Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis

• Published in: Cell reports. Medicine 2024-04, Vol.5 (4), p.101490, Article 101490
• Main Authors: Cordano, Christian, Werneburg, Sebastian, Abdelhak, Ahmed, Bennett, Daniel J., Beaudry-Richard, Alexandra, Duncan, Greg J., Oertel, Frederike C., Boscardin, W. John, Yiu, Hao H., Jabassini, Nora, Merritt, Lauren, Nocera, Sonia, Sin, Jung H., Samana, Isaac P., Condor Montes, Shivany Y., Ananth, Kirtana, Bischof, Antje, Oksenberg, Jorge, Henry, Roland, Baranzini, Sergio, Wilson, Michael, Bove, Riley, Cuneo, Richard, Gupta, Sasha, Sabatino, Joseph, Guo, Joanne, Sacco, Simone, Papinutto, Nico, Hollenbach, Jill, Gelfand, Jeff, Pleasure, Sam, Zamvil, Scott, Goodin, Douglas, Waubant, Emmanuelle, Gomez, Refujia, Cerono, Gabriel, Nourbakhsh, Bardia, Hauser, Stephen L., Cree, Bruce A.C., Emery, Ben, Schafer, Dorothy P., Chan, Jonah R., Green, Ari J.
• Format: Article
• Language: English
• Subjects: Animals; Atrophy - pathology; blood biomarkers; demyelination; EAE; experimental autoimmune encephalomyelitis; Humans; Models, Animal; Multiple Sclerosis - pathology; Neurons - pathology; optical coherence tomography; retina; Retina - pathology; serum proteomics; synaptic injury
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101490

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination—prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression. [Display omitted] •Synaptic injury is an early event associated with downstream demyelination in EAE•Accelerated retinal synaptic injury precedes disease progression in people with MS•Blood biomarkers of myelin injury and synaptic loss are independently associated Cordano et al. demonstrate that atrophy of the IPL (constituted by connections between ganglion cells and deeper retinal layers) could function as a biologically relevant prognostic biomarker for relentlessly progressive disease. Their work also unravels a strong correlation between demyelination and synaptic loss using blood biomarkers in an independent cohort.