Photoreceptor Layer Thinning Is an Early Biomarker for Age-Related Macular Degeneration

Zekavat, Seyedeh M.; Sekimitsu, Sayuri; Ye, Yixuan; Raghu, Vineet K.; Zhao, Hongyu; Elze, Tobias; Segrè, Ayellet V.; Wiggs, Janey L.; Natarajan, Pradeep; Priore, Lucian Del; Zebardast, Nazlee; Wang, Jay C.

doi:10.1016/j.ophtha.2022.02.001

Cited by 38 publications

(24 citation statements)

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“… 28 Additionally, a recent study found that photoreceptor segment thinning was genetically associated with AMD development, serving as a potential early biomarker before RPE-Bruch's membrane complex thickening. 29 Given these findings, it may suggest that HUA could be an early indicator of retinal damage at PROS, which would potentially be applied in a clinical settings.…”

Section: Discussionmentioning

confidence: 96%

Short-Term Hyperuricemia Leads to Structural Retinal Changes That Can be Reversed by Serum Uric Acid Lowering Agents in Mice

Pai

Hsieh

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Metabolic disorders have been implicated in ocular diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Recently, hyperuricemia (HUA) has been proposed as another risk factor for AMD, although no cause-and-effect experimental data have been published. In this study, we investigated whether HUA would initiate AMD or related retinal damages in hyperuricemic mice. Methods HUA was induced in male ICR mice by dietary supplements of uric acid and oxonic acid potassium salt, with or without treatments by allopurinol or benzbromarone for various durations. Serum uric acid and angiotensin II concentrations were measured by enzyme-linked immunosorbent assay (ELISA) at regular intervals. The retinal damages were assessed by hematoxylin and eosin staining, immunostaining, and TUNEL assay. The cause-and-effect of HUA was compared among the study groups. Results The results showed that the total thickness of photoreceptor inner and outer segments, as well as the thickness of the photoreceptor outer segment alone, were reduced under HUA. Furthermore, HUA elevated serum angiotensin II, which indicated activation of the renin–angiotensin system (RAS), leading to higher matrix metalloproteinase-2 (MMP-2) expression, and glial activation in the ganglion cell layer. HUA also led to the reduction of retinal pigment epithelium gap junction protein connexin-43 and apoptosis. Uric acid lowering agents, allopurinol or benzbromarone, were effective in ameliorating the impairments. Conclusions HUA may pose as a causative factor of retinal injuries. The reduction of serum uric acid may reduce the detrimental effects caused by HUA.

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Section: Discussionmentioning

confidence: 96%

Short-Term Hyperuricemia Leads to Structural Retinal Changes That Can be Reversed by Serum Uric Acid Lowering Agents in Mice

Pai

Hsieh

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…Visual function is ascertained using a visual electrophysiology system [ 31 ], a dark adaptation test [ 29 ], and by assessing the macular pigment density [ 32 , 33 ]. Among these parameters, an increased risk for AMD was reported for eyes with low levels of macular pigment density [ 33 , 34 ] and for eyes which exhibited thinning of the photoreceptor segment; this was measured using OCT [ 35 ]. For eyes with choriocapillaris flow deficits, further details can be found in our previous study [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Retinal Pigment Epithelial Abnormality and Choroidal Large Vascular Flow Imbalance Are Associated with Choriocapillaris Flow Deficits in Age-Related Macular Degeneration in Fellow Eyes

Nagai

Mushiga

Ozawa

2023

JCM

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Choriocapillaris flow deficits detected on optical coherence tomography angiographs were retrospectively analyzed. In 38 age-related macular degeneration (AMD) fellow eyes, without fundus findings (26 men, 71.7 ± 1.9 years old), and 22 control eyes (11 men, 69.4 ± 1.8), the choriocapillaris flow area (CCFA) ratio and coefficient of variation (CV) of the CCFA ratio (which represented the heterogeneity of the ratio), negatively and positively correlated with age (all p < 0.01), respectively. Moreover, the respective mean values were lower (p = 0.0031) and greater (p = 0.002) in AMD fellow eyes than in the control eyes. The high-risk condition of AMD fellow eyes was defined by a CCFA ratio <58.5%, and the CV of the CCFA ratio ≥0.165 (odds ratio (OR), 5.408; 95% confidence interval (CI): 1.117–21.118, p = 0.035, after adjusting for age and sex) was related to the presence of fundus autofluorescence abnormality (OR, 16.440; 95% CI, 1.262–214.240; p = 0.033) and asymmetrically dilated choroidal large vasculature (OR, 4.176; 95% CI, 1.057–16.503; p = 0.042), after adjusting for age and sex. The presence of fundus autofluorescence abnormality indicated a retinal pigment epithelium (RPE) abnormality. The RPE volume was reduced in the latter eye group, particularly in the thinner choroidal vasculature. In addition to aging, RPE abnormality and choroidal large vascular flow imbalances were associated with exacerbated heterogeneous choriocapillaris flow deficits in AMD fellow eyes without macular neovascularization.

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“…Despite the fact that the exact causes remain unknown, photoreceptors have been implicated to be the primary cellular effectors in the onset and progression of AMD. The epidemiological and genetic study has recently revealed that photoreceptor thinning, rather than retinal pigment epithelium (RPE) and Bruch’s membrane (BM) thickening, could be an early-stage biomarker for the likelihood of future AMD development ( Zekavat et al, 2022 ). For nAMD, photoreceptor degeneration appears to be a secondary event to the loss of choroidal vasculature instead of presumably dysfunction in RPE ( Kurihara et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Automatic quantification of retinal photoreceptor integrity to predict persistent disease activity in neovascular age-related macular degeneration using deep learning

Xianming

Xu²,

Li³

et al. 2022

Front. Neurosci.

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PurposeUsing deep learning (DL)-based technique, we identify risk factors and create a prediction model for refractory neovascular age-related macular degeneration (nAMD) characterized by persistent disease activity (PDA) in spectral domain optical coherence tomography (SD-OCT) images.Materials and methodsA total of 671 typical B-scans were collected from 186 eyes of 186 patients with nAMD. Spectral domain optical coherence tomography images were analyzed using a classification convolutional neural network (CNN) and a fully convolutional network (FCN) algorithm to extract six features involved in nAMD, including ellipsoid zone (EZ), external limiting membrane (ELM), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelium detachment (PED), and subretinal hyperreflective material (SHRM). Random forest models were probed to predict 1-year disease activity (stable, PDA, and cured) based on the quantitative features computed from automated segmentation and evaluated with cross-validation.ResultsThe algorithm to segment six SD-OCT features achieved the mean accuracy of 0.930 (95% CI: 0.916–0.943), dice coefficients of 0.873 (95% CI: 0.847–0.899), a sensitivity of 0.873 (95% CI: 0.844–0.910), and a specificity of 0.922 (95% CI: 0.905–0.940). The six-metric model including EZ and ELM achieved the optimal performance to predict 1-year disease activity, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.980, the accuracy of 0.930, the sensitivity of 0.920, and the specificity of 0.962. The integrity of EZ and ELM significantly improved the performance of the six-metric model than that of the four-metric model.ConclusionThe prediction model reveals the potential to predict PDA in nAMD eyes. The integrity of EZ and ELM constituted the strongest predictive factor for PDA in nAMD eyes in real-world clinical practice. The results of this study are a significant step toward image-guided prediction of long-term disease activity in the management of nAMD and highlight the importance of the automatic identification of photoreceptor layers.

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Photoreceptor Layer Thinning Is an Early Biomarker for Age-Related Macular Degeneration

Cited by 38 publications

References 38 publications

Short-Term Hyperuricemia Leads to Structural Retinal Changes That Can be Reversed by Serum Uric Acid Lowering Agents in Mice

Short-Term Hyperuricemia Leads to Structural Retinal Changes That Can be Reversed by Serum Uric Acid Lowering Agents in Mice

Retinal Pigment Epithelial Abnormality and Choroidal Large Vascular Flow Imbalance Are Associated with Choriocapillaris Flow Deficits in Age-Related Macular Degeneration in Fellow Eyes

Automatic quantification of retinal photoreceptor integrity to predict persistent disease activity in neovascular age-related macular degeneration using deep learning

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