Deep Neural Networks for Automated Outer Plexiform Layer Subsidence Detection on Retinal OCT of Patients With Intermediate AMD.

Purpose: The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker. Methods: The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively. Results: The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set. Conclusions: DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections. Translational Relevance: DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Gene and cell therapy for age-related macular degeneration: A review.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years.

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

BACKGROUND: To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. METHODS: Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. RESULTS: The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p ≤ 0.002). CONCLUSIONS: Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

Complete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: A Longitudinal Evaluation.

PURPOSE: There is a need for robust earlier biomarkers of atrophic age-related macular degeneration (AMD) that could act as surrogate endpoints for the geographic atrophy (GA) in early interventional trials. This study sought to examine the risk of progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) to the traditional atrophic endpoint of GA on color fundus photography (CFP). This study also compared the risk of progression for cRORA to that associated with the specific OCT features that define nascent GA (nGA), a strong predictor for GA development. METHODS: One-hundred and forty participants with bilateral large drusen at baseline underwent OCT imaging and CFP at 6-monthly intervals for up to 36 months. OCT volume scans were graded for the presence of cRORA and nGA, and CFPs were graded for the presence of GA. The association and rate of progression to GA for cRORA and nGA were examined. RESULTS: Both cRORA and nGA were significantly associated with GA development (adjusted hazard ratio [HR], 65.7 and 76.8 respectively; both P<0.001). The probability of progression of cRORA to GA over 24-months (26%) was significantly lower than the probability for progression of nGA (38%; P=0.039). CONCLUSIONS: This study confirmed that cRORA was a significant risk factor for developing GA, although its rate of progression was slightly lower compared to nGA. Whilst requiring replication in future studies, these findings suggest that the specific features of photoreceptor degeneration used to define nGA appear important when assessing risk of progression.

Inter-night variability of in-home, overnight pulse oximetry screening in an asymptomatic older adult population.

PURPOSE: Obstructive sleep apnoea (OSA) is common, yet often undiagnosed. Self-administered, overnight pulse oximetry (OPO) could screen for OSA in asymptomatic, older populations. However, the inter-night variability of OPO in an asymptomatic, older population is unknown. We determined the inter-night variability of home OPO parameters in an older population and correlated with sleep questionnaires. METHODS: Participants > 50 years without a diagnosis of OSA undertook home OPO for three consecutive nights and completed two sleep questionnaires (STOP-BANG (SBQ) and Epworth Sleepiness Score (ESS)). Analysis was performed with linear mixed models and Spearman's correlation coefficient. RESULTS: There was no difference in oxygen desaturation index (ODI), MeanSpO2, MinimumSpO2, and time spent with SpO2 < 90% (T90) across two or three nights (P ≥ 0.282). However, the variability of all parameters across nights increased with the magnitude of departure from normal values (P ≤ 0.002). All OPO parameters were associated with age (P ≤ 0.034) and body mass index (P ≤ 0.049). There was a weak correlation between three OPO parameters and SBQ (absolute ρ = 0.22 to 0.32; P ≤ 0.021), but not ESS (P ≥ 0.254). CONCLUSION: Inter-night variability of home OPO was minimal when values were near-normal in an older population. However, as values depart from normal, the inter-night variability increases, indicating the need for multiple night recordings. Low correlation to sleep questionnaires suggest the need for more robust OSA questionnaires in an asymptomatic population.

Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration.

PURPOSE: A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. METHODS: We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. MAIN OUTCOME MEASURES: Association of PRS2023 and PRS2016 with AMD risk at baseline. RESULTS: At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41-7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%-95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). CONCLUSIONS: A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Choroidal signal hypertransmission on optical coherence tomography imaging: Association with development of geographic atrophy in age-related macular degeneration.

BACKGROUND: To examine the association between large choroidal signal hypertransmission ≥250 µm (LHyperT) on optical coherence tomography (OCT) with the risk of developing geographic atrophy (GA) and compare this risk with those associated with nascent geographic atrophy (nGA). METHODS: Two hundred and eighty eyes from 140 participants with bilateral large drusen and without late age-related macular degeneration (AMD) or nGA at baseline underwent OCT imaging and colour fundus photography (CFP) at 6-monthly intervals up to 5 years. OCT scans were graded for the presence of LHyperT and nGA, and CFPs were graded for the presence of GA. RESULTS: The five-year incidence of LHyperT and nGA were 37% and 27% respectively (p = 0.003), and the two-year probability of their progression to GA were 17% and 40%, respectively (p = 0.002). LHyperT and nGA explained 81% and 91% of the variance in the time to develop GA, respectively (p = 0.032), and they were both associated with a significantly higher rate of GA development compared to eyes without these lesions (adjusted hazard ratio = 110.8 and 183.2, respectively; p < 0.001 for both). CONCLUSIONS: LHyperT and nGA were both high-risk features for GA development, but the latter showed a higher rate of GA progression and explained a significantly greater proportion of the variance in the time to develop GA. As such, nGA may be a more robust surrogate endpoint than LHyperT for the conventional clinical endpoint of CFP-defined GA for intervention trials in the early stages of AMD.

Visual Sensitivity Loss in Geographic Atrophy: Structure-Function Evaluation Using Defect-Mapping Microperimetry.

Purpose: To examine the structure-function relationship in eyes with geographic atrophy (GA) using defect-mapping microperimetry, a testing strategy optimized to quantify the spatial extent of deep visual sensitivity losses. Methods: Fifty participants with GA underwent defect-mapping microperimetry testing of the central 8°-radius region (208 locations tested once with a 10-decibel stimuli) and fundus autofluorescence imaging in one eye. The GA extent in the corresponding central 8°-radius was derived by manual annotations and image co-registration to examine the global structure-function relationship. The distance of each test location from the GA margin was also derived, and regions defined, to examine the local structure-function relationship. Results: GA extent in the central 8° explained a substantial proportion of variance in the percentage of locations missed (nonresponse) on microperimetry at the global level (R2 = 0.90). At a local level, the probability of missing stimuli at the outer junctional zone (0-500 µm outside the GA margin) and GA margin (probability = 7% and 34%, respectively) was higher than at the outer nonlesional zone (>500 µm outside the GA margin; probability = 2%; P < 0.001 for both). The probability of missing stimuli at the inner junctional zone (0-250 µm inside the GA margin) was also lower than at the inner lesional zone (>250 µm inside the GA margin; probability = 64% and 88%; P < 0.001). Conclusions: This study confirms the expected functional relevance of the region with GA on fundus autofluorescence imaging and underscores the potential effectiveness of defect-mapping microperimetry testing for capturing visual function changes when evaluating new GA treatments.

Functional Evaluation of Retinal Pigment Epithelium and Outer Retinal Atrophy by High-Density Targeted Microperimetry Testing.

Purpose: Complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA) on OCT imaging has recently been proposed to describe end-stage atrophy in age-related macular degeneration (AMD) by international consensus and expected to be associated with a dense scotoma, but such functional evidence is lacking. This study sought to examine the visual sensitivity defects associated with cRORA and to determine OCT features associated with deep defects. Design: Observational study. Participants: Sixty eyes from 53 participants, including 342 microperimetry tests over 171 study visits. Methods: Participants underwent targeted high-density threshold-based microperimetry testing of atrophic lesions (with at least incomplete RPE and outer retinal atrophy [iRORA]) with a 3.5° diameter grid. The maximum extent of signs of atrophy for all lesions was graded on OCT imaging. Main Outcome Measures: Number of deep visual sensitivity defects (threshold ≤ 10 decibels [dB]). Results: Presence of choroidal signal hypertransmission ≥ 500 µm, complete RPE loss ≥250 µm, and inner nuclear layer and outer plexiform layer subsidence, and hyporeflective wedge-shaped band (defined as nascent geographic atrophy [nGA]) ≥ 500 µm (P ≤ 0.020), but not RPE attenuation or disruption (P ≥ 0.192), were all independently associated with a significant increase in the number of deep visual sensitivity defects ≤ 10 dB. Only cRORA lesions with hypertransmission ≥ 500 µm or complete RPE loss ≥ 250 µm, or with both of these features (P < 0.001), but not lesions with only hypertransmission 250-499 µm (P = 0.303), had significantly more deep visual sensitivity defects ≤ 10 dB compared with iRORA lesions. Lesions with nGA ≥ 500 µm, irrespective of the presence of hypertransmission ≥ 500 µm and/or complete RPE loss ≥ 250 µm, also showed a higher number of deep visual sensitivity defects ≤ 10 dB compared with lesions without nGA ≥ 500 µm (P ≤ 0.011). Conclusions: Not all cRORA lesions show a difference in the number of deep visual sensitivity defects compared with iRORA. Instead, hypertransmission ≥ 500 µm, complete RPE loss ≥ 250 µm, and nGA ≥ 500 µm are all OCT features independently associated with deep visual sensitivity detects that could help inform the definition of end-stage atrophy on OCT imaging. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Targeted High-Density Microperimetry Testing of Nascent Geographic Atrophy in Age-Related Macular Degeneration.

Purpose: To examine the effectiveness of a targeted high-density microperimetry testing strategy for detecting visual sensitivity abnormalities in eyes with nascent geographic atrophy (nGA) when compared with standard central microperimetry testing. Design: Observational study. Participants: Three-hundred and twenty-one eyes from 176 individuals with nonneovascular age-related macular degeneration (AMD). Methods: Thirty-five eyes from 33 participants underwent targeted high-density microperimetry testing of atrophic lesions (either nGA or geographic atrophy [GA]) within a 1.75° radius (or approximately 1000 µm diameter) region. Another cohort of 286 eyes from 143 participants with bilateral large drusen at baseline underwent standard microperimetry testing of the central 6° radius region at 6-monthly intervals for up to 36 months and thus included eyes that developed nGA and GA over the follow-up. All eyes underwent 2 tests at each visit to evaluate intrasession measurement repeatability. Main Outcome Measures: Magnitude of visual sensitivity abnormalities based on mean sensitivity (MS), pointwise sensitivity standard deviation (PSD), and the number of test locations with a threshold of ≤ 10 decibels (dB; or deep defects) in eyes with nGA, compared between eyes that underwent targeted high-density microperimetry testing and standard central microperimetry testing. Results: The magnitude of visual sensitivity abnormalities based on MS, PSD and the number of deep defects were all significantly greater in eyes with nGA using targeted, high-density microperimetry testing compared with eyes with nGA using standard central microperimetry testing (all P < 0.001) and were all significantly less than eyes with GA using targeted, high-density microperimetry testing (all P ≤ 0.004). The intrasession coefficient of repeatability, where 95% of the test-retest differences are expected to occur, for MS in eyes with atrophic changes was 0.9 dB with the targeted, high-density microperimetry testing, and 1.8 dB with standard central microperimetry testing. Conclusions: Targeted, high-density microperimetry testing enabled the detection of a significantly greater magnitude of visual sensitivity abnormalities in eyes with nGA than standard microperimetry testing. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Deep Learning Approaches for Detecting of Nascent Geographic Atrophy in Age-Related Macular Degeneration.

Purpose: Nascent geographic atrophy (nGA) refers to specific features seen on OCT B-scans, which are strongly associated with the future development of geographic atrophy (GA). This study sought to develop a deep learning model to screen OCT B-scans for nGA that warrant further manual review (an artificial intelligence [AI]-assisted approach), and to determine the extent of reduction in OCT B-scan load requiring manual review while maintaining near-perfect nGA detection performance. Design: Development and evaluation of a deep learning model. Participants: One thousand eight hundred and eighty four OCT volume scans (49 B-scans per volume) without neovascular age-related macular degeneration from 280 eyes of 140 participants with bilateral large drusen at baseline, seen at 6-monthly intervals up to a 36-month period (from which 40 eyes developed nGA). Methods: OCT volume and B-scans were labeled for the presence of nGA. Their presence at the volume scan level provided the ground truth for training a deep learning model to identify OCT B-scans that potentially showed nGA requiring manual review. Using a threshold that provided a sensitivity of 0.99, the B-scans identified were assigned the ground truth label with the AI-assisted approach. The performance of this approach for detecting nGA across all visits, or at the visit of nGA onset, was evaluated using fivefold cross-validation. Main Outcome Measures: Sensitivity for detecting nGA, and proportion of OCT B-scans requiring manual review. Results: The AI-assisted approach (utilizing outputs from the deep learning model to guide manual review) had a sensitivity of 0.97 (95% confidence interval [CI] = 0.93-1.00) and 0.95 (95% CI = 0.87-1.00) for detecting nGA across all visits and at the visit of nGA onset, respectively, when requiring manual review of only 2.7% and 1.9% of selected OCT B-scans, respectively. Conclusions: A deep learning model could be used to enable near-perfect detection of nGA onset while reducing the number of OCT B-scans requiring manual review by over 50-fold. This AI-assisted approach shows promise for substantially reducing the current burden of manual review of OCT B-scans to detect this crucial feature that portends future development of GA. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessment of Choriocapillaris Flow Prior to Nascent Geographic Atrophy Development Using Optical Coherence Tomography Angiography.

Purpose: To assess the relationship between choriocapillaris (CC) loss and the development of nascent geographic atrophy (nGA) using optical coherence tomography angiography (OCTA) imaging. Methods: In total, 105 from 62 participants with bilateral large drusen, without late age-related macular degeneration (AMD) or nGA at baseline, were included in this prospective, longitudinal, observational study. Participants underwent swept-source OCTA imaging at 6-month intervals. CC flow deficit percentage (FD%) and drusen volume measurements were determined for the visit prior to nGA development or the second-to-last visit if nGA did not develop. Global and local analyses, the latter based on analyses within superpixels (120 × 120-µm regions), were performed to examine the association between CC FD% and future nGA development. Results: A total of 15 (14%) eyes from 12 (19%) participants developed nGA. There was no significant difference in global CC FD% at the visit prior to nGA development between eyes that developed nGA and those that did not (P = 0.399). In contrast, CC FD% was significantly higher in superpixels that subsequently developed nGA compared to those that did not (P < 0.001), and a model utilizing CC FD% was significantly better at predicting foci of future nGA development at the superpixel level than a model using drusen volume alone (P ≤ 0.040). Conclusions: This study showed that significant impairments in CC blood flow could be detected locally prior to the development of nGA. These findings add to our understanding of the pathophysiologic changes that occur with atrophy development in AMD.

Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

PURPOSE: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. RESULTS: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. CONCLUSION: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.