Ahsanuddin Sofia, Rios Hernan A, Otero-Marquez Oscar, Macanian Jason, Zhou Davis, Rich Collin, Rosen Richard B
Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States.
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Front Ophthalmol (Lausanne). 2023 Feb 16;3:1110501. doi: 10.3389/fopht.2023.1110501. eCollection 2023.
Recent studies of glaucoma, age-related macular degeneration, and diabetic retinopathy have demonstrated that flavoprotein fluorescence (FPF) can be utilized non-invasively as an indicator of mitochondrial oxidative stress in the retina. However, a comprehensive assessment of the validity and reliability of FPF in differentiating between healthy and diseased eyes across multiple disease states is lacking. Here, we evaluate the sensitivity and specificity of FPF in discriminating between healthy and diseased eyes in four leading causes of visual impairment worldwide, one of which has not been previously evaluated using FPF. We also evaluate the association between FPF and visual acuity.
A total of 88 eyes [21 eyes of 21 unaffected controls, 20 eyes from 20 retinal vein occlusion (RVO) patients, 20 eyes from 20 diabetic retinopathy (DR) patients, 17 eyes from 17 chronic exudative age-related macular degeneration (exudative AMD) patients, and 10 eyes from 10 central serous retinopathy (CSR) patients] were included in the present cross-sectional observational study. Eyes were imaged non-invasively using a specially configured fundus camera OcuMet Beacon (OcuSciences, Ann Arbor, MI). The macula was illuminated using a narrow bandwidth blue light (455 - 470 nm) and fluorescence was recorded using a narrow notch filter to match the peak emission of flavoproteins from 520 to 540 nm. AUROC analysis was used to determine the sensitivity of FPF in discriminating between diseased eyes and healthy eyes. Nonparametric Kruskal-Wallis Tests with Mann Whitney U tests with the Holm-Bonferroni correction were performed to assess differences in FPF intensity, FPF heterogeneity, and best corrected visual acuity (BCVA) between the five groups. Spearman rank correlation coefficients were calculated to assess the relationship between FPF and BCVA.
AUROC analysis indicated that FPF intensity is highly sensitive for detecting disease, particularly for exudative AMD subjects (0.989; 95% CI = 0.963 - 1.000, =3.0 x 10). A significant difference was detected between the FPF intensity, FPF heterogeneity, and BCVA in all four disease states compared to unaffected controls (Kruskal-Wallis Tests, = 1.06 x 10, = 0.002, = 5.54 x 10, respectively). Compared to healthy controls, FPF intensity values were significantly higher in RVO, DR, exudative AMD, and CSR ( < 0.001 < 0.001 < 0.001, and = 0.001, respectively). Spearman rank correlation coefficient between FPF intensity and BCVA was ρ ( = 9.62 x 10).
Despite variations in structural retinal findings, FPF was found to be highly sensitive for detecting retinal disease. Significant FPF elevation were seen in all four disease states, with the exudative AMD patients exhibiting the highest FPF values compared to DR, CSR, and RVO subjects. This is consistent with the hypothesis that there is elevated oxidative stress in all of these conditions as previously demonstrated by blood studies. FPF intensity is moderately correlated with the late-in disease-marker BCVA, which suggests that the degree of FPF elevation can be used as a metabolic indicator of disease severity.
近期关于青光眼、年龄相关性黄斑变性和糖尿病视网膜病变的研究表明，黄素蛋白荧光（FPF）可作为视网膜线粒体氧化应激的非侵入性指标。然而，目前缺乏对FPF在多种疾病状态下区分健康眼和患病眼的有效性和可靠性的全面评估。在此，我们评估FPF在全球四大主要视力损害原因中区分健康眼和患病眼的敏感性和特异性，其中一种疾病此前尚未使用FPF进行评估。我们还评估了FPF与视力之间的关联。
本横断面观察性研究共纳入88只眼[21名未受影响对照者的21只眼、20名视网膜静脉阻塞（RVO）患者的20只眼、20名糖尿病视网膜病变（DR）患者的20只眼、17名慢性渗出性年龄相关性黄斑变性（渗出性AMD）患者的17只眼和10名中心性浆液性视网膜病变（CSR）患者的10只眼]。使用专门配置的眼底相机OcuMet Beacon（OcuSciences，安阿伯，密歇根州）对眼睛进行非侵入性成像。使用窄带蓝光（455 - 470 nm）照射黄斑，并使用窄带陷波滤光片记录荧光，以匹配黄素蛋白从520至540 nm的峰值发射。使用受试者工作特征曲线下面积（AUROC）分析来确定FPF区分患病眼和健康眼的敏感性。进行非参数Kruskal-Wallis检验以及采用Holm-Bonferroni校正的Mann-Whitney U检验，以评估五组之间FPF强度、FPF异质性和最佳矫正视力（BCVA）的差异。计算Spearman等级相关系数以评估FPF与BCVA之间的关系。
AUROC分析表明，FPF强度对检测疾病高度敏感，尤其是对渗出性AMD受试者（0.989；95%置信区间 = 0.963 - 1.000，P = 3.0 x 10⁻⁴）。与未受影响的对照相比，所有四种疾病状态下的FPF强度、FPF异质性和BCVA均存在显著差异（Kruskal-Wallis检验，P分别为1.06 x 10⁻⁵、0.002、5.54 x 10⁻⁴）。与健康对照相比，RVO、DR、渗出性AMD和CSR中的FPF强度值显著更高（P均 < 0.001）。FPF强度与BCVA之间的Spearman等级相关系数为ρ = -0.329（P = 9.62 x 10⁻⁴）。
尽管视网膜结构检查结果存在差异，但发现FPF对检测视网膜疾病高度敏感。在所有四种疾病状态下均观察到FPF显著升高，与DR、CSR和RVO受试者相比，渗出性AMD患者的FPF值最高。这与血液研究先前证明的在所有这些情况下氧化应激升高的假设一致。FPF强度与疾病晚期标志物BCVA呈中度相关，这表明FPF升高的程度可作为疾病严重程度的代谢指标。
