Abstract Details

Title Synaptic Injury in the IPL of the Retina Is a Predictor of Progression in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P6 - Poster Session 6 (8:00 AM-9:00 AM)

Poster/Presentation
Number 6-003

Objective

To analyze retinal signs of synaptic injury in an animal model of inflammatory demyelination and neurodegeneration, i.e., EAE; to evaluate quantified assessment of a retinal layer with major synaptic component for predicting relentlessly progressive disability in MS; and to use a proteome-wide analysis of a deeply characterized MS population to explore the possibility of developing a serum-based biomarker that can quantify global synaptic injury.

Background

The role of synaptic injury in MS disability is only partially identified.

Design/Methods

We investigated inner-plexiform-layer (IPL) synaptic density in EAE at day 12,18 and 60 post-immunization (dpi), quantifying IHC for presynaptic (Bassoon, VGluT1) and postsynaptic (Homer1) markers. We compared the annualized change of IPL thickness of nineteen people with MS (pwMS) with at least two OCT timepoints before their year of transition to SPMS with 38 matched pwMS with stable MS. We conducted a hypothesis-driven analysis from a proteome-wide dataset [166 serum samples from 47 pwMS, mean age at inclusion 39.4 yrs(±10.3), dd 4.4 yrs(±3.6)] from the ReBUILD trial exploring the association between an established synaptic damage marker (SNAP-25), and markers of oligodendrocyte damage (OMgp), myelin injury (MOG), astrocyte (GFAP) and microglia (sTREM2) activation, astrocyte and microglia involvement (CHI3L1), B-cell recruitment/activation (CXCL-13) and T-cell activation (CD27).

Results

EAE experiments showed that IPL atrophy is already present at the first day of symptoms (12 dpi). Further, we found that IPL atrophy in MS precedes disability worsening [loss of a mean (SD) of 0.259 µm(±0.096)/yr; while stable MS cohort showed no changes over time (p=0.0097)]. Furthermore, SNAP-25 normalized protein expression correlated positively with MOG (Estimate: 0.53[0.32–0.73],p<0.001), OMgp (0.10[0.01–0.20],p=0.034), GFAP (0.25[0.09–0.41],p=0.003), and CHI3L1 (0.16[0.03–0.30],p=0.017). Those associations remained significant after correction for the degree of ongoing neuroaxonal injury, as assessed by NfL.

Conclusions

Monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Authors/Disclosures
Christian Cordano, MD, PhD (UCSF) PRESENTER	Dr. Cordano has nothing to disclose.
Sebastian Werneburg	No disclosure on file
Ahmed Abdelhak, MD (UCSF Weill Institute of Neuroscience)	The institution of Dr. Abdelhak has received research support from German Multiple Sclerosis Society.
Daniel Bennett (UCSF School Of Medicine)	No disclosure on file
Alexandra Beaudry-richard (UCSF)	Alexandra Beaudry-richard has received research support from the Multiple Sclerosis Society of Canada. Alexandra Beaudry-richard has received research support from the Canadian Institutes of Health Research .
Greg Duncan (OHSU)	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.
John Boscardin	No disclosure on file
Hao Yiu	No disclosure on file
Nora Jabassini	No disclosure on file
Lauren Carito (Atalanta Therapeutics)	No disclosure on file
Sonia Nocera (UCSF)	No disclosure on file
Jung Sin	No disclosure on file
Shivany Condor Montes (Sandler Neurosciences Center)	No disclosure on file
Kirtana Ananth	An immediate family member of Kirtana Ananth has received personal compensation in the range of $10,000-$49,999 for serving as a Whole Time Member with Securities and Exchange Board of India (SEBI).
Antje Bischof, MD	Dr. Bischof has nothing to disclose.
Bardia Nourbakhsh, MD (Johns Hopkins University)	Dr. Nourbakhsh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics . Dr. Nourbakhsh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alkermes. The institution of Dr. Nourbakhsh has received research support from Genentech. The institution of Dr. Nourbakhsh has received research support from National MS Society . The institution of Dr. Nourbakhsh has received research support from Department of Defense. The institution of Dr. Nourbakhsh has received research support from NIH. The institution of Dr. Nourbakhsh has received research support from Axsome Therapeutics. The institution of Dr. Nourbakhsh has received research support from TG Therapeutics .
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)	Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.
Bruce A. Cree, MD, PhD, MAS, FAAN (UCSF, Multiple Sclerosis Center)	The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. The institution of Dr. Cree has received research support from Kyverna. Dr. Cree has received publishing royalties from a publication relating to health care.
Ben Emery (Oregon Health & Science University)	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 Contineum 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 Contineum 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.
Dorothy Schafer	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.

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