limited.
Methods
This retrospective monocentric study analyzed CSF and serum from patients with (meningo-)encephalitis/myelitis (TI+; n =48), meningitis (TI–; n =80), (cranial) nerve palsies/polyradiculitis (PND; n =61), and 113 non-neuroinflammatory/non-neurodegenerative controls. A bi-compartmental model using scatter plots and simple linear regression was applied to assess the origin of blood biomarker levels and discriminate between central and peripheral pathology.
Results
CSF and serum NfL and GFAP z-scores were significantly higher in TI+ compared with TI– (CSF-GFAP p <0.001/sGFAP p =0.0083; CSF-NfL p =0.003/sNfL p =0.0004). TI+ and PND differed only in GFAP levels, which were higher in TI+ (CSF-GFAP p =0.0049/sGFAP p =0.003). Bi-compartmental analysis revealed simultaneous elevation of CSF and serum NfL in TI+, indicating predominantly central origin, whereas PND demonstrated a shift toward higher sNfL levels suggesting peripheral origin. Higher clinical severity (modified Rankin Scale 3–5) was associated with elevated serum and CSF GFAP and NfL (sGFAP p =0.012/sNfL p =0.002; CSF-GFAP p <0.0001/CSF-NfL p =0.0001), which also predicted unfavorable outcome at discharge (sGFAP p =0.006/sNfL p =0.004; CSF-GFAP p =0.003/CSF-NfL p =0.012).
Conclusions
NfL and GFAP were associated with brain/myelon involvement in NID, predominantly reflecting central pathology. Despite strong CSF–serum correlations, bi-compartmental approaches provide additional insight into biomarker origin and disease compartment.
What is already known on this topic
Despite antiviral therapy, especially viral encephalitis remains associated with substantial mortality and long-term neurological sequelae. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are established biomarkers of neuroaxonal and astroglial injury and are increasingly used across neurological diseases. Previous studies in neuroinfectious diseases demonstrated elevated CSF and blood levels of NfL and GFAP, but mainly relied on central or peripheral compartments separately. These analyses do not fully reflect the origin of the measured biomarkers in either blood or CSF. Additionally, combined CSF–serum analyses with age-adjusted values in different manifestations of neuroinfectious diseases (NID), also in correlation with clinical outcome measurements, are limited.
What this study adds
This study demonstrates that NID patients with central nervous system involvement had higher CSF and serum NfL and GFAP values than those without. Bi-compartmental analyses using CSF–serum biomarker scatter plots and log– transformed values in a simple linear regression showed distinct patterns for encephalitis (bi-compartmental increase of values for NfL and GFAP), meningitis (similar to patient controls), and peripheral infectious nerve disease (NfL shift towards serum elevations). Biomarker values in CSF and serum at initial lumbar puncture (LP) were significantly higher in patients with longer hospitalization length and in patients with worse outcome at discharge according to the modified Rankin scale (mRS).
How this study might affect research, practice or policy
Our study offers a potential approach for the early biochemical detection of encephalitic involvement, possibly preceding overt clinical manifestations. Furthermore, as biomarker values at admission are associated with worse clinical outcome (mRS), those parameters could help clinicians in decision-making and in early detection of potential encephalitic courses.
