Probing Deposit-Driven Age-Related Macular Degeneration Via Thicknesses of Outer Retinal Bands and Choroid: ALSTAR2 Baseline.

Purpose: We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort. Methods: Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups. Results: This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant. Conclusions: With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE.

Parafoveal cone function in choroideremia assessed with adaptive optics optoretinography.

Choroideremia (CHM) is an X-linked retinal degeneration leading to loss of the photoreceptors, retinal pigment epithelium (RPE), and choroid. Adaptive optics optoretinography is an emerging technique for noninvasive, objective assessment of photoreceptor function. Here, we investigate parafoveal cone function in CHM using adaptive optics optoretinography and compare with cone structure and clinical assessments of vision. Parafoveal cone mosaics of 10 CHM and four normal-sighted participants were imaged with an adaptive optics scanning light ophthalmoscope. While acquiring video sequences, a 2 s 550Δ10 nm, 450 nW/deg2 stimulus was presented. Videos were registered and the intensity of each cone in each frame was extracted, normalized, standardized, and aggregated to generate the population optoretinogram (ORG) over time. A gamma-pdf was fit to the ORG and the peak was extracted as ORG amplitude. CHM ORG amplitudes were compared to normal and were correlated with bound cone density, ellipsoid zone to RPE/Bruch's membrane (EZ-to-RPE/BrM) distance, and foveal sensitivity using Pearson correlation analysis. ORG amplitude was significantly reduced in CHM compared to normal (0.22 ± 0.15 vs. 1.34 ± 0.31). In addition, CHM ORG amplitude was positively correlated with cone density, EZ-to-RPE/BrM distance, and foveal sensitivity. Our results demonstrate promise for using ORG as a biomarker of photoreceptor function.

Reduced Thickness of the Retina in de novo Parkinson's Disease Shows A Distinct Pattern, Different from Glaucoma.

Background: Parkinson's disease (PD) patients experience visual symptoms and retinal degeneration. Studies using optical coherence tomography (OCT) have shown reduced thickness of the retina in PD, also a key characteristic of glaucoma. Objective: To identify the presence and pattern of retinal changes in de novo, treatment-naive PD patients compared to healthy controls (HC) and early primary open angle glaucoma (POAG) patients. Methods: Macular OCT data (10×10 mm) were collected from HC, PD, and early POAG patients, at the University Medical Center Groningen. Bayesian informative hypotheses statistical analyses were carried out comparing HC, PD-, and POAG patients, within each retinal cell layer. Results: In total 100 HC, 121 PD, and 78 POAG patients were included. We showed significant reduced thickness of the inner plexiform layer and retinal pigment epithelium in PD compared to HC. POAG patients presented with a significantly thinner retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, outer plexiform layer, and outer photoreceptor and subretinal virtual space compared to PD. Only the outer segment layer and retinal pigment epithelium were significantly thinner in PD compared to POAG. Conclusions: De novo PD patients show reduced thickness of the retina compared to HC, especially of the inner plexiform layer, which differs significantly from POAG, showing a more extensive and widespread pattern of reduced thickness across layers. OCT is a useful tool to detect retinal changes in de novo PD, but its specificity versus other neurodegenerative disorders has to be established.

Long-term Follow-Up and Regeneration of Retinal Pigment Epithelium (RPE) after Tears of the Epithelium in Exudative Age-Related Macular Degeneration (AMD).

BACKGROUND: The goals of this study are to evaluate potential long-term visual deterioration associated with retinal pigment epithelial (RPE) tears in patients with neovascular age-related macular degeneration (nAMD) and to find treatment-related and morphological factors that might influence the outcomes. PATIENTS AND METHODS: This retrospective study enrolled 21 eyes of 21 patients from the database of Vista Eye Clinic Binningen, Switzerland, diagnosed with RPE tears, as confirmed by spectral domain optical coherence tomography (SD-OCT), with a minimum follow-up period of 12 months. Treatment history before and after RPE rupture with anti-VEGF therapy, visual acuity, and imaging (SD-OCT) were analyzed and statistically evaluated for possible correlations. RESULTS: Mean patient age was 80.5 ± 6.2 years. The mean length of total follow-up was 39.7 ± 13.9 months. The mean pigment epithelial detachment (PED) height increased by 363.8 ± 355.5 µm from the first consultation to 562.8 ± 251.5 µm at the last consultation prior to rupture. Therefore, a higher risk of RPE rupture is implied as a result of an increase in PED height (p = 0.004, n = 14). The mean visual acuity before rupture was 66.2 ± 16.0 letters. Mean visual acuity deteriorated to 60.8 ± 18.6 letters at the first consultation after rupture (p = 0.052, n = 21). A statistically nonsignificant decrease in vision was noted in the follow-up period. After 2 years, the mean BCVA decreased by 10.5 ± 23.7 ETDRS letters (p = 0.23, n = 19). PED characteristics before rupture and amount of anti-VEGF injections after rupture did not affect the visual outcome. None of the 21 patients included in our study showed a visual improvement in the long-term follow-up. RPE atrophy increased significantly from 3.35 ± 2.94 mm2 (baseline) to 6.81 ± 6.25 mm2 over the course of 2 years (p = 0.000 013, n = 20). CONCLUSIONS: The overall mean vision decrease after rupture was without statistical significance. There was no significant change in BCVA at the 2-year follow-up, independent of the amount of anti-VEGF injections provided. In this study, there was a significant increase in RPE defect over a follow-up of 2 years, implying progression of contraction of RPE and/or macular atrophy.

Intrinsic signal optoretinography of dark adaptation abnormality due to rod photoreceptor degeneration.

This research aims to investigate the potential of using intrinsic optical signal (IOS) optoretinography (ORG) to objectively detect dark adaptation (DA) abnormalities related to rod photoreceptor degeneration. Functional optical coherence tomography (OCT) was employed in both wild-type (WT) and retinal degeneration 10 (rd10) mice to conduct this assessment. Dynamic OCT measurements captured the changes in retinal thickness and reflectance from light-to-dark transition. Comparative analysis revealed significant IOS alterations within the outer retina. Specifically, a reduction in thickness from external limiting membrane (ELM) peak to retinal pigment epithelium (RPE) peak was observed (WT: 1.13 ± 0.69 µm, 30 min DA; rd10: 2.64 ± 0.86 µm, 30 min DA), as well as a decrease in the intensity of the inner segment ellipsoid zone (EZ) in 30 min DA compared to light adaptation (LA). The reduction of relative EZ intensity was notable in rd10 after 5 min DA and in WT after 15 min DA, with a distinguishable difference between rd10 and WT after 10 min DA. Furthermore, our findings indicated a significant decrease in the relative intensity of the hypo-reflective band between EZ and RPE in rd10 retinas during DA, which primarily corresponds to the outer segment (OS) region. In conclusion, the observed DA-IOS abnormalities, including changes in ELM-RPE thickness, EZ, and OS intensity, hold promise as differentiators between WT and rd10 mice before noticeable morphological abnormalities occur. These findings suggest the potential of this non-invasive imaging technique for the early detection of dysfunction in retinal photoreceptors.

Retro-mode imaging in acute posterior multifocal placoid pigment epitheliopathy.

AIM: to provide a detailed description and multimodal imaging (MMI) including retro-mode imaging of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). METHODS: Case report of a young male patient presenting with APMPPE picture. Initially, visual acuity testing was performed, followed by biomicroscopic and fundus examinations along with MMI including Optical Coherence Tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), Indocyanine Green (ICG) angiography, and Retro-mode imaging. The patient was then monitored over a duration of two months. RESULTS: visual acuity was 20/20 with normal biomicroscopic examination; fundus examination detected multiple pale placoid lesions. MMI was consistent with typical APMPPE. Notably, Retro-mode imaging revealed numerous crater-like round lesions that corresponded to those observed on angiography. CONCLUSION: Retromode imaging in APMPPE can serve as a non-invasive tool that highlights the number and distribution of lesions as well as on angiography.

QUANTITATIVE AUTOFLUORESCENCE IN CENTRAL SEROUS CHORIORETINOPATHY.

BACKGROUND/PURPOSE: Central serous chorioretinopathy (CSC) is associated with pachychoroid and dysfunctional retinal pigment epithelium. Autofluorescence (AF) is typically altered. The authors performed this study to quantify these alterations using quantitative AF (qAF) in patients with CSC and in their fellow eye in comparison with a healthy control group. METHODS: Patients with CSC and healthy controls were recruited prospectively. All patients received a full clinical examination including best-corrected visual acuity, enhanced depth imaging-optical coherence tomography, and qAF. Quantitative autofluorescence images were taken with a confocal scanning laser ophthalmoscope (Heidelberg Engineering). Quantitative autofluorescence values were assessed in specified regions of the inner eight and the middle ring of the Delori grid. RESULTS: In total, 141 eyes of 77 patients with CSC were included. Ninety eyes had a manifest CSC (group 1) while 51 fellow eyes (group 2) did not show signs of CSC. There were no significant differences of qAF values between these two groups: mean qAF values were 241.3 (inner eight) and 212.8 (middle ring) in group 1 and 235.9 (inner eight) and 210.0 (middle ring) in group 2 ( P = 1.0 and 1.0). We compared these eyes with healthy controls comprising 39 eyes. Quantitative autofluorescence signals (inner eight: 164.7; middle ring: 148.9) differed significantly compared with both CSC manifest ( P < 0.001) and fellow eyes ( P < 0.001). CONCLUSION: Our results show that patients with CSC have increased qAF values in both eyes with manifest CSC and asymptomatic, clinically unremarkable fellow eyes in comparison with healthy controls. This finding suggests that qAF alterations are present even before clinical signs can be observed.

Presumed acute posterior multifocal placoid pigmentary epitheliopathy associated with Bartonella infection.

To report a unique case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in a patient with positive serology for Bartonella, presenting with ocular signs and symptoms not attributable to other diseases. A 27-year-old woman presented with decreased visual acuity in both eyes. Multimodal fundus image analysis was performed. A color fundus photograph of both eyes revealed peripapillary and macular yellow-white placoid lesions. The fundus autofluorescence of both eyes demonstrated hypo- and hyperautofluorescence of the macular lesions. Fluorescein angiography showed early-stage hypofluorescence and late staining of placoid lesions in both eyes. Spectral domain optical coherence tomography (SD-OCT) of both eyes revealed irregular elevations in the retinal pigment epithelium with the disruption of the ellipsoid zone on the topography of macular lesions. At 3 months after the treatment initiation for Bartonella infection, the placoid lesions became atrophic and hyperpigmented, and SD-OCT revealed loss of both the outer retinal layers and retinal pigment epithelium on the topography of macular lesions in both eyes.

Metabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus.

The retina is an important target organ of diabetes mellitus, with increasing evidence from patients and animal models suggesting that retinal pigment epithelium (RPE) may serve as an early marker for diabetes-related damages. However, their longitudinal relationship and the biological underpinnings remain less well understood. Here, we demonstrate that reduced in vivo measurements of RPE thickness (RPET) represents a significant risk factor for future type 2 diabetes mellitus (T2DM) and its microvascular phenotypes. After performing systematic analyses of circulating plasma metabolites using two complementary approaches, we identify a wide range of RPET metabolic fingerprints that are independently associated with reduced RPET. These fingerprints hold their potential to improve predictability and clinical utility for stratifying future T2DM and related microvascular phenotypes beyond traditional clinical indicators, providing insights into the promising role of retinas as a window to systemic health.

Self-supervised semantic segmentation of retinal pigment epithelium cells in flatmount fluorescent microscopy images.

MOTIVATION: Morphological analyses with flatmount fluorescent images are essential to retinal pigment epithelial (RPE) aging studies and thus require accurate RPE cell segmentation. Although rapid technology advances in deep learning semantic segmentation have achieved great success in many biomedical research, the performance of these supervised learning methods for RPE cell segmentation is still limited by inadequate training data with high-quality annotations. RESULTS: To address this problem, we develop a Self-Supervised Semantic Segmentation (S4) method that utilizes a self-supervised learning strategy to train a semantic segmentation network with an encoder-decoder architecture. We employ a reconstruction and a pairwise representation loss to make the encoder extract structural information, while we create a morphology loss to produce the segmentation map. In addition, we develop a novel image augmentation algorithm (AugCut) to produce multiple views for self-supervised learning and enhance the network training performance. To validate the efficacy of our method, we applied our developed S4 method for RPE cell segmentation to a large set of flatmount fluorescent microscopy images, we compare our developed method for RPE cell segmentation with other state-of-the-art deep learning approaches. Compared with other state-of-the-art deep learning approaches, our method demonstrates better performance in both qualitative and quantitative evaluations, suggesting its promising potential to support large-scale cell morphological analyses in RPE aging investigations. AVAILABILITY AND IMPLEMENTATION: The codes and the documentation are available at: https://github.com/jkonglab/S4_RPE.

Novel Fractal-Based Sub-RPE Compartment OCT Radiomics Biomarkers Are Associated With Subfoveal Geographic Atrophy in Dry AMD.

OBJECTIVE: The purpose of this study was to quantitatively characterize the shape of the sub-retinal pigment epithelium (sub-RPE, i.e., space bounded by RPE and Bruch's membrane) compartment on SD-OCT using fractal dimension (FD) features and evaluate their impact on risk of subfoveal geographic atrophy (sfGA) progression. METHODS: This was an IRB-approved retrospective study of 137 subjects with dry age-related macular degeneration (AMD) with subfoveal GA. Based on sfGA status at year five, eyes were categorized as "Progressors" and "Non-progressors". FD analysis allows quantification of the degree of shape complexity and architectural disorder associated with a structure. To characterize the structural irregularities along the sub-RPE surface between the two groups of patients, a total of 15 shape descriptors of FD were extracted from the sub-RPE compartment of baseline OCT scans. The top four features were identified using minimum Redundancy maximum Relevance (mRmR) feature selection method and evaluated with Random Forest (RF) classifier using three-fold cross validation from the training set (N = 90). Classifier performance was subsequently validated on the independent test set (N = 47). RESULTS: Using the top four FD features, a RF classifier yielded an AUC of 0.85 on the independent test set. Mean fractal entropy (p-value = 4.8e-05) was identified as the most significant biomarker; higher values of entropy being associated with greater shape disorder and risk for sfGA progression. CONCLUSIONS: FD assessment holds promise for identifying high-risk eyes for GA progression. SIGNIFICANCE: With further validation, FD features could be potentially used for clinical trial enrichment and assessments for therapeutic response in dry AMD patients.

Pigment epithelial detachment composition indices (PEDCI) in neovascular age-related macular degeneration.

We provide an automated analysis of the pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (nAMD) and estimate areas of serous, neovascular, and fibrous tissues within PEDs. A retrospective analysis of high-definition spectral-domain OCT B-scans from 43 eyes of 37 patients with nAMD with presence of fibrovascular PED was done. PEDs were manually segmented and then filtered using 2D kernels to classify pixels within the PED as serous, neovascular, or fibrous. A set of PED composition indices were calculated on a per-image basis using relative PED area of serous (PEDCI-S), neovascular (PEDCI-N), and fibrous (PEDCI-F) tissue. Accuracy of segmentation and classification within the PED were graded in masked fashion. Mean overall intra-observer repeatability and inter-observer reproducibility were 0.86 ± 0.07 and 0.86 ± 0.03 respectively using intraclass correlations. The mean graded scores were 96.99 ± 8.18, 92.12 ± 7.97, 91.48 ± 8.93, and 92.29 ± 8.97 for segmentation, serous, neovascular, and fibrous respectively. Mean (range) PEDCI-S, PEDCI-N, and PEDCI-F were 0.253 (0-0.952), 0.554 (0-1), and 0.193 (0-0.693). A kernel-based image processing approach demonstrates potential for approximating PED composition. Evaluating follow up changes during nAMD treatment with respect to PEDCI would be useful for further clinical applications.

Retinal pigment epithelial changes in Parkinson's disease: A spectral domain optical coherence tomography study.

OBJECTIVE: To evaluate retinal pigment epithelium (RPE) changes in Parkinson's Disease (PD) and to compare choroidal thickness (CT) and retinal layers with healthy controls. METHODS: Parkinson's patients older than 18 and the age-sex match control group were included in this prospective observational study. The neurological and ophthalmological evaluation was performed. All participants were examined by spectral-domain optical coherence tomography. Focal RPE changes were defined as local RPE changes observed in any macula scan. RESULTS: Forty (24 male, mean age 69.2 years) participants were included in the study group, and 44 (24 male, mean age 68.9 years) participants in the control group. There was no significant difference between groups in terms of age and sex. All patients were using oral dopaminergic and/or non-dopaminergic therapy. The RPE changes in the macular area were observed in 14/40 PD eyes (35%) and were significantly more frequent than in the control group (2/44, 4.5%, P = 0.001). All of the RPE changes were RPE thickening (±additional finding: subretinal deposit, subRPE deposit). The logistic regression model for possible factors that may affect RPE changes revealed statistical significance in prolonging disease duration; however, age, sex, and the presence of hypertension were not significant. Inferior 3-mm RPE layer thickness was found to be thicker in PD. There was no significant difference between groups in terms of CT, retinal layers, and peripapillary retinal nerve fiber layer thickness (RNFLT), except inferonasal RNFLT which was thinner in the study group. CONCLUSIONS: The RPE changes are more frequent in patients with PD than in the control group in the macular area. The most frequent RPE change is the focal thickening of RPE, and RPE changes were associated with disease duration. We cannot distinguish a potential drug effect from a true potential effect of the disease in question.

NINE-YEAR PROGRESSION OF PENTOSAN MACULOPATHY WITH MULTIMODAL RETINAL IMAGING.

BACKGROUND/PURPOSE: The purpose of this study was to describe the characteristic pattern of progression of pentosan polysulfate (PPS) maculopathy with multimodal retinal imaging in two patients, including one with over 9 years of follow-up. METHODS: Two patients with PPS maculopathy were sequentially evaluated with near-infrared reflectance (NIR) and optical coherence tomography. RESULTS: Near-infrared reflectance showed characteristic centrifugal progression of the parafoveal hyperreflective lesions toward the vascular arcades with the development of hyporeflective areas in both cases. Optical coherence tomography demonstrated focal retinal pigment epithelium (RPE) thickening that corresponded to the hyperreflective lesions on NIR. On subsequent optical coherence tomography scans, the hyperreflective areas resolved with the development of ellipsoid zone attenuation, RPE disruption, and atrophy, which colocalized with hyporeflectivity on NIR. CONCLUSION: This report describes the progression of pentosan polysulfate maculopathy over almost 10 years of PPS treatment and highlights the importance of NIR as a tool for the diagnosis and monitoring of PPS maculopathy. Pentosan polysulfate lesions present as areas of focal RPE thickening with ensuing development of ellipsoid zone loss and RPE drop-out. The pathophysiology of PPS toxicity is unknown and may either result from primary RPE or choroidal toxicity.

Thickness of retinal pigment epithelium-Bruch's membrane complex in adult Chinese using optical coherence tomography.

PURPOSE: To study thickness of RPE-BM complex in adult Chinese subjects and its correlation with systemic and ocular biometric parameters. DESIGN: Population-based longitudinal study. Cross-sectional study. PARTICIPANTS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6 ± 9.8 years (range: 50-93 years). METHODS: A detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (SD OCT) for measurement of the thickness of RPE-BM complex. Use Heidelberg software "Heidelberg Eye Explorer" for segmentation and measurements. MAIN OUTCOME MEASURE: Thickness of RPE-BM complex. RESULTS: In total, 3276 people (6530 eyes) were included in the study. In total, 1844 (56.3%) subjects were female. The mean age was 64.3 ± 9.6 years (range: 50-93 years). The mean refractive error (spherical equivalent) was -0.18 ± 2.04 diopters (range: -22.0 to +7.50 diopters). Mean thickness of the RPE-BM complex at the foveal center was 25.09 ± 3.98 µm (range: 17-37 µm). In multiple regression analysis, subfoveal thickness of the RPE-BM complex was associated with age (p = 0.039; beta: 0.22; B: 0.10 (95% CI: 0.01, 0.20)) and hypertension history (p = 0.038; beta: 0.23; B: 1.96 (95% CI: 0.12, 3.81)). CONCLUSION: Mean subfoveal thickness of the RPE-BM complex was 25.09 ± 3.98 µm in elderly subjects with a mean age of 64.3 years increased with age and hypertension history. The increase in the thickness of RPE-BM complex may play a role in the pathophysiologic features of various age-related ocular conditions.