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

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.

doi:10.1016/j.xcrm.2024.101490

Cited by 4 publications

(2 citation statements)

References 64 publications

(87 reference statements)

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“…Significantly, there were no important connections found for macular volume, and the research did not have information on GCL or IPL thickness to be included in the study [ 54 ]. Recently, Cordano et al reported that synaptic injury within the IPL precedes disease progression from relapsing–remitting MS to secondary progressive MS, correlating with IPL thinning observed in OCT scans [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…A noteworthy finding is that almost every individual with MS will exhibit a decline in pRNFL and thinning of the macular ganglion cell layer (GCL) over time, irrespective of ON history [ 5 ]. Recent research suggests synaptic injury preceding neuronal loss in MS, with early thinning of the inner plexiform layer (IPL) identified as a potential independent biomarker for disease progression [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Macular OCT’s Proficiency in Identifying Retrochiasmal Visual Pathway Lesions in Multiple Sclerosis—A Pilot Study

Cujbă,

Banc,

Stan

et al. 2024

Diagnostics

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Optical coherence tomography (OCT) is a non-invasive imaging technique based on the principle of low-coherence interferometry that captures detailed images of ocular structures. Multiple sclerosis (MS) is a neurodegenerative disease that can lead to damage of the optic nerve and retina, which can be depicted by OCT. The purpose of this pilot study is to determine whether macular OCT can be used as a biomarker in the detection of retrochiasmal lesions of the visual pathway in MS patients. We conducted a prospective study in which we included 52 MS patients and 27 healthy controls. All participants underwent brain MRI, visual field testing, and OCT evaluation of the thicknesses of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer (GCL), and macular inner plexiform layer (IPL). OCT measurements were adjusted for optic neuritis (ON). VF demonstrated poor capability to depict a retrochiasmal lesion identified by brain MRI (PPV 0.50). In conclusion, the OCT analysis of the macula appears to excel in identifying retrochiasmal MS lesions compared to VF changes. The alterations in the GCL and IPL demonstrate the most accurate detection of retrochiasmal visual pathway changes in MS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Macular OCT’s Proficiency in Identifying Retrochiasmal Visual Pathway Lesions in Multiple Sclerosis—A Pilot Study

Cujbă,

Banc,

Stan

et al. 2024

Diagnostics

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Multimodal Longitudinal Optical Imaging Reveals Optic Neuritis Preceding Retinal Pathology in Experimental Autoimmune Encephalomyelitis

Raspe,

Günther,

Uecker

et al. 2025

Neurol Neuroimmunol Neuroinflamm

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Background and Objectives Inflammatory demyelinating diseases of the CNS, chief among them multiple sclerosis (MS), are a major cause of disability in young adults. Early manifestations of MS commonly involve visual dysfunction, which is often caused by optic neuritis and is accompanied by quantifiable structural changes of the anterior visual pathway. Retinal optical coherence tomography (OCT) has emerged as an important tool for clinical assessment of these structural alterations, but the underlying pathobiological mechanisms and temporal dynamics are yet poorly understood at a cellular level. Methods Using the experimental autoimmune encephalomyelitis (EAE) model of MS in fluorescent reporter mouse strains for neuronal function and innate immune cells, we use a unique combination of retinal intravital 2-photon microscopy (2PM) and OCT. In this fashion, we elucidate the spatiotemporal interplay of functional and structural retinal changes over the course of 1 month after EAE induction, with histopathologic imaging validating main results. Results While all mice display histologic signs of optic neuritis early after EAE induction and independently of motor symptom severity, retinal signs of neuronal stress and parenchymal immune activation spike well after clinical peak of disease, with no signs of lasting structural damage appearing within 1 month after EAE induction. Thus, local retinal endpoints appear to be functions of downstream axonal damage rather than of immediate immune activation directed at the retina. However, as early as 1 week after EAE induction, retinal 2PM can detect recruitment of perivascular immune cells towards the optic nerve (ON), providing the earliest sign of disease activity in otherwise clinically inconspicuous mice. Discussion Our work identifies the recruitment of CX3CR1+ cells to the ON as an early sign of disease underlining the importance of combined structural and functional retinal imaging for the spatiotemporal characterization of neuroinflammatory and neurodegenerative processes. It further proposes retinal phagocyte orientation, morphology, and abundance as potential surrogate markers for neurodegenerative activity.

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Decreased Expression of the EAAT5 Glutamate Transporter at Photoreceptor Synapses in Early, Pre-Clinical Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis

El Samad,

Jaffal,

Ibrahim

et al. 2024

Biomedicines

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Background: Multiple sclerosis is a frequent neuroinflammatory and neurodegenerative disease of the central nervous system that includes alterations in the white and gray matter of the brain. The visual system is frequently affected in multiple sclerosis. Glutamate excitotoxicity might play a role in disease pathogenesis. Methodology: In the present study, we analyzed with qualitative and quantitative immunofluorescence microscopy and Western blot analyses whether alterations in the EAAT5 (SLC1A7) glutamate transporter could be involved in the previously observed alterations in structure and function of glutamatergic photoreceptor ribbon synapses in the EAE mouse model of MS. EAAT5 is a presynaptic glutamate transporter located near the presynaptic release sites. Results: We found that EAAT5 was strongly reduced at the photoreceptor synapses of EAE retinas in comparison to the photoreceptor synapses of the respective control retinas as early as day 9 post-immunization. The Western blot analyses demonstrated a decreased EAAT5 expression in EAE retinas. Conclusions: Our data illustrate early alterations of the EAAT5 glutamate transporter in the early pre-clinical phase of EAE/MS and suggest an involvement of EAAT5 in the previously observed early synaptic changes at photoreceptor synapses. The precise mechanisms need to be elucidated by future investigations.

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

Cited by 4 publications

References 64 publications

Macular OCT’s Proficiency in Identifying Retrochiasmal Visual Pathway Lesions in Multiple Sclerosis—A Pilot Study

Macular OCT’s Proficiency in Identifying Retrochiasmal Visual Pathway Lesions in Multiple Sclerosis—A Pilot Study

Multimodal Longitudinal Optical Imaging Reveals Optic Neuritis Preceding Retinal Pathology in Experimental Autoimmune Encephalomyelitis

Decreased Expression of the EAAT5 Glutamate Transporter at Photoreceptor Synapses in Early, Pre-Clinical Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis

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