Transient vitreous opacity following combined intravitreal injection of pegcetacoplan and faricimab-svoa in patients with neovascular age-related macular degeneration and geographic atrophy.

Sigma-2 receptor modulators alter low-density lipoprotein receptor-mediated lipid uptake in retinal pigment epithelial cells.

Geographic atrophy (GA) enlargement rates are generally stable over time for any given eye, a property which may help improve GA clinical trial efficiency by preserving statistical power with smaller sample sizes. One strategy is to incorporate a run-in phase into randomized clinical trials (RCT) to collect natural history data before randomization, while another strategy is a single-arm trial, in which all participants receive the study drug and enlargement rates are compared between run-in and treatment phases. To evaluate whether run-in phase RCTs or single-arm trial designs might improve trial efficiency using power analyses and trial simulations. This diagnostic/prognostic study uses in silico clinical trial power analyses. Parameters were derived from participants in the GA Minocycline Trial with baseline GA area of 2.5 to 17.5 mm2. Data were analyzed from November 2025 to March 2026. The primary outcome was the required sample size for a given power, using square root GA area as the trial outcome. Sample size requirements for 80% and 90% power were estimated using linear mixed-model analyses and validated empirically by trial simulations (10 000 replications), assuming 25% treatment effect and α = .05. First, RCTs (1:1 randomization) with vs without a run-in phase were compared, keeping total follow-up constant. Second, RCTs were compared with a single-arm trial of equal duration. The Geographic Atrophy Minocycline Trial comprised 133 visits, 28 eyes, and 28 participants. The sample size estimate was smaller for an RCT with vs without a run-in phase. Sample size was incrementally smaller with longer run-in duration. For 2-year trials with 90% power, the sample size was 156 for an RCT vs 82, 40, and 26 for RCTs with run-in phases of 3, 6, and 9 months, respectively. Sample size estimates were smaller for single-arm trials than RCTs. The sample size for a 2-year single-arm trial (9-month run-in phase and 15-month treatment) was 14 vs 26 for an RCT (same phase durations). For all comparisons, similar patterns were observed for trials with 1-year duration, 80% power, nonsubfoveal GA only, or untransformed enlargement rates. For GA clinical trials, this diagnostic/prognostic study suggests incorporating run-in phases into RCTs or using single-arm designs can improve trial efficiency by exploiting the inherent stability of GA enlargement rates. These sample size estimates may apply to a wide range of GA trial designs.

To investigate associations between imaging biomarkers and quantitative contrast sensitivity (CS) function (qCSF) metrics in geographic atrophy (GA). Cross-sectional study including 97 eyes from 70 patients (>55 years) with GA within 1500 µm of the fovea and visual acuity (VA)>20/320. Participants underwent VA and qCSF testing (area under the log CS function (AULCSF), contrast acuity (CA), and CS at 1-18 cycles per degree (cpd)) and multimodal imaging with blue autofluorescence (BAF), optical coherence tomography (OCT), and, in 55 eyes, swept-source OCT angiography (SS-OCTA). Imaging biomarkers included GA size, prior growth rate, configuration, BAF pattern, circularity, percentage of foveal involvement (%FI), foveal distance and macular inner choroid flow deficit percentage (mICFD%). Generalised linear mixed-effects and random forest (GRF) models evaluated structure-function relationships. Participants (age 78.8±5.6 years; 70% female) had a median GA size of 4.0 mm², with 64% showing subfoveal involvement. Larger GA size and higher %FI were significantly associated with worse VA, AULCSF, CA and CS at 1-12 cpd (all p<0.01). Unifocal lesions correlated with lower VA and CS at 6 cpd, while diffuse/banded BAF patterns and greater mICFD% were linked to reduced CS at 1-1.5 cpd. GRF analysis identified GA size and %FI as primary predictors of CS loss, with best performance for AULCSF and CS at 3 cpd (R²=0.319, 0.314). GA size and %FI are key determinants of CS loss in GA. qCSF outperformed VA in predictive accuracy, supporting its use as a sensitive functional endpoint in GA trials.

Metabolic reprogramming and mitochondrial dynamics: Novel therapeutic perspectives for age-related macular degeneration.

Geographic atrophy, the advanced form of dry age-related macular degeneration (AMD), has historically been evaluated using structural endpoints and best-corrected visual acuity (BCVA). This review examines the growing rationale for a function-first approach. Emerging data demonstrate that functional deficits often decline earlier and more profoundly than BCVA. Recently approved complement inhibitors have shown slowing of geographic atrophy lesion growth but without consistent improvements in traditional visual acuity endpoints. Extension studies and post hoc analyses suggest some functional benefits. Next-generation therapies are increasingly incorporating functional endpoints into trial design. Structural slowing alone does not fully capture therapeutic value in geographic atrophy. Functional measures provide a more sensitive and patient-centered assessment of disease progression and treatment impact.

This work describes the design and methodological framework of the I-SCREEN project, which aims to develop an artificial intelligence (AI)-based infrastructure utilising optical coherence tomography (OCT) for early detection of AMD and assessment of progression risk. The pan-European project is conducted across clinics and optometry/optician practices in six European countries. I-SCREEN encompasses seven work packages covering community-based AMD identification, clinical follow-up, AI development and project dissemination. Three interconnected clinical studies are carried out by optometry/optician practices (PYRENEES) and ophthalmology clinics (SUDETES and APENNINES). The PYRENEES study is a prospective, cross-sectional study evaluating the feasibility of detecting subclinical AMD in optometry/optician practices under ophthalmologist supervision via telemedicine. A robust screening network comprising 28 community-based optometry/optician practices and 7 ophthalmology clinics has been established. Patients with suspected non-neovascular AMD are referred to partneredclinics. In the hospital setting, patients with early or intermediate AMD are followed in the longitudinal SUDETES study, while patients with non-foveal geographic atrophy are invited to take part in the APENNINES study. Data obtained inform AI development for community-based AMD detection and monitoring. Predictive modelling will further enable personalised risk assessments. I-SCREEN brings together multidisciplinary experts across Europe to establish an AI-driven shared care model for AMD detection and monitoring. By combining high-quality OCT imaging from community practices with longitudinal clinical studies, the initiative provides novel insights into early AMD progression and establishes a foundation for innovative AI-based detection and prediction throughout the real-world population.

Unsuccessful Clinical Trials in Retina: Lessons Learned.

To compare macular atrophy following neovascular age-related macular degeneration (nAMD) vs. geographic atrophy (GA) following dry AMD. We analysed 60 eyes from 44 patients: 30 eyes with de novo GA and 30 with macular atrophy secondary to nAMD. All patients had monthly follow-ups before GA onset and continued for at least two years after. GA was defined as complete retinal pigment epithelium atrophy ≥250 μm using OCT scans. OCT biomarkers at GA onset, including central macular thickness (CMT), subfoveal choroidal thickness (SFCT), epiretinal membrane (ERM), double-layer sign (DLS), subretinal hyperreflective material (SRHM), hyperreflective foci (HRF), outer retinal tubulation (ORT), and intraretinal fluid (IRF), were assessed. Chi-square test, Spearman correlation, and linear mixed models were used. The mean age was 80.06 ± 8.60 years, with 50.0% male. Eyes with nAMD progressed to macular atrophy after 31.38 ± 30.72 months and 8.86 ± 10.84 anti-vascular endothelial growth factor (VEGF) injections. Compared to de novo GA, eyes with macular atrophy following nAMD had larger baseline atrophic area (3.791 ± 2.661 mm² vs. 1.115 ± 0.951 mm²; P < 0.001) and greater atrophy growth (2.646 ± 2.014 mm² vs. 0.652 ± 0.722 mm²; P < 0.001), with more frequent ERM, DLS, HRF, SRHM, ORT, and IRF. Atrophy growth correlated with baseline SFCT (r = -0.545, P = 0.002) and GA area (r = 0.501, P = 0.005) but not with the number of anti-VEGF injections (p > 0.05). Eyes with macular atrophy secondary to nAMD exhibit larger initial atrophic areas and faster progression compared to de novo GA. OCT biomarkers may detect previous exudation, helping identify cases where recently FDA-approved GA therapies may be relatively contraindicated due to prior disease.

To provide expert-driven, practical guidelines for the optimal use of optical coherence tomography angiography (OCTA) in the clinical management of age-related macular degeneration (AMD). Given the heterogeneity of AMD and the versatility of OCTA, clinicians require scenario-specific recommendations to navigate imaging strategies effectively across various stages and phenotypes of the disease. An expert panel from the European Young Retinal Imaging and Retina Study Group conducted a consensus-based review integrating the latest evidence and extensive clinical experience. The panel focused on developing OCTA-based protocols tailored to distinct clinical scenarios in AMD, including neovascular subtypes, geographic atrophy, non-exudative neovascularization, and ambiguous fluid accumulations. Recommendations emphasize appropriate scan sizes, slab selections, and strategies for interpreting flow signals across disease presentations. The expert panel delineated structured OCTA protocols for a range of AMD phenotypes to enhance diagnostic accuracy and clinical decision-making. In neovascular AMD, OCTA enables detailed characterization of macular neovascularization (MNV) subtypes—types 1, 2, and 3—through high-resolution, depth-resolved imaging. Recommendations include the use of cross-sectional OCTA to localize flow and appropriate selection of en face slabs to optimize lesion visualization. In geographic atrophy (GA), while structural OCT remains the primary modality, OCTA may assist in identifying subclinical or complicating MNV and in assessing choriocapillaris perfusion in the peri-atrophic zone, which may have prognostic implications. In cases of early and intermediate AMD, OCTA plays a critical role in detecting non-exudative MNV—particularly type 1 and type 3 lesions—providing valuable prognostic information given the risk of exudative conversion. Additionally, OCTA contributes to the differential diagnosis of pseudovitelliform lesions, detection of deep retinal age-related microvascular anomalies (DRAMAs), and exclusion of neovascularization in cases presenting with atypical intraretinal or subretinal fluid. This expert consensus offers a pragmatic framework for applying OCTA in AMD clinics, advocating for individualized imaging approaches based on lesion type and anatomical complexity. By enhancing diagnostic precision and enabling tailored monitoring strategies, OCTA integration into clinical workflows may significantly improve patient outcomes across the AMD spectrum.

Optical coherence tomography (OCT) plays a crucial role in diagnosing retinal diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), as well as in identifying neurodegenerative biomarkers. Despite advancements in U-Net-based convolutional networks for OCT image segmentation, there is a lack of systematic reviews comparing their performance with expert manual segmentations. This review aims to assess the efficacy of these automated networks in segmenting retinal fluid and pathology in OCT images. By searching three different databases, PubMed, Web of Science, and Scopus, over the past five years, we conducted this systematic review and meta-analysis using data from 16 diagnostic-accuracy studies. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. The analysis used mean and standard deviation for the continuous outcomes and employed a random-effects model. Analyses were performed using Review Manager software version 5.4 (The Cochrane Collaboration, London, UK, 2020). Artificial intelligence (AI) and human Dice scores did not differ significantly (standardized mean difference (SMD) = -0.08; 95% CI: -1.16 to 0.99; p = 0.88), nor did intraclass correlation coefficient (ICC) values (SMD = -0.13; 95% CI: -5.70 to 5.45; p = 0.96). However, very high heterogeneity (I² > 90%) limits the reliability of these pooled estimates. AI achieved expert-level Dice scores for subretinal fluid (0.88-0.96) and geographic atrophy (0.94). Intraretinal fluid was more challenging (Dice 0.79-0.89). Volumetric reliability was strong (ICCs > 0.94). Device-dependent variability was substantial; kappa was 0.37 for ZEISS versus 0.73 for Spectralis, indicating a need for device-specific optimization. Volumetric analyses revealed minor systematic overestimation (mean difference: -0.05 mm²). Processing times ranged from 100 milliseconds per B-scan to several seconds per volume, representing substantial time savings versus manual segmentation. Fully automated U-Net pipelines reach expert-level accuracy for subretinal fluid and geographic atrophy but remain limited for intraretinal fluid and show marked device-dependent variability. Clinical translation requires four priorities: standardized multi-device benchmarks, domain adaptation for cross-platform robustness, hybrid AI-human workflows pairing automated pre-segmentation with expert oversight, and prospective clinical trials. These steps are needed to move AI segmentation from a research tool to a clinical decision-support system.

Tropomyosin-Related Kinase Receptor Type B Agonism in Geographic Atrophy – The Translational Challenges From Preclinical Data to a First-in-Human Trial

This review examines commonly prescribed systemic medications and their possible associations with age-related macular degeneration (AMD) development and progression. With the limitations and risks of current intravitreal therapies, there is growing interest in oral pharmacotherapy for AMD management. The following review synthesizes observational studies, meta-analyses, and ongoing clinical trials to evaluate the potential effects of commonly used systemic medications on AMD. Metformin demonstrates conflicting evidence, with several meta-analyses and large cohort study showing reduced AMD odds, while a recent randomized phase II trial found no effect on geographic atrophy progression. For statins, emerging evidence suggests that treatment duration exceeding 2 years and medium-intensity to high-intensity dosing may confer protection against AMD development. Aspirin demonstrates discordant results between different study designs: two large randomized controlled trials showed no benefit for AMD, while a 10-year observational study suggested protective effects.Fenofibrates show promise in preclinical models but require additional clinical investigation. Danicopan also shows modest effects in complement-related disorders and is currently undergoing a phase 2 trial to evaluate efficacy in patients with geographic atrophy. Finally, dopamine agonists appear to improve visual acuity and reduce subretinal fluid and central retinal thickness in newly diagnosed exudative AMD, as shown in an open-label pilot study, but require further investigation. Multiple systemic medications have highlighted mixed or stage-dependent benefits on AMD development and progression. Some agents such as metformin and aspirin have shown conflicting findings, having been evaluated in randomized trials and large observational studies. Other medications including GLP-1 agonists, dopamine agonists, statins, fenofibrates, and danicopan show early promise in more limited studies, but require further clinical validation.

To evaluate the safety and efficacy of multiwavelength photobiomodulation (PBM) in nonexudative (dry) age-related macular degeneration (AMD). LIGHTSITE III used a double-masked, randomized, sham-controlled, parallel-group, prospective study design. Subjects were enrolled with a diagnosis of dry AMD and treated with multiwavelength PBM (Valeda Light Delivery System; 590, 660, and 850 nm) or sham treatment. A treatment series included 9 PBM or sham treatments delivered 3x/week over 3 to 5 weeks every 4 months (M) for 24M. A total of 148 eyes (100 subjects) with dry AMD were randomized into the study. LIGHTSITE III met the prespecified primary BCVA efficacy end point at M21 with a significant difference between treatment groups ( P = 0.0036) and a +6.2 letter gain after PBM. At M21, 61.5% of PBM-treated eyes showed ≥5, 23.1% showed ≥10, and 4.4% showed ≥15 letter gains. A favorable safety profile was observed with no signs of phototoxicity. Disease progression to Geographic Atrophy (GA) showed a significant decrease in incidence (Sham, 24.0% vs. PBM, 6.8%; P = 0.007) after PBM treatment at M24. Significant benefit in vision QoL was observed. Multiwavelength PBM represents an interventional therapy that restores visual function and has potential disease-modifying effects in intermediate dry AMD.

To evaluate the association between spectrally resolved fundus autofluorescence (Sr-FAF) signals and four macular lesion types identified on spectral-domain optical coherence tomography (SD-OCT): (1) drusen, (2) incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA), (3) retinal pigment epithelium (RPE) and outer retinal atrophy, and (4) nascent geographic atrophy (nGA) in eyes with intermediate and atrophic age-related macular degeneration (AMD). This cross-sectional observational study analyzed 775 SD-OCT B-scans from 62 eyes (62 patients) with AMD. Lesions were classified according to established OCT criteria (290 drusen, 49 iRORA, 390 cRORA, 46 nGA). All eyes underwent SD-OCT imaging (97 B-scans) and Sr-FAF using a 450-nm wavelength. Quantitative Sr-FAF metrics (average red emission fluorescence component [REFC] and average green emission fluorescence component [GEFC]) were determined using custom software, and lesion groups were compared via one-way analysis of variance with Scheffé post hoc testing. Significant differences among lesion types were observed for REFC (F = 59.3, P < 0.001) and GEFC (F = 13.5, P < 0.001). Drusen exhibited higher REFC intensities than iRORA, cRORA, and nGA (all P < 0.001), and higher GEFC intensities than cRORA (P < 0.001) and nGA (P = 0.002). Wavelength (nm) progressively decreased from drusen to iRORA, nGA, and cRORA. Lesion size (in pixels) differed significantly (iRORA < nGA < drusen < cRORA; P < 0.001) and was the strongest predictor (β = -0.31, P < 0.001) in the regression analysis. Sr-FAF reveals distinct metabolic signatures across AMD lesion types. Higher fluorophore signals in drusen suggest preserved photoreceptor-RPE activity, whereas reduced signals in cRORA and nGA reflect advanced atrophy. Combined SD-OCT and Sr-FAF may enhance the detection of early atrophic changes and improve AMD risk stratification.

Vision loss caused by retinal diseases remains a leading global cause of disability. Optical coherence tomography (OCT) is an imaging technique that is used for diagnosing retinal diseases. Computational models can use OCT images for various diagnostic and prognostic tasks, but most existing approaches fail to fully leverage the rich three-dimensional (3D) structure of OCT data and lack the capability to integrate other retinal imaging modalities into the analysis. Here, to address these limitations, we present OCTCube-M, a 3D OCT-based multi-modal framework designed for the integrated analysis of 3D OCT and 2D en face (EF) images. OCTCube-M exploits COEP, an effective multi-modal contrastive learning method, to integrate OCT with other retinal imaging modalities, such as fundus autofluorescence imaging and infrared retinal imaging (IR). Using the OCTCube-M framework, we developed three models: OCTCube (uni-modal), OCTCube-IR (bi-modal) and OCTCube-EF (tri-modal). OCTCube, a 3D foundation model pre-trained on 26,605 3D OCT volumes comprising 1.62 million 2D OCT slices, achieved state-of-the-art performance in predicting 8 retinal diseases while demonstrating robust generalizability across cohorts, devices and modalities. OCTCube-IR extends OCTCube by incorporating 26,685 pairs of OCT and IR images, enabling accurate cross-modality retrieval and joint analysis of these two modalities. OCTCube-EF, trained on over 4 million 2D OCT slices and 400 thousand EF retinal images, excels in predicting the growth rate of geographic atrophy across datasets collected from 6 multi-centre clinical trials across 23 countries. Collectively, OCTCube-M is a 3D multi-modal foundation model framework for integrating OCT and other retinal imaging modalities. It demonstrated substantial advancements in cross-site, cross-device, cross-modality and systemic disease prediction, while offering substantial utility in geographic atrophy clinical trials.

Purpose: To evaluate visual acuity and microperimetry correlated with anatomical changes in eyes with macular diseases implanted with the EyeMax Mono intraocular lens (IOL) (SharpView Ophthalmology). Methods: A single-center retrospective, real-world case series set in Knappschaft Eye Hospital, Sulzbach, Germany. Patients with macular disease who underwent EyeMax Mono IOL implantation were included. The outcome measures were corrected distance visual acuity (CDVA) and microperimetry indices: fixation stability and bivariate contour ellipse areas (BCEAs) at 63% and 95%. The geographic atrophy (GA) monitor (RetInSight) was used to analyze changes in retinal integrity. Results: Twenty-one eyes (11 patients; mean age 72.8±8.3 years, mean follow-up 7.4±4.0 months) were included. Preoperative GA measured 4.7±4.0 mm2 (n=14) and EZ loss on SD-OCT was 2433.1±1009.5 µm (n=17). The CDVA improved by 0.2 logMAR (p=0.007, n=21), with 12 eyes gaining ≥1 line and seven eyes gaining ≥3 lines. Fixation stability improved in two eyes, stabilized in nine eyes, and worsened in four eyes. The changes in BCEA were not statistically significant. Higher preoperative BCEA correlated with greater postoperative improvement (p&lt;0.001). In the foveal fixation group (n=4), 75% and 50% of patients showed improved BCEA and CDVA, respectively. In extrafoveal fixation (n=11), BCEA improved in 50% of patients, while 64% showed CDVA improvement. The GA monitor showed worsening in 9/15 eyes, and 4 eyes showed worsening on microperimetry without a CDVA decline. Anatomical changes stabilized in six eyes; of these, two exhibited a decline in microperimetry without a CDVA decline. Conclusions: EyeMax Mono IOL improved CDVA, although no significant changes were observed in the microperimetry indices. Better microperimetry outcomes were observed in extrafoveal fixation cases. While the optical design of the IOL likely contributes to visual improvement, the small sample size limited the statistical power to detect significant microperimetry changes.

To determine the relationship between the baseline junctional retinal sensitivity measured with microperimetry and the atrophy progression rate in eyes with geographic atrophy (GA) secondary to age-related macular degeneration. In this prospective cohort study, patients with GA were examined with fundus autofluorescence (FAF) to determine the atrophy area at baseline and at follow-up of 13.1 ± 2.5 months in order to determine the atrophy progression rate. Microperimetry and optical coherence tomography (OCT) were evaluated at baseline. Microperimetry was superimposed on the baseline FAF image to determine mean junctional sensitivity. Multivariable linear regression was performed adjusting for age, presence of junctional intraretinal hyperreflective foci (HRF), subretinal drusenoid deposits (SDD) and FAF pattern. Fifty-six eyes with GA of 56 patients were included. There was a significant association between baseline junctional sensitivity and the atrophy progression rate in GA eyes (β, -8.84 μm/year/dB; 95% CI, -16.56 to -1.11; p = 0.026) tested with simple linear regression. However, when adjusting for age, structural factors and junctional FAF patterns in a multivariable linear regression model, the association between junctional sensitivity and atrophy progression rate was no longer statistically significant (β, -6.40 μm/year/dB; 95% CI, -16.04 to 3.25; p = 0.18). The diffuse trickling FAF pattern was independently and significantly associated with progression rate (p = 0.019). Microperimetric junctional sensitivity may have relevance in predicting atrophy progression rate in eyes with GA, although the FAF pattern may be of greater importance. Larger, longitudinal studies are necessary to further elucidate this relationship.

Background/Objectives: Age-related macular degeneration, particularly geographic atrophy, is a major cause of irreversible vision loss and shares pathological features with myopic chorioretinal atrophy (CRA). This study was designed as an exploratory methodological analysis to evaluate the feasibility of using the fellow eye as an internal control in early-phase clinical trials for myopic CRA. Methods: This exploratory and methodological retrospective study included eight patients (16 eyes) with myopic CRA who visited the Department of Ophthalmology at Nagoya City University Hospital between January 2010 and August 2023. Atrophic areas in both eyes were measured, and the longitudinal changes were analyzed. Three mixed-effects models were compared to assess the impact of inter-individual and inter-ocular variability on atrophic area progression. Subsequently, fixed-effects and mixed-effects models were compared using the Akaike Information Criterion (AIC). Finally, the square root of the variance ratio was calculated to quantify the contribution of inter-ocular variability to atrophic area progression. Results: In all eyes, the square root of the atrophic area increased over time. The model including random intercepts and slopes for each eye nested within patients had the lowest AIC of 69.4, suggesting that accounting for both inter-individual and inter-ocular variability improved model accuracy. The mixed-effects model had a lower AIC than the fixed-effects model, indicating a better fit. The square root of the variance ratio was 0.34 in the mixed-effects model, indicating that the inter-ocular variability was lower than the inter-individual variability, though it remained appreciable. Conclusions: This study quantitatively supports the feasibility and methodological validity of inter-ocular comparison designs for early-phase clinical trials in myopic CRA.

To investigate whether specific imaging biomarkers predict progression to neovascular AMD (nAMD) or geographic atrophy (GA) in eyes with high-risk intermediate age-related macular degeneration (iAMD) and avascular pigment epithelial detachment (PED). Prospective longitudinal cohort study of eyes with iAMD and avascular PED from the University of Colorado AMD registry (August 2014 - August 2023) with ≥1 month of follow-up through February 2024. Multimodal imaging, including color fundus photos (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT), was graded by two reviewers for presence of specific imaging biomarkers. Time-to-progression survival analysis was conducted with hazard ratios calculated. Over a median follow-up period of 35 months, 224 eyes (142 patients) were included. 31 (13.8%) eyes progressed to nAMD, and 63 (28.1%) to GA. Progression to nAMD was significantly predicted by pigmentary changes on CFP (HR=4.43 (95%CI: 1.77, 11.1), p=0.001) and intraretinal hyperreflective foci (iHRF) on OCT (HR=4.90 (95%CI: 2.02, 11.9), p=0.0005). Progression to GA was significantly predicted by pigmentary changes on CFP (HR=3.60 (95%CI: 1.94, 6.67), p<0.0001), iHRF (HR=4.13 (95%CI: 2.14, 7.94), p<0.0001), acquired vitelliform lesions (AVL; (HR=2.97 (95%CI: 1.55, 5.68), p=0.001)) and incomplete retinal pigment epithelium and outer retina atrophy (iRORA; (HR=4.18 (95%CI: 1.52, 11.4), p=0.006)). No other biomarkers demonstrated significance. In eyes with avascular PED, pigmentary changes and iHRF were significantly associated with progression to nAMD and GA, while AVL and iRORA were specifically to GA. We highlight in this study important imaging biomarkers that help identify high-risk eyes that may warrant closer monitoring to ensure timely therapeutic intervention.