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.

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.

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.

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.

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.

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.

Diagnostic accuracy of self-reported age-related macular degeneration in the ASPREE Longitudinal Study of Older Persons.

BACKGROUND: The validity of findings from epidemiological studies using self-report of ophthalmic conditions depends on several factors. We assessed the diagnostic accuracy of self-reported age-related macular degeneration (AMD) among older Australians enroled in a primary prevention clinical trial and compared diagnostic accuracy between demographic subgroups. METHODS: At baseline (2010-2015), Australian sub-study participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, underwent bilateral two-field, 45° non-mydriatic colour retinal photography. Beckman classification of any-stage AMD was used as the reference standard diagnosis. Participants were asked whether a doctor had ever diagnosed them with "macular degeneration" (the index test) via a paper-based questionnaire as part of the ASPREE Longitudinal Study of Older Persons (ALSOP) within the first year of enrolment. RESULTS: In total, 4193 participants were included (aged 70-92 years, 50.8% female). Of those, 262 (6.3%) reported having AMD and 92 (2.2%) were unsure. Retinal grading detected 2592 (61.8%) with no AMD, 867 (20.7%) with early, 686 (16.4%) with intermediate and 48 (1.1%) with late AMD (n = 1601 with any-stage AMD, 38.2%). Self-reported AMD had 11.4% sensitivity (95% CI 9.9-13.1) and 96.9% specificity (95% CI 96.2-97.6) for any-stage AMD, with 69.8% and 63.9% positive and negative predictive values. Sensitivity was higher among participants with late-stage AMD (87.5%), older participants (26.8%), and those with poorer vision (41.0%). CONCLUSIONS: Although most participants with late-stage AMD were aware of having AMD, the majority with early and intermediate AMD were not. Therefore, findings from studies that rely on disease self-report should be interpreted with caution.

HYPERREFLECTIVE FOCI NOT SEEN AS HYPERPIGMENTARY ABNORMALITIES ON COLOR FUNDUS PHOTOGRAPHS IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the prognostic value of quantifying optical coherence tomography (OCT)-defined hyperreflective foci (HRF) that do not correspond to hyperpigmentary abnormalities (HPAs) on color fundus photographs (CFPs)-HRF (OCT+/CFP-) -when considered in addition to HPA extent, for predicting late age-related macular degeneration development. This study sought to understand the impact of HRF (OCT+/CFP-) extent on visual sensitivity. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent imaging and microperimetry at baseline, and then 6-monthly for 3-years. The extent of HPAs on CFPs and HRF (OCT+/CFP-) on OCT was quantified at baseline. Predictive models for progression to late age-related macular degeneration, accounting for drusen volume and age, were developed using HPA extent, with and without HRF (OCT+/CFP-) extent. The association between HPA and HRF (OCT+/CFP-) extent with sector-based visual sensitivity was also evaluated. RESULTS: Incorporating HRF (OCT+/CFP-) extent did not improve the predictive performance for late age-related macular degeneration development ( P ≥ 0.32). Increasing HPA and HRF (OCT+/CFP-) extent in each sector were independently and significantly associated with reduced sector-based visual sensitivity ( P ≤ 0.004). CONCLUSION: The addition of HRF (OCT+/CFP-) extent to HPA extent did not improve the prediction of late age-related macular degeneration development. HRF (OCT+/CFP-) extent was also independently associated with local reductions in visual sensitivity, after accounting for HPAs.

Acute effects of caffeine and glucose intake on retinal vessel calibres in healthy volunteers.

PURPOSE: To evaluate the acute effects of caffeine and glucose intake on retinal vascular calibre of healthy adults. METHODS: This prospective crossover study was conducted at the Centre for Eye Research Australia (Melbourne, Australia). Standardized doses of 300 mg caffeine (approximately 3 cups coffee), 30 g glucose or 300 ml of water, were each given to 19 healthy subjects on separate days. Retinal photographs and blood pressure measurements were taken at baseline, 30-, 60- and 120-min after ingestion of each solution. Central retinal artery and vein equivalents (CRAE, CRVE) and the arterio-venule ratio were measured using computer-assisted software. The mean retinal vascular calibre measurements were compared between pre- and post-ingestion images. RESULTS: After caffeine intake, significant reductions were observed in mean CRAE of - 9.3 µm, - 10.4 µm and - 8.5 µm and CRVE of - 16.9 µm, - 18.7 µm and - 16.1 µm at 30-, 60- and 120-min after intake when compared with baseline (p ≤ 0.002 for all; paired t test). No significant changes were observed in mean retinal vascular calibre measurements after intake of either glucose or water when compared to baseline (p ≥ 0.072 for all). When controlling for baseline characteristics and blood pressure measurements, only caffeine intake had a significant effect on reducing both CRAE and CRVE at all time points post ingestion (p ≤ 0.003 for all, multiple linear regression model). CONCLUSION: Caffeine is associated with an acute vasoconstrictive effect on retinal arterioles and venules in healthy subjects. Factors other than blood pressure-induced autoregulation play a significant role in caffeine-associated retinal vasoconstriction.

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

PURPOSE: To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). DESIGN: Retrospective analysis of data from a longitudinal study. PARTICIPANTS: A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. METHODS: OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. MAIN OUTCOME MEASURES: Association with and variance explained in time to GA development. RESULTS: A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent or incident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P = 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P = 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2 = 43%) was significantly lower than explained by nGA alone (R2 = 91%; P = 0.010). CONCLUSIONS: In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.

Exploring Reticular Pseudodrusen Extent and Impact on Mesopic Visual Sensitivity in Intermediate Age-Related Macular Degeneration.

Purpose: To explore the impact of the extent of reticular pseudodrusen (RPD) on mesopic visual sensitivity in individuals with intermediate age-related macular degeneration (AMD). Methods: In total, 570 eyes from 285 participants with bilateral large drusen underwent microperimetry testing to assess the visual sensitivity of the central 3.6-mm region and multimodal imaging to determine the extent of RPD in the central 20° × 20° region (at the eye level). Mean visual sensitivity within five sectors in the central 3.6-mm region sampled on microperimetry and the extent of RPD in these sectors were derived. Linear mixed models were used to examine the association between the extent of RPD on overall mean visual sensitivity and sector-based mean sensitivity. Results: An increasing extent of RPD at the eye level and within sectors was associated with a significant reduction in overall and sector-based mean sensitivity, respectively (P < 0.001 for both). However, when both RPD parameters were considered together in a multivariable model, only an increasing extent of RPD at the eye level (P < 0.001) and not within each sector (P = 0.178) was independently associated with reduced sector-based mean sensitivity. Conclusions: Mesopic visual sensitivity is generally reduced in eyes with large drusen and coexistent RPD compared to eyes without RPD, with greater reductions with an increasing extent of RPD. However, reduced sector-based visual sensitivities are explained by the overall extent of RPD present, rather than their extent within the sector itself. These findings suggest that there are generalized pathogenic changes in eyes with RPD accounting for the observed mesopic visual dysfunction.

Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration.

PURPOSE: To examine the association between reticular pseudodrusen (RPD) and progression to late age-related macular degeneration (AMD) in individuals with intermediate AMD. DESIGN: Prospective cohort study. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent multimodal imaging (MMI), including optical coherence tomography (OCT), near-infrared reflectance (NIR), fundus autofluorescence, and color fundus photography (CFP), at 6-monthly intervals up over a 36-month follow-up period. The presence of RPD per eye was determined based on either a combined MMI criterion, or each individual imaging modality, and their extent measured on combined OCT and NIR imaging. The association between the presence of RPD on different imaging modalities, and their extent, with the development of late AMD (including OCT-defined atrophy) was evaluated. RESULTS: The presence of RPD on MMI, or any of its individual modalities, at baseline was not significantly associated with an increased rate of developing late AMD, with or without adjusting for risk factors for AMD progression (age, drusen volume on OCT, and pigmentary abnormalities on CFP; all P ≥ 0.205). The extent of RPD present was also not significantly associated with an increased rate of developing late AMD, with or without adjustment for risk factors for AMD progression (both P ≥ 0.522). CONCLUSIONS: In this cohort with bilateral large drusen, the presence of RPD was not significantly associated with an increased risk of developing late AMD. Additional longitudinal studies in all stages of AMD are needed to understand the implications of RPD on vision loss in this condition.

Cuticular Drusen in Age-Related Macular Degeneration: Association with Progression and Impact on Visual Sensitivity.

PURPOSE: To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration (AMD). DESIGN: Longitudinal, observational study. PARTICIPANTS: Participants aged 50 years or older, with bilateral large conventional drusen, without late AMD. METHODS: Multimodal imaging (MMI) and microperimetry were performed at baseline and then every 6 months for up to 3 years. Eyes were graded for the MMI-based presence of cuticular drusen at baseline. Color fundus photographs were used to grade for the presence of pigmentary abnormalities. OCT scans were used to calculate drusen volume. The associations between cuticular drusen and progression to MMI-defined late AMD (including OCT signs of atrophy) and the impact on visual sensitivity were examined with and without adjustment for the confounders of baseline age, pigmentary abnormalities, and drusen volume. MAIN OUTCOME MEASURES: Time to develop MMI-defined late AMD and change in mean visual sensitivity. RESULTS: A total of 280 eyes from 140 participants were included, with 70 eyes from 35 individuals (25%) having cuticular drusen at baseline. Cuticular drusen were not significantly associated with an increased rate of progression to late AMD with and without adjustment for confounders (P ≥ 0.784 for both). In an adjusted model, cuticular drusen were not associated with lower baseline visual sensitivity (P = 0.758) or a faster rate of visual sensitivity decline (P = 0.196). CONCLUSIONS: In a cohort with bilateral large conventional drusen, individuals with the cuticular drusen phenotype had neither a higher nor lower risk of developing late AMD over 3 years and were not associated with a difference in rate of visual sensitivity decline compared with those without this phenotype. As such, individuals with this phenotype currently warrant similar monitoring strategies as those with conventional drusen.

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

Hyporeflective Cores within Drusen: Association with Progression of Age-Related Macular Degeneration and Impact on Visual Sensitivity.

PURPOSE: To examine the association between hyporeflective cores within drusen (HCD) and disease progression in age-related macular degeneration (AMD) and with visual function. DESIGN: Longitudinal observational study. PARTICIPANTS: Two hundred and eighty eyes from 140 participants with bilateral large drusen, without late AMD. METHODS: Multimodal imaging and microperimetry were performed at baseline and subsequently every 6 months for up to 3 years. Baseline OCT scans were graded for the presence of HCD and used to calculate drusen volume. The total area of the drusenoid lesions containing hyporeflective cores (HCD extent) on color fundus photographs (CFPs) was calculated. CFPs were also graded for the presence of pigmentary abnormalities. The association between HCD extent with progression to late AMD (including OCT signs of atrophy) and visual sensitivity measured using microperimetry at baseline and its rate of change over time was evaluated with and without adjustment for confounders of drusen volume, pigmentary abnormalities, and age. MAIN OUTCOME MEASURES: Time to develop late AMD and visual sensitivity. RESULTS: Twenty (7%) eyes from 12 (9%) individuals were found to have HCD at baseline, which was associated with a nonsignificantly increased rate of progression to late AMD (unadjusted P = 0.050). HCD extent was significantly associated with an increased rate of progression to late AMD (unadjusted P = 0.034) and lower visual sensitivity at baseline (unadjusted P < 0.001). However, these associations were no longer significant (P ≥ 0.264 for both) after adjusting for known risk factors for AMD progression. HCD extent was also not associated with a faster rate of visual sensitivity decline before the development of late AMD, with or without adjustment (P ≥ 0.674 for both). Increasing age and larger drusen volume were associated with HCD extent (P ≤ 0.041). CONCLUSIONS: In a cohort with bilateral large drusen, HCD presence and extent were not independently associated with an increased rate of progression to late AMD over 3 years, nor with lower visual sensitivity or an increased rate of visual sensitivity decline before the development of late AMD, after adjusting for known risk factors for disease progression.

Dose Response in the Subthreshold Nanosecond Laser Trial in Early Stages of AMD: A LEAD Study Report.

BACKGROUND AND OBJECTIVE: To examine the association between treatment parameters and the progression to late age-related macular degeneration (AMD) in the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a randomized, controlled trial of a subthreshold nanosecond laser (SNL) for slowing disease progression in the early stages of AMD. PATIENTS AND METHODS: The association between treatment parameters early in the trial period for participants in the SNL arm of the LEAD study and time to develop late AMD during the 3-year trial duration was examined. Parameters included treatment energy at the baseline and 6-month visits and the number of laser spots visible on fundus autofluorescence (FAF) imaging taken at 6 and 12 months (taken as a proxy measure of early, adequate delivery of the laser treatment at the baseline and 6-month visits, respectively). RESULTS: A multivariable analysis revealed there were no significant associations between time to develop late AMD and number of FAF-visible laser spots at 6-months (adjusted P = .537) nor laser energy used at baseline (adjusted P = .910). No significant associations were also observed when evaluating FAF-visible spots at 12-months (adjusted P = .107) and the average laser energy used at baseline and 6 months (adjusted P = .558). CONCLUSIONS: This study did not find any evidence to suggest that there was a dose response for the effect of laser treatment using these treatment parameters on the progression of AMD. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:380-386.].

Deep Learning Applied to Automated Segmentation of Geographic Atrophy in Fundus Autofluorescence Images.

Purpose: This study describes the development of a deep learning algorithm based on the U-Net architecture for automated segmentation of geographic atrophy (GA) lesions in fundus autofluorescence (FAF) images. Methods: Image preprocessing and normalization by modified adaptive histogram equalization were used for image standardization to improve effectiveness of deep learning. A U-Net-based deep learning algorithm was developed and trained and tested by fivefold cross-validation using FAF images from clinical datasets. The following metrics were used for evaluating the performance for lesion segmentation in GA: dice similarity coefficient (DSC), DSC loss, sensitivity, specificity, mean absolute error (MAE), accuracy, recall, and precision. Results: In total, 702 FAF images from 51 patients were analyzed. After fivefold cross-validation for lesion segmentation, the average training and validation scores were found for the most important metric, DSC (0.9874 and 0.9779), for accuracy (0.9912 and 0.9815), for sensitivity (0.9955 and 0.9928), and for specificity (0.8686 and 0.7261). Scores for testing were all similar to the validation scores. The algorithm segmented GA lesions six times more quickly than human performance. Conclusions: The deep learning algorithm can be implemented using clinical data with a very high level of performance for lesion segmentation. Automation of diagnostics for GA assessment has the potential to provide savings with respect to patient visit duration, operational cost and measurement reliability in routine GA assessments. Translational Relevance: A deep learning algorithm based on the U-Net architecture and image preprocessing appears to be suitable for automated segmentation of GA lesions on clinical data, producing fast and accurate results.