The disorganization of retinal inner layers (DRIL) in eyes with diabetic macular edema is correlated to Muller Cells dysfunction: an imaging and omic study

Abstract

Purpose : The definition and pathophysiology of disorganization of retinal inner layers (DRIL) remains a controversial issue among diabetic retinopathy OCT biomarkers. The aim of this work was to characterize in vivo, with both detailed retinal imaging and liquid biopsy, DRIL in eyes with diabetic macular edema (DME).

Methods : Patients affected by non proliferative diabetic retinopathy and previously untreated center-involved DME were enrolled. All patients underwent detailed imaging evaluation with Spectral Domain OCT and proteomic and metabolomic (Omic) analysis of aqueous humor (AH), before any treatment. DRIL was defined according to standard definition and classified by two independent, blinded, graders. 57 inflammatory biomarkers (including VEGF, VEGF receptors and interleukins) were quantified using glass chip protein array. Glial fibrillary acidic protein (GFAP), a biomarker of Muller cells dysfunction, was also quantified using commercial high-sensitive enzyme-linked immunosorbent assay (ELISA).

Results : Nineteen eyes of 19 DME patients were enrolled. DRIL was present in 10 eyes (52.63%). The intergrader agreement about DRIL classification was almost perfect among graders (ICC:0.85). No statistically significant difference was found among DME eyes, with or without DRIL, considering the AH concentration of biomarkers related to pure inflammation (including interleukins), extracellular matrix regulation (e.g. TIMP, TACE) tissue remodeling (e.g. osteopontin), neurons survival and growth (e.g. neurotrophins), vasculo and angiogenesis (VEGF, PDGF), cell death regulation (TNF, Fas-ligand) (p>0.05), except for GFAP, biomarker of Muller cells dysfunction, which was significantly different between eyes with and without DRIL (p=0.0084).

Conclusions : Several biochemical biomarkers related to inflammation and angiogenesis have already shown to be altered in DME. The combination between imaging and omic data is of primary relevance to better understand the pathophysiologic origin of distinct morphologic markers in DME, such as DRIL. Our imaging and omic results, support the hypothesis that DRIL, in DME eyes, strictly depends on the dysfunction of Muller cells, compared to other mechanisms involved in DME, explaining its role not only as imaging biomarker, but also a visual function Muller-related parameter.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.