Stable isotope labeling kinetics of neurofilament light in vitro and in vivo
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Importance
Neurofilament light (NfL) is elevated in CSF and blood across a range of traumatic, inflammatory and neurodegenerative diseases of the central nervous system, and has been increasingly included in clinical trials as an outcome measure of target engagement. Interpreting trajectories of NfL post-treatment has been challenging, prompting a greater need and focus on understanding its pathophysiology.
Objective
We measured NfL kinetics in the human central nervous system using stable isotope labeling kinetics (SILK).
Design
Observational study. Participants underwent SILK protocol. Infusion of 16 hours with 4mg/kg/h and follow-up lumbar punctures scheduled at 7, 14, 60 and 120 days post-labeling.
Setting
Referral center – specialist neurology clinic.
Participants
Participants with diagnosed primary tauopathies (n=10) were recruited to the Human CNS Tau Kinetics in Tauopathies (TANGLES) study. A control case was examined post-mortem to assess the technical background of the SILK method.
Exposure
Intravenous infusion of 13 C 6 -leucine, with rates of label incorporation representative of fractional synthesis and fractional clearance rates in vivo and in vitro .
Main outcome and Measure
Level of incorporation of 13 C 6 -leucine tracer into newly-translated NfL divided by the pool of NfL with previously incorporated 12 C 6 -leucine, expressed as a percentage tracer-to-tracee (TTR) ratio.
Results
NfL is rapidly translated in human brain within hours but takes 53 – 162 days to appear in cerebrospinal fluid (CSF). Labeled NfL remains detectable in post-mortem brain tissue 1.5 years post-labeling, indicating an extremely slow turnover in the human CNS. Together, these data suggest the greatest contribution of CSF NfL in neurodegeneration is from slow release of a large pool of previously translated NfL. However, release of newly translated NfL makes a significant contribution.
Conclusion and relevance
Rapid increases in CSF NfL seen within weeks of disease processes or interventions are likely to reflect release of pre-existing NfL from damaged neurons, but later increases in NfL (>3 months) may also reflect new NfL translation and release. Clinical trials using NfL as an outcome measure to track neurodegeneration would particularly benefit from substantially longer follow-up periods due to the slow turnover of the protein in the central nervous system.
