Neurofilament light chain reference values in serum and cerebrospinal fluid: a bi-compartmental analysis in neurological diseases

• Published in: Journal of neurology Vol. 272; no. 8; p. 535
• Main Authors: Halbgebauer, Steffen, Klose, Veronika, Fazeli, Badrieh, Klassen, Paula, Alexudis, Christoforos, Nagel, Gabriele, Rosenbohm, Angela, Rothenbacher, Dietrich, Gomez de San Jose, Nerea, Witzel, Simon, Elmas, Zeynep, Wiesenfarth, Maximilian, Schuster, Joachim, Dorst, Johannes, Huss, Andre, Bachhuber, Franziska, Otto, Markus, Landwehrmeyer, G. Bernhard, Ludolph, Albert C., Tumani, Hayrettin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 25.07.2025; Springer Nature B.V
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging - blood; Aging - cerebrospinal fluid; Amyotrophic lateral sclerosis; Biomarkers - blood; Biomarkers - cerebrospinal fluid; Central nervous system; Cerebrospinal fluid; Child; Child, Preschool; Female; Females; Guillain-Barre syndrome; Humans; Male; Medicine; Medicine & Public Health; Microfluidics; Middle Aged; Multiple sclerosis; Nervous system; Nervous System Diseases - blood; Nervous System Diseases - cerebrospinal fluid; Nervous System Diseases - diagnosis; Neurodegeneration; Neurofilament Proteins - blood; Neurofilament Proteins - cerebrospinal fluid; Neurological diseases; Neurology; Neuroradiology; Neurosciences; Original Communication; Reference Values; Young Adult; United States > US; Z-score; Neurofilament; NfL; CSF; Serum; Age reference values; Bi-compartment model
• ISSN: 0340-5354; 1432-1459; 1432-1459
• DOI: 10.1007/s00415-025-13271-1

Background Concentrations of neurofilament light chain (NfL), a neuroaxonal damage marker, increase with age. Therefore, age-dependent reference values are important in clinical practice. However, so far these have only been established with a bead-based system and age-dependent z-scores for CSF are missing. In addition, we here propose how the combined analysis of CSF and serum NfL could help in the discrimination between central (CNS) and peripheral nervous system (PNS) axonal degeneration. Methods For the calculation of age reference values, serum and CSF NfL concentrations from 1,514 control subjects, measured using the microfluidic Ella system, were applied. Results Age-dependent NfL levels were calculated with additive quantile regression and presented with percentiles and z-scores. We observed a non-linear increase of NfL in serum and CSF. The spearman r of the association with age was 0.81 (95% CI 0.78–0.83), p  < 0.0001 and 0.82 (95% CI 0.79–0.85), p  < 0.0001 for serum and CSF NfL, respectively. Serum and CSF NfL levels were also associated with each other ( r  = 0.68 (95%CI 0.62–0.73), p  < 0.0001). Furthermore, we used this association to establish a bi-compartmental CSF and serum NfL model allowing to differentiate between peripheral or central origin of neurodegeneration. Conclusions The age reference curves corroborate findings of an exponential elevation of NfL in serum and CSF with increasing age. As NfL values from different platforms are not interchangeable, this is of additional high relevance. Moreover, the association between CSF and serum NfL values could be applied for clinical use regarding overlapping symptoms of CNS and PNS-based neurological diseases.