Acute and Chronic Demyelination Independent of Inflammation Promotes Tissue- and Blood-markers of Neuroaxonal Pathology
Ahmed Abdelhak1, Christian Cordano1, Katie Emberley2, Greg Duncan2, Sonia Nocera1, Kirtana Ananth3, Nora Jabassini1, Kiarra Ning1, Henriette Reinsberg1, Frederike Oertel4, Alexandra Beaudry-Richard1, Jens Kuhle5, Trent Watkins1, Jonah Chan1, Ben Emery2, Ari Green1
1Department of Neurology, UCSF Weill Institute for Neurosciences, 2Jungers Center for Neurosciences, Oregon Health & Science University, 3Department of Neurology, UCSF Weill Institute of Neuroscience, 4NeuroCure Clinical Research Center, 5University Hospital of Basel
Objective:
To determine whether standalone oligodendrocyte and myelin damage do not only increase neuronal vulnerability but are sufficient to cause neuroaxonal injury.
Background:
Neuroaxonal injury is a significant driver of permanent disability in various neurological conditions, despite heterogeneous underlying pathophysiologies. Accurate understanding of common drivers of neuroaxonal loss is critical for developing broadly effective neuroprotective strategies.
Design/Methods:
Neurofilament-light chain (NfL)-based tissue and blood markers reflected the magnitude of neuroaxonal pathology in both immune-mediated demyelination (experimental autoimmune encephalomyelitis [EAE]) and non-immune-mediated demyelination models (conditional knockout of Myrf transcription-factor in oligodendrocyte [MyrfΔiPLP]). To confirm the findings in a human demyelinating condition, multiple sclerosis, novel blood markers of myelin injury (MOG), and oligodendrocyte injury (OMgp), we evaluated samples from people with MS (pwMS).
Results:
In EAE, serum NfL was significantly elevated at day 21 post-immunization (mean 5007 pg/ml) compared to age-matched sham mice (229.6, p=0.004). EAE-derived spinal cord lesions showed higher number NfL DegenoTag-positive axons at EAE peak, which colocalized with inflammatory cell infiltration and myelin loss. In MyrfΔiPLP mice, NfL levels were substantially elevated at the peak of demyelination at week 10 post tamoxifen relative to wild-type controls (303.8 vs. 46.6 pg/ml, p<0.001) and were substantially reduced during remyelination (134.6, p= 0.001). Moreover, blood NfL levels matched DegenoTag staining in spinal cord white matter. In stable non-active pwMS, serum MOG and OMgp levels were associated with higher NfL (Estimate 0.62 [95%CI 0.36 – 0.89] and 0.19 [0.08 – 0.30], p≤0.001 for both). In addition, delayed VEP latency correlated with NfL levels (0.02 [0.01 – 0.03], p=0.003).
Conclusions:
Our study provides a translational framework for understanding neuroaxonal injury in demyelinating conditions. Tissue and blood NfL-based markers of neuroaxonal injury increased following demyelination and exhibited a dose-dependent effect. Remyelination was associated with reduction of NfL-based evidence of neuroaxonal pathology. Myelin integrity appears to be crucial for maintaining axonal health.