Early localized alterations of the retinal inner plexiform layer in association with visual field worsening in glaucoma patients.

Rukiye Aydın,Tongalp H Tezel,Mine Barış,Jeffrey M Liebmann,George A Cioffi,Dana M Blumberg,Ceren Durmaz-Engin,Lama A Al-Aswad,Gülgün Tezel,Sanjoy Bhattacharya

doi:10.1371/journal.pone.0247401

Abstract

Glaucoma is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness, worldwide. While the experimental research using animal models provides growing information about cellular and molecular processes, parallel analysis of the clinical presentation of glaucoma accelerates the translational progress towards improved understanding, treatment, and clinical testing of glaucoma. Optic nerve axon injury triggers early alterations of retinal ganglion cell (RGC) synapses with function deficits prior to manifest RGC loss in animal models of glaucoma. For testing the clinical relevance of experimental observations, this study analyzed the functional correlation of localized alterations in the inner plexiform layer (IPL), where RGCs establish synaptic connections with retinal bipolar and amacrine cells. Participants of the study included a retrospective cohort of 36 eyes with glaucoma and a control group of 18 non-glaucomatous subjects followed for two-years. The IPL was analyzed on consecutively collected macular SD-OCT scans, and functional correlations with corresponding 10–2 visual field scores were tested using generalized estimating equations (GEE) models. The GEE-estimated rate of decrease in IPL thickness (R = 0.36, P<0.001) and IPL density (R = 0.36, P<0.001), as opposed to unchanged or increased IPL thickness or density, was significantly associated with visual field worsening at corresponding analysis locations. Based on multivariate logistic regression analysis, this association was independent from the patients’ age, the baseline visual field scores, or the baseline thickness or alterations of retinal nerve fiber or RGC layers (P>0.05). These findings support early localized IPL alterations in correlation with progressing visual field defects in glaucomatous eyes. Considering the experimental data, glaucoma-related increase in IPL thickness/density might reflect dendritic remodeling, mitochondrial redistribution, and glial responses for synapse maintenance, but decreased IPL thickness/density might correspond to dendrite atrophy. The bridging of experimental data with clinical findings encourages further research along the translational path.

Highlights

Glaucoma is a leading cause of blindness, which affects approximately 80 million people worldwide
Despite a number of previous studies that analyzed the RGC layer (RGCL)-inner plexiform layer (IPL) complex [23,24,25,26], studies of isolated IPL remain limited, which include a few studies that were cross-sectional and only used the IPL thickness obtained with the automated segmentation software of spectral domain optical coherence tomography (SD-OCT)
This study reported that the IPL thickness shows a stronger association with corresponding 24–2 visual field scores compared with the thickness of retinal nerve fiber layer (RNFL) or RGCL

Summary

Introduction

Glaucoma is a leading cause of blindness, which affects approximately 80 million people worldwide. This chronic neurodegenerative disease is characterized by the progressive loss of retinal ganglion cells (RGCs), optic nerve axons, and synapses in the retina and brain. Experimental evidence from animal models of glaucoma suggests that RGC dendrites, which are arborized in the inner plexiform layer (IPL) of the retina and establish synaptic connections with bipolar and amacrine cells, may present structural and functional alterations in earlier stages of the disease process prior to detectable loss of RGC somas. Since synapse plasticity may allow rewiring, it has been suggested that early alterations in the RGC dendritic arbor provide a treatment window to recover synapse dysfunction and prevent further injury to RGCs in this blinding disease [10,11,12]. Present observations and potential translational implications are based on animal models, and despite a few clinical studies [13,14,15], current understanding of IPL alterations in human glaucoma remains highly limited

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