Synaptic Injury in the IPL of the Retina Is a Predictor of Progression in Multiple Sclerosis
Christian Cordano1, Sebastian Werneburg2, Ahmed Abdelhak1, Daniel Bennett1, Alexandra Beaudry-richard1, Greg Duncan3, Frederike Oertel4, John Boscardin1, Hao Yiu5, Nora Jabassini1, Lauren Merritt6, Sonia Nocera1, Jung Sin1, Shivany Condor Montes1, Kirtana Ananth1, Antje Bischof7, Bardia Nourbakhsh8, Stephen Hauser1, Bruce Cree1, Ben Emery9, Jonah Chan1, Dorothy Schafer6, Ari Green1
1UCSF, 2University of Michigan, 3OHSU, 4NeuroCure Clinical Research Center, 5University of Maryland, 6University of Massachusetts Chan Medical School, 7Munster University, 8Johns Hopkins University, 9Oregon Health & Science University
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.

10.1212/WNL.0000000000206314