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 (<i>p</i> &lt; .001) and 0.63 (<i>p</i> = .013), respectively. Multivariable regression analysis revealed that median EZ/RPE20% and EZ/ONL ratios were lower in CPEO (<i>r </i>= -0.12, <i>p</i> = .036, and <i>r</i> = -0.59, <i>p</i> = .011), DOA (<i>r </i>= -0.16, <i>p</i> = .049, and <i>r </i>= -0.55, <i>p</i> = .082), PPON (<i>r </i>= -0.17, <i>p</i> = .014, and <i>r </i>= -0.57, <i>p</i> = .037), and ON (<i>r </i>= -0.11, <i>p</i> = .013, and <i>r </i>= -0.42, <i>p</i> = .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.

黄斑光学相干断层扫描（optical coherence tomography, OCT）图像上的椭圆体带（ellipsoid zone, EZ）因富含具有光散射特性的线粒体（mitochondria）而呈现高信号强度，其反射特性有望成为线粒体功能的潜在标志物。本研究开发了一款可靠的分析工具，用于提取相对EZ反射率，并探索其作为多种疾病生物标志物的潜力。

我们对视神经炎（optic neuritis, ON）、原发性进展性视神经病变（primary progressive optic neuropathy, PPON）、慢性进行性眼外肌麻痹（chronic progressive external ophthalmoplegia, CPEO）、显性遗传性视神经萎缩（dominant optic atrophy, DOA）患者及健康对照者的OCT扫描图像进行了分析。对EZ反射率（以视网膜色素上皮（retina pigment epithelium, RPE）与外核层（outer nuclear layer, ONL）进行归一化处理）进行了评估。采用组内相关系数（intraclass correlation coefficients, ICC）评估其可靠性，通过多元线性回归（multivariable linear regression）分析组间差异，并校正相关混杂因素（confounders）。

本研究共纳入12名健康对照者、23名视神经炎患者、7名慢性进行性眼外肌麻痹患者、13名显性遗传性视神经萎缩患者及13名原发性进展性视神经病变患者。

EZ/RPE20%与EZ/ONL比值展现出良好的重测信度（test–retest reliability），ICC分别为0.76（*p* < .001）与0.63（*p* = .013）。

多元回归分析显示，与健康对照相比，慢性进行性眼外肌麻痹患者的中位EZ/RPE20%与EZ/ONL比值分别降低（*r* = -0.12, *p* = .036；*r* = -0.59, *p* = .011），显性遗传性视神经萎缩患者分别为（*r* = -0.16, *p* = .049；*r* = -0.55, *p* = .082），原发性进展性视神经病变患者分别为（*r* = -0.17, *p* = .014；*r* = -0.57, *p* = .037），视神经炎患者分别为（*r* = -0.11, *p* = .013；*r* = -0.42, *p* = .006）。

本研究结果表明，可通过OCT扫描可靠地测定EZ反射率，且该指标在神经炎症性疾病与线粒体疾病中均出现降低。后续需在更大规模的前瞻性队列中进一步验证，但本研究结果提示EZ反射率有望成为一种无创的体内线粒体健康状态生物标志物。