Indicators of Axonal Damage in Blood and Tissue Induced by Demyelination
Overview
This study demonstrates a robust association between neurofilament light chain (NfL) levels in blood and tissue with the severity of inflammatory demyelination in experimental models and multiple sclerosis (MS) patients. It reveals that demyelination alone can induce measurable neuroaxonal changes, and that NfL dynamics correlate with both demyelination and remyelination processes.
Background
Neuroaxonal injury is a key driver of irreversible disability in demyelinating diseases such as MS. Measuring NfL, a neuronal cytoskeletal protein, in blood offers a promising biomarker for tracking neuroaxonal injury longitudinally with high pathological specificity. Although elevated NfL levels are linked to neurodegeneration, the biological mechanisms underlying NfL changes in demyelination remain incompletely understood. This study investigates the relationship between demyelination, axonal damage, and circulating NfL using animal models and human cohorts.
Data Highlights
Model
Finding
Measurement
Experimental Autoimmune Encephalomyelitis (EAE)
Peak NfL levels correlated with severity of demyelination and tissue NfL loss
Blood and tissue NfL via antibody targeting same epitopes
Myrf Conditional Knockout Mice
Serum NfL peaked at demyelination and decreased after remyelination
Longitudinal serum NfL measurements
Multiple Sclerosis Patients (ReBUILD trial and UK Biobank)
Association between NfL and myelin breakdown proteins confirmed
Olink proximity extension assays on blood samples
Key Findings
Blood NfL levels strongly correlate with tissue neuroaxonal injury and inflammatory demyelination severity in EAE mice.
Inducible genetic demyelination via Myrf knockout causes serum NfL elevation that normalizes following remyelination.
In MS patients, circulating NfL correlates with proteins indicative of myelin breakdown, validating translational relevance.
Elevated NfL does not necessarily require axonal structural membrane damage, suggesting myelin integrity changes alone can alter NfL levels.
Remyelination therapies may reduce NfL levels rapidly, indicating potential for monitoring reversible neuroaxonal pathology.
Clinical Implications
NfL measurement in blood provides a sensitive biomarker to monitor neuroaxonal injury linked to demyelination and remyelination in MS and related conditions. This supports its use for tracking disease activity and therapeutic response, including remyelination strategies. Understanding that myelin integrity changes alone can influence NfL levels may refine interpretation of biomarker fluctuations in clinical practice.
Conclusion
This study establishes a translational framework linking demyelination-induced neuroaxonal injury with blood NfL dynamics, highlighting NfL as a valuable biomarker for monitoring potentially reversible neuroaxonal pathology in both experimental models and humans.
by Ahmed Abdelhak, Christian Cordano, Greg J Duncan, Katie Emberley, Sonia Nocera, Wendy Xin, Kirtana Ananth, Nour Jabassini, Kiarra Ning, Henriette Reinsberg, Frederike Cosima Oertel, Alexandra Beaudry-Richard, Jens Kuhle, Axel Petzold, Praveen J Patel, Ana P Ribeiro Reis, Paul J Foster, UKBB Eye and Vision Consortium, Trent Watkins, Jonah R Chan, Ben Emery, Ari J Green
