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Background: This study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS)., Methods: NfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood-brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics., Results: Serum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers., Conclusion: NfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls., Competing Interests: Declaration of competing interest J.H. Schäfer reports travel reimbursement from Bayer AG. S. Bittner reports travel grants from Merck Serono, speaking honoraria from Biogen Idec, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA and research support from Deutsche Forschungsgemeinschaft (DFG), Hertie foundation, as well as the Hermann and Lilly Schilling Foundation. C. Foerch reports speaker honoraria and honoraria for participating in advisory boards from Alexion, Bristol Myers Squibb, Novartis, Teva, Merck, Sanofi Genzyme, and Roche, CF received research support from Novartis and Sanofi Genzyme. Y. Yalachkov has been supported by travel grants from Novartis and Sanofi Genzyme and has received honoraria for active participation in advisory boards and speaker/writing honoraria by Bristol Meyers Squibb, Kassenärztliche Vereinigung Hessen, Landesärztekammer Hessen, Merck, Novartis, RG Gesellschaft für Information und organization mbH, Roche, Sanofi Genzyme, TEVA. His research is funded by Deutsche Forschungsgemeinschaft (DFG), Fachbereich Medizin der Goethe-Universität Frankfurt, Heinrich und Erna Schaufler Stiftung and Novartis. K. Koerbel, M. Maiworm, M. Schaller-Paule, J. Jakob, L. Friedauer and F. Steffen report no COI relevant to this study., (Copyright © 2024. Published by Elsevier B.V.)

Background: Definitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP))., Methods: We recruited 77 patients with relapsing-remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse., Results: After adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.00008; p cNfL  = 0.004) as well as the presence of infratentorial lesions on MRI (p sNfL  = 0.0003; p cNfL  < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.001), presence of more than 20 T2-lesions (p sNfL  = 0.049) as well as the presence of infratentorial lesions on MRI (p sNfL  = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (p sNfL  = 0.011) and presence of more than 20 T2-lesions (p sNfL  = 0.029)., Conclusions: Among proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone., (© 2024. The Author(s).)