Ellipsoid Zone Reflectivity: Exploring its Potential as a Novel Non-Invasive Biomarker for Assessing Mitochondrial Function

The ellipsoid zone (EZ) on macular optical coherence tomography (OCT) scans exhibits high intensity due to a high density of light-scattering mitochondria, making its reflectivity a potential marker for mitochondrial function. Here, we developed a reliable analysis tool for extracting relative EZ reflectivity and explore its potential as a biomarker in various diseases. We analysed OCT scans of patients with optic neuritis (ON), primary progressive optic neuropathy (PPON), chronic progressive external ophthalmoplegia (CPEO), dominant optic atrophy (DOA), and healthy controls. EZ reflectivity (normalised to the retina pigment epithelium (RPE) and outer nuclear layer (ONL)) was evaluated. Reliability was assessed using intraclass correlation coefficients (ICC), and group differences were analysed through multivariable linear regression, adjusting for relevant confounders. In total, 12 controls, 23 ON patients, 7 CPEO patients, 13 DOA patients, and 13 PPON patients were included. EZ/RPE20% and EZ/ONL ratios demonstrated good test–retest reliability with ICCs of 0.76 (p <.001) and 0.63 (p =.013), respectively. Multivariable regression analysis revealed that median EZ/RPE20% and EZ/ONL ratios were lower in CPEO (r = -0.12, p =.036, and r = -0.59, p =.011), DOA (r = -0.16, p =.049, and r = -0.55, p =.082), PPON (r = -0.17, p =.014, and r = -0.57, p =.037), and ON (r = -0.11, p =.013, and r = -0.42, p =.006) compared to controls, respectively. These data show that EZ reflectivity can be reliably determined from OCT scans and appears to be reduced in neuroinflammatory and mitochondrial disorders. Further validation in larger prospective cohorts is warranted, but our findings suggest that EZ reflectivity might serve as a non-invasive in-vivo biomarker for mitochondrial health.