Abstract Details

Title Acute and Chronic Demyelination Independent of Inflammation Promotes Tissue- and Blood-markers of Neuroaxonal Pathology

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (2:48 PM-3:00 PM)

Poster/Presentation
Number 010

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.

Objective To determine whether standalone oligodendrocyte and myelin damage do not only increase neuronal vulnerability but are sufficient to cause neuroaxonal injury.

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 [Myrf^ΔiPLP]). 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 Myrf^ΔiPLP 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.

Authors/Disclosures
Ahmed Abdelhak, MD (UCSF Weill Institute of Neuroscience) PRESENTER	The institution of Dr. Abdelhak has received research support from German Multiple Sclerosis Society.
Christian Cordano, MD, PhD (UCSF)	Dr. Cordano has nothing to disclose.
Katie Emberley (Oregon Health & Science University)	No disclosure on file
Greg Duncan (OHSU)	No disclosure on file
Sonia Nocera (UCSF)	No disclosure on file
Kirtana Ananth	No disclosure on file
Nora Jabassini	No disclosure on file
Kiarra Ning	No disclosure on file
Henriette Reinsberg	No disclosure on file
Frederike Cosima Oertel, MD (University of California, San Francisco)	The institution of Dr. Oertel has received research support from AAN. The institution of Dr. Oertel has received research support from Hertie Foundation. Dr. Oertel has received personal compensation in the range of $500-$4,999 for serving as a Recipient (Travel Grant) with ECTRIMS. Dr. Oertel has received personal compensation in the range of $500-$4,999 for serving as a Recipient (Travel Grant) with NMSS. Dr. Oertel has received personal compensation in the range of $500-$4,999 for serving as a Recipient (Travel Grant) with ACTRIMS.
Alexandra Beaudry-richard (UCSF)	No disclosure on file
Jens Kuhle, MD	Dr. Kuhle has nothing to disclose.
Trent Watkins (University of California at San Francisco)	No disclosure on file
Jonah Chan, PhD (UCSF)	Jonah Chan, PhD has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Pipeline Therapeutics. Jonah Chan, PhD has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for SFN. Jonah Chan, PhD has stock in Pipeline Therapeutics. The institution of Jonah Chan, PhD has received research support from Mead Johnson. Jonah Chan, PhD has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with NIH/NINDS.
Ben Emery (Oregon Health & Science University)	No disclosure on file
Ari Green, MD (UCSF)	Dr. Green has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pipeline Therapeutics. Dr. Green has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bionure. Dr. Green has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. The institution of Dr. Green has received research support from NINDS. The institution of Dr. Green has received research support from NMSS. The institution of Dr. Green has received research support from NIA. The institution of Dr. Green has received research support from Adelson Research Foundation. Dr. Green has received intellectual property interests from a discovery or technology relating to health care. Dr. Green has received personal compensation in the range of $500-$4,999 for serving as a Study Section with NINDS. Dr. Green has a non-compensated relationship as a Author with Viela Bio that is relevant to AAN interests or activities.