Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS

Abstract

Objective:In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.Methods:Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point.Results:One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum.Conclusions:The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.ClinicalTrials.gov identifier:NCT01719159.

Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology‐based cohort

“…However, these indicators show much lower levels in blood samples compared to CSF, and highly sensitive immunochemical methods for their detection are needed. Importantly, recent studies have reported that tau and NF-L can be detected in blood [20][21][22][23][24]31,32,37]. To be able to define the reliability of these tests, different diseases and their combinations need to be examined.…”

Potential biomarker breakthrough for Huntington's disease

“…4 NfL concentrations were as much as 3·6 times greater in patients with manifest Huntington's disease compared with controls, and there was a very clear gradient from controls to early premanifest (far from expected motor onset), late premanifest (close to expected motor onset), and then to manifest Huntington's disease. The NfL increases in manifest Huntington's disease were similar to those in multiple sclerosis relapses, 5 and were at least as great as in other neurodegenerative diseases including progressive supranuclear palsy, 6 multiple system atrophy, 7 and corticobasal syndrome. In Parkinson's disease 7 and Alzheimer's disease, 8 plasma and blood NfL concentrations are not substantially different from those of controls, partly because of the wide range of disease severity and subtypes within those diseases.…”

Promise, Progress, and Pitfalls in the Search for Central Nervous System Biomarkers in Neuroimmunological Diseases: A Role for Cerebrospinal Fluid Immunophenotyping

“…axonal marker neurofilament-light chain [NF-L]) can be successfully measured in the blood using highly-sensitive assays, 30 serum levels of these CNS-originating biomarkers explain between 38–60% of variance of the CSF levels. 31,32 This 40–62% “noise” is likely due to intra-individual differences in CSF clearance, affected by cardiac output, 33 sleep, 34 physical activity and aging, 35–36 as well as systemic clearance and hepatic metabolism of soluble biomarkers. While this level of accuracy may be sufficient for some indications, such as providing prognostic value of recovery from CNS injury, 37 introducing 40–62% noise in pharmacodynamic outcomes in drug development or precision medicine applications may not be acceptable.…”