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

Christian Cordano; Sebastian Werneburg; Ahmed Abdelhak; Daniel J Bennett; Alexandra Beaudry-Richard; Greg J Duncan; Frederike C Oertel; W John Boscardin; Hao H Yiu; Nora Jabassini; Lauren Merritt; Sonia Nocera; Jung H Sin; Isaac P Samana; Shivany Y Condor Montes; Kirtana Ananth; Antje Bischof; UCSF MS EPIC Team; Bardia Nourbakhsh; Stephen L Hauser; Bruce A C Cree; Ben Emery; Dorothy P Schafer; Jonah R Chan; Ari J Green

doi:10.1016/j.xcrm.2024.101490

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

Cell Rep Med. 2024 Apr 16;5(4):101490. doi: 10.1016/j.xcrm.2024.101490. Epub 2024 Apr 3.

Authors

Christian Cordano¹, Sebastian Werneburg², Ahmed Abdelhak³, Daniel J Bennett³, Alexandra Beaudry-Richard³, Greg J Duncan⁴, Frederike C Oertel³, W John Boscardin⁵, Hao H Yiu⁶, Nora Jabassini³, Lauren Merritt⁷, Sonia Nocera³, Jung H Sin³, Isaac P Samana³, Shivany Y Condor Montes³, Kirtana Ananth³, Antje Bischof³; UCSF MS EPIC Team³; Bardia Nourbakhsh⁸, Stephen L Hauser³, Bruce A C Cree³, Ben Emery⁴, Dorothy P Schafer⁷, Jonah R Chan⁹, Ari J Green¹⁰

Collaborators

UCSF MS EPIC Team:
Jorge Oksenberg, Roland Henry, Sergio Baranzini, Michael Wilson, Riley Bove, Richard Cuneo, Sasha Gupta, Joseph Sabatino, Joanne Guo, Simone Sacco, Nico Papinutto, Jill Hollenbach, Jeff Gelfand, Sam Pleasure, Scott Zamvil, Douglas Goodin, Emmanuelle Waubant, Refujia Gomez, Gabriel Cerono

Affiliations

¹ UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
² Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Ophthalmology & Visual Sciences, Michigan Neuroscience Institute, University of Michigan - Michigan Medicine, Ann Arbor, MI, USA.
³ UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁴ Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
⁵ Department of Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Biology, University of Maryland, College Park, MD, USA.
⁷ Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁸ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
⁹ UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: jonah.chan@ucsf.edu.
¹⁰ UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: agreen@ucsf.edu.

Abstract

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.

Keywords: EAE; blood biomarkers; demyelination; experimental autoimmune encephalomyelitis; optical coherence tomography; retina; serum proteomics; synaptic injury.

MeSH terms

Animals
Atrophy / pathology
Humans
Models, Animal
Multiple Sclerosis* / pathology
Neurons / pathology
Retina / pathology

Grants and funding

R01 NS105741/NS/NINDS NIH HHS/United States