Ellipsoid zone reflectivity as a functional imaging biomarker for age-related macular degeneration: a MACUSTAR study report

Abstract

This study evaluated the functional relevance of relative ellipsoid zone reflectivity (rEZR) on spectral-domain optical coherence tomography as a structural biomarker for retinal integrity, focusing on its association with retinal function. Participants with age-related macular degeneration (AMD) and controls from the MACUSTAR study underwent functional testing, including mesopic fundus-controlled perimetry, best-corrected visual acuity, low-luminance visual acuity, low-luminance deficit, Moorfields Acuity Test, and Pelli-Robson contrast sensitivity, along with spectral-domain optical coherence tomography imaging. Structural and functional data were analyzed globally and spatially aligned for topographic analysis. Linear-mixed effects models, adjusted for age, sex, and eccentricity of the rEZR, assessed associations between rEZR and functional metrics. A total of 275 eyes (early AMD, n = 34; intermediate AMD, n = 152; late AMD, n = 36; controls, n = 53) from 275 participants (mean ± standard deviation age: 71.1 ± 7.2 years; 63.3% female) were included. In global analyses, rEZR was associated with the mean average threshold in mesopic fundus-controlled perimetry (coefficient estimate 0.0492, 95% confidence interval 0.0190-0.0794, p = 0.0015), low-luminance visual acuity (coefficient estimate - 0.0015, 95% confidence interval - 0.0026 to - 0.0004, p = 0.0092), Moorfields Acuity Test (coefficient estimate 0.0092, 95% confidence interval - 0.0022 to - 0.0001, p = 0.0285), and Pelli-Robson contrast sensitivity (coefficient estimate 0.0030, 95% confidence interval 0.0015-0.0045, p = 0.0001). Topographic analysis further revealed an association of rEZR with mesopic retinal sensitivity (coefficient estimate 0.0065, 95% confidence interval 0.0026-0.0104, p < 0.0001). Higher outer retinal reflectivity is linked to better retinal function in AMD and controls, supporting its potential as a biomarker for retinal integrity and function.

Fig. 1

Exemplary cases of an healthy individual (A) and a participant with intermediate age-related macular degeneration (B) with (from left to right) confocal near-infrared en-face imaging, the horizontal OCT line through the fovea and a heat-map representation of the spatial association of the relative ellipsoid zone reflectivity (rEZR) and retinal sensitivity as tested by mesopic fundus-controlled perimetry (FCP). In the heat-map representation, the rEZR (AU) is represented in the background with lower and higher values ranging from red to green, while point-wise retinal sensitivity is demonstrated by superimposed specific values (dB) and also color-coded stimulus points, again with lower values in red and higher values in green. Note the association of lower rEZR values (more red-colored areas) with worse retinal function, as well as higher rEZR values (more green-colored areas) with better retinal function.

Fig. 2

A representative case illustrating peak determination by the automated method. The left panel shows an OCT B-scan with the external limiting membrane (ELM), ellipsoid zone (EZ), and retinal pigment epithelium (RPE) labeled. White lines indicate the region of interest used for reflectivity analysis. The right panel presents the corresponding pixel intensity profile, where green and red vertical lines mark the peak detection areas for EZ and ELM, respectively. Colored rectangles denote peaks identified by the algorithm: RPE (red), EZ (yellow), and ELM (purple).

Fig. 3

Illustratration of the alignment process of structural, i.e. Spectralis spectral-domain optical coherence tomography (SD-OCT) imaging derived, and functional, i.e. MAIA fundus-controlled perimetry (FCP)-derived, study data. The near-infrared image (NIR) of the FCP-data was cropped and resized to match the image dimensions of the SD-OCT derived NIR image. The deep-learning algorithm “SuperRetina” by Liu et al. was applied to align the NIR images of the FCP and SD-OCT study data using landmark correspondences.