Age-Related Eye Disease Study Research Articles

Outer Retinal Thickness Is Associated With Cognitive Function in Normal Aging to Intermediate Age-Related Macular Degeneration.

Research on Alzheimer's disease (AD) and precursor states demonstrates a thinner retinal nerve fiber layer (NFL) compared to age-similar controls. Because AD and age-related macular degeneration (AMD) both impact older adults and share risk factors, we asked if retinal layer thicknesses, including NFL, are associated with cognition in AMD. Adults ≥ 70 years with normal retinal aging, early AMD, or intermediate AMD per Age-Related Eye Disease Study (AREDS) nine-step grading of color fundus photography were enrolled in a cross-sectional study. Optical coherence tomography (OCT) volumes underwent 11-line segmentation and adjustments by a trained operator. Evaluated thicknesses reflect the vertical organization of retinal neurons and two vascular watersheds: NFL, ganglion cell layer-inner plexiform layer complex (GCL-IPL), inner retina, outer retina (including retinal pigment epithelium-Bruch's membrane), and total retina. Thicknesses were area weighted to achieve mean thickness across the 6-mm-diameter Early Treatment of Diabetic Retinopathy Study (ETDRS) grid. Cognitive status was assessed by the National Institutes of Health Toolbox cognitive battery for fluid and crystallized cognition. Correlations estimated associations between cognition and thicknesses, adjusting for age. Based on 63 subjects (21 per group), thinning of the outer retina was significantly correlated with lower cognition scores (P < 0.05). No other retinal thickness variables were associated with cognition. Only the outer retina (photoreceptors, supporting glia, retinal pigment epithelium, Bruch's membrane) is associated with cognition in aging to intermediate AMD; NFL was not associated with cognition, contrary to AD-associated condition reports. Early and intermediate AMD constitute a retinal disease whose earliest, primary impact is in the outer retina. Our findings hint at a unique impact on the brain from the outer retina in persons with AMD.

Nutritional Supplements for Healthy Aging: A Critical Analysis Review

Background: Healthy aging is defined as survival to advanced age while retaining autonomy in activities of daily living, high societal participation, and good quality of life. Sarcopenia, insomnia, cognitive impairment, and changes in sensation can be key hinderances to healthy aging, but nutritional supplements may abate their impact. As research advances, an updated review on their efficacy on age-related conditions is warranted. Results: Sarcopenia can be mitigated through proper protein intake, supplements like creatine, and in certain situations Branched-Chain Amino Acids and Vitamin D, in adults over 65. Melatonin supplementation has moderate evidence for improving sleep, while valerian root lacks evidence. Magnesium, tart cherry, and kiwifruits have shown promising impacts on sleep in limited articles. Magnesium, Vitamin D, and B vitamin supplementation have been shown to improve cognition in those with mild cognitive impairment and Alzheimer’s disease but require further study prior to recommendation. The Age-Related Eye Disease Study supplement combination is routinely recommended to reduce risk of progression to advance stages of age-related macular degeneration. Alpha-Lipoic Acid and Folate have been investigated for their roles in mitigating age-related hearing losses. Conclusions: Nutritional supplements and lifestyle changes may mitigate disabilities across multiple domains of age-related illnesses and promote healthy aging.

An Updated Simplified Severity Scale for Age-Related Macular Degeneration, Incorporating Reticular Pseudodrusen: Age-Related Eye Disease Study Report No. 42

PurposeTo update the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale for risk of late age-related macular degeneration (AMD), including incorporation of reticular pseudodrusen (RPD), and to perform external validation on the AREDS2. DesignPost hoc analysis of two clinical trial cohorts: AREDS and AREDS2. ParticipantsParticipants with no late AMD in either eye at baseline in AREDS (n=2719) and AREDS2 (n=1472). MethodsFive-year rates of progression to late AMD were calculated according to levels 0-4 on the Simplified Severity Scale, following two updates: (i) non-central GA considered part of the outcome rather than a risk feature, and (ii) scale separation according to RPD status (determined by validated deep learning grading of color fundus photographs).Main outcome measures:Five-year rate of progression to late AMD (defined as neovascular AMD or any GA). ResultsIn the AREDS, following the first scale update, the five-year rates of progression to late AMD for levels 0-4 were 0.3%, 4.5%, 12.9%, 32.2%, and 55.6%, respectively. Following both updates, the proportion progressing to late AMD by five years was 8.4% in participants without RPD and 40.6% in those with RPD. As the final Simplified Severity Scale, the five-year progression rates for levels 0-4, respectively, were 0.3%, 4.3%, 11.6%, 26.7%, and 50.0%, for participants without RPD at baseline, and 2.8%, 8.0%, 29.0%, 58.7%, and 72.2%, for participants with RPD at baseline. In external validation on the AREDS2, for levels 2-4, the progression rates were similar, at 15.0%, 27.7%, and 45.7% (RPD absent) and 26.2%, 46.0%, and 73.0% (RPD present), respectively. ConclusionsThe AREDS AMD Simplified Severity Scale has been modernized with two important updates. The new scale for individuals without RPD has five-year progression rates of ∼0.5%, 4%, 12%, ∼25%, and 50%, such that the rates on the original scale remain accurate. The new scale for individuals with RPD has five-year progression rates of 3%, 8%, ∼30%, ∼60%, and ∼70%, i.e., approximately double for most levels. This scale fits updated definitions of late AMD, has increased prognostic accuracy, appears generalizable to similar populations, but remains simple for broad risk categorization.

Age-related macular degeneration discordance in monozygotic twin pairs.

To examine age-related macular degeneration (AMD) and retinal pigment epithelium (RPE)-Bruch's membrane (BrM) complex volume associations in monozygotic twin pairs. In this study, 106 elderly twins (53 twin pairs) from the Finnish Twin Cohort study were recruited. Each participant underwent dilated 35-degree digital colour fundus photography (CFP), and spectral domain optical coherence tomography (OCT) and replied to a structured study questionnaire. The CFPs were graded according to the Age-Related Eye Disease Study (AREDS) classification. The OCT images were segmented and volumetric data of the RPE-BrM complex volume was calculated with the Orion™ software. The worse eye according to AREDS classification was used for the analysis. Twenty-nine (55%) of the twin pairs were discordant with regard to AREDS classification. Fourteen (26%) pairs were discordant with one twin participant having AMD (AREDS 2-4) and the other being unaffected (AREDS 1). Four (8%) pairs had one twin participant with intermediate or late AMD (AREDS 3-4) versus the other being unaffected (AREDS 1). The within-pair polychoric correlation for AREDS was 0.605 (95% confidence interval 0.418-0.792). In multivariate analysis intermediate and late AMD as well as age associated with RPE-BrM complex volume. RPE-BrM complex volume showed a within twin pair correlation, r = 0.430 (95% confidence interval 0.172-0.688, p < 0.01). A substantial proportion of monozygotic twin pairs are discordant with regard to age-related macular degeneration phenotype. RPE-BrM complex volume associated with age and intermediate and late AMD.

Comparing 2-dimensional macular pigment optical density with objective and subjective perimetry and visual acuity in age-related macular degeneration.

To compare diagnostic power for different severities of age-related macular degeneration (AMD) of two-dimensional macular pigment optical densities (2D-MPOD) and spatially matched objective perimetry, with standard perimetry and best-corrected visual acuity (BCVA). The ObjectiveField Analyser (OFA) provided objective perimetry, and a Heidelberg Spectralis optical coherence tomography (OCT) measured 2D-MPOD in AMD patients, both completed twice over 0.99 ± 0.16years. From each 2D-MPOD image, we extracted 20 regions/macula, matched to the 20 OFA stimuli/macula. For each region, we calculated 7 measures from the 2D-MPOD pixel values and correlated those with OFA sensitivities and delays. We quantified 2D-MPOD changes, the ability of 2D-MPOD and OFA to discriminate AMD stages, and the discriminatory power of Matrix perimetry and BCVA using percentage area under receiver operator characteristic plots (%AUROC). In 58 eyes of 29 subjects (71.6 ± 6.3years, 22 females), we found significant correlations between 2D-MPOD and OFA sensitivities for Age-Related Eye Disease Studies (AREDS)-3 and AREDS-4 severities. Delays showed significant correlations with AREDS-2. For AREDS-4, correlations extended across all eccentricities. Regression associated with the Bland-Altman plots showed significant changes in 2D-MPOD over the study period, especially variability measures. MPOD per-region medians discriminated AREDS-1 from AREDS-3 eyes at a %AUROC of 80.0 ± 6.3%, outperforming OFA, Matrix perimetry, and BCVA. MPOD changes correlated with central functional changes and significant correlations extended peripherally in later-stage AMD. Good diagnostic power for earlier-stage AMD and significant change over the study suggest that 2D-MPOD and OFA may provide effective biomarkers.

Saffron therapy for the ongoing treatment of age-related macular degeneration

ObjectiveTo assess the long-term efficacy and safety of oral saffron, a natural antioxidant, in treating mild/moderate age-related macular degeneration (AMD).Methods and analysisOpen-label, extension trial of 93 adults (>50 years) with...

Genetics and Age-Related Macular Degeneration: A Practical Review for Clinicians.

Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in complement factor H (CFH) and age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase-1 (ARMS2/HTRA1). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care.

A deep network DeepOpacityNet for detection of cataracts from color fundus photographs

BackgroundCataract diagnosis typically requires in-person evaluation by an ophthalmologist. However, color fundus photography (CFP) is widely performed outside ophthalmology clinics, which could be exploited to increase the accessibility of cataract screening by automated detection.MethodsDeepOpacityNet was developed to detect cataracts from CFP and highlight the most relevant CFP features associated with cataracts. We used 17,514 CFPs from 2573 AREDS2 participants curated from the Age-Related Eye Diseases Study 2 (AREDS2) dataset, of which 8681 CFPs were labeled with cataracts. The ground truth labels were transferred from slit-lamp examination of nuclear cataracts and reading center grading of anterior segment photographs for cortical and posterior subcapsular cataracts. DeepOpacityNet was internally validated on an independent test set (20%), compared to three ophthalmologists on a subset of the test set (100 CFPs), externally validated on three datasets obtained from the Singapore Epidemiology of Eye Diseases study (SEED), and visualized to highlight important features.ResultsInternally, DeepOpacityNet achieved a superior accuracy of 0.66 (95% confidence interval (CI): 0.64–0.68) and an area under the curve (AUC) of 0.72 (95% CI: 0.70–0.74), compared to that of other state-of-the-art methods. DeepOpacityNet achieved an accuracy of 0.75, compared to an accuracy of 0.67 for the ophthalmologist with the highest performance. Externally, DeepOpacityNet achieved AUC scores of 0.86, 0.88, and 0.89 on SEED datasets, demonstrating the generalizability of our proposed method. Visualizations show that the visibility of blood vessels could be characteristic of cataract absence while blurred regions could be characteristic of cataract presence.ConclusionsDeepOpacityNet could detect cataracts from CFPs in AREDS2 with performance superior to that of ophthalmologists and generate interpretable results. The code and models are available at https://github.com/ncbi/DeepOpacityNet (https://doi.org/10.5281/zenodo.10127002).

Retinal pigment epithelium-Bruch's membrane volume in grading of age-related macular degeneration.

To assess the agreement of optical coherence tomography (OCT) algorithm-based retinal pigment epithelium -Bruch's membrane complex volume (RBV) with fundus photograph-based age-related macular degeneration (AMD) grading. Digital color fundus photographs (CFPs) and spectral domain OCT images were acquired from 96 elderly subjects. CFPs were graded according to Age-Related Eye Disease Study (AREDS) classification. OCT image segmentation and RBV data calculation were done with Orion™ software. Univariate and multivariate analyses were performed to find out whether AMD lesion features associated with higher RBVs. RBV correlated with AMD grading (rs=0.338, P=0.001), the correlation was slightly stronger in early AMD (n=52; rs=0.432, P=0.001). RBV was higher in subjects with early AMD compared with those with no AMD lesions evident in fundus photographs (1.05±0.20 vs 0.96±0.13 mm3, P=0.023). In multivariate analysis higher RBVs were associated significantly with higher total drusen (β=0.388, P=0.027) and pigmentation areas (β=0.319, P=0.020) in fundus photographs, whereas depigmentation area (β=-0.295, P=0.015) associated with lower RBV. RBV correlate with AMD grading status, with a stronger association in patients with moderate, non-late AMD grades. This effect is driven mostly by lesions with drusen or pigmentation. Lesions with depigmentation tend to have lower values. RBV is more comprehensive measurement of the key area of AMD pathogenesis, compared to sole drusen volume analysis. RBV measurements are independent on grader variations and offer a possibility to quantify early and middle grade AMD lesions in a research setting, but may not substitute fundus photograph-based grading in the whole range of AMD spectrum.

Vitamin E and Supplements Offer Eye Neuroprotection – Myth or Reality?

Background: Several studies suggested that nutrition might have an effect on eye health. Although exposure to nutrients is ubiquitous, on the other hand without it, we generally cannot survive and an exposure too high or too low causes health problems. Vitamins are a good example and the ubiquitous exposure to vitamins has led to many epidemiological studies for many diseases, including glaucoma.&#x0D; Abstract: Leading causes of vision loss include several eye conditions such as cataract and glaucoma. The role of nutritional supplementation to prevent the progression of ocular disease is of great interest to health care professionals. It is recognized that the crystalline lens and retina suffer oxidative damage and the most protective agents are anti-oxidant vitamins A, C and E. The Age-Related Eye Disease Study (AREDS), found that supplementation with vitamins C and E, reduced the risk of developing various ocular diseases. The RDA for vitamin E is 15 mg/day α-tocopherol for both women and men. Vitamin E exists naturally in nuts and seeds, in addition to dark leafy vegetables. In a recent study reported lower plasma levels of vitamin E in POAG subjects.&#x0D; Conclusion: In conclusion, exposure to nutrients although is ubiquitous, without it, in general we cannot survive. Conflicting evidence is presented for vitamins A and E in prevention of ocular disease. A number of epidemiological studies showed an increased risk of nuclear or cortical cataract in people with low blood levels of vitamin E. Furthermore, a number of studies suggested that nutrition might have an effect on the intraocular pressure (IOP) or glaucoma, arbitrated by oxidative stress.

A Deep-Learning Algorithm to Predict Short-Term Progression to Geographic Atrophy on Spectral-Domain Optical Coherence Tomography

The identification of patients at risk of progressing from intermediate age-related macular degeneration (iAMD) to geographic atrophy (GA) is essential for clinical trials aimed at preventing disease progression. DeepGAze is a fully automated and accurate convolutional neural network-based deep learning algorithm for predicting progression from iAMD to GA within 1 year from spectral-domain optical coherence tomography (SD-OCT) scans. To develop a deep-learning algorithm based on volumetric SD-OCT scans to predict the progression from iAMD to GA during the year following the scan. This retrospective cohort study included participants with iAMD at baseline and who either progressed or did not progress to GA within the subsequent 13 months. Participants were included from centers in 4 US states. Data set 1 included patients from the Age-Related Eye Disease Study 2 AREDS2 (Ancillary Spectral-Domain Optical Coherence Tomography) A2A study (July 2008 to August 2015). Data sets 2 and 3 included patients with imaging taken in routine clinical care at a tertiary referral center and associated satellites between January 2013 and January 2023. The stored imaging data were retrieved for the purpose of this study from July 1, 2022, to February 1, 2023. Data were analyzed from May 2021 to July 2023. A position-aware convolutional neural network with proactive pseudointervention was trained and cross-validated on Bioptigen SD-OCT volumes (data set 1) and validated on 2 external data sets comprising Heidelberg Spectralis SD-OCT scans (data sets 2 and 3). Prediction of progression to GA within 13 months was evaluated with area under the receiver-operator characteristic curves (AUROC) as well as area under the precision-recall curve (AUPRC), sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. The study included a total of 417 patients: 316 in data set 1 (mean [SD] age, 74 [8]; 185 [59%] female), 53 in data set 2, (mean [SD] age, 83 [8]; 32 [60%] female), and 48 in data set 3 (mean [SD] age, 81 [8]; 32 [67%] female). The AUROC for prediction of progression from iAMD to GA within 1 year was 0.94 (95% CI, 0.92-0.95; AUPRC, 0.90 [95% CI, 0.85-0.95]; sensitivity, 0.88 [95% CI, 0.84-0.92]; specificity, 0.90 [95% CI, 0.87-0.92]) for data set 1. The addition of expert-annotated SD-OCT features to the model resulted in no improvement compared to the fully autonomous model (AUROC, 0.95; 95% CI, 0.92-0.95; P = .19). On an independent validation data set (data set 2), the model predicted progression to GA with an AUROC of 0.94 (95% CI, 0.91-0.96; AUPRC, 0.92 [0.89-0.94]; sensitivity, 0.91 [95% CI, 0.74-0.98]; specificity, 0.80 [95% CI, 0.63-0.91]). At a high-specificity operating point, simulated clinical trial recruitment was enriched for patients progressing to GA within 1 year by 8.3- to 20.7-fold (data sets 2 and 3). The fully automated, position-aware deep-learning algorithm assessed in this study successfully predicted progression from iAMD to GA over a clinically meaningful time frame. The ability to predict imminent GA progression could facilitate clinical trials aimed at preventing the condition and could guide clinical decision-making regarding screening frequency or treatment initiation.

Association of macular pigment optical density with retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma

ObjectiveTo investigate associations between baseline macular pigment optical density (MPOD) and retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma (POAG) in the Carotenoids in Age-Related Eye...

Choriocapillaris Impairment Is Associated With Delayed Rod-Mediated Dark Adaptation in Age-Related Macular Degeneration.

Progress toward treatment and prevention of age-related macular degeneration (AMD) requires imaging end points that relate to vision. We investigated choriocapillaris flow signal deficits (FD%) and visual function in eyes of individuals aged ≥60 years, with and without AMD. One eye of each participant in the baseline visit of the Alabama Study on Early Age-Related Macular Degeneration 2 (ALSTAR2; NCT04112667) was studied. AMD presence and severity was determined using the Age-Related Eye Disease Study (AREDS) grading system. FD% was quantified using macular spectral domain optical coherence tomography angiography (OCTA) scans. Vision tests included rod-mediated dark adaptation (RMDA), best-corrected visual acuity, and contrast sensitivity (photopic and mesopic), and microperimetric light sensitivity (scotopic, mesopic, and photopic). Presence of subretinal drusenoid deposits (SDD) was determined using multimodal imaging. In 410 study eyes of 410 participants (mean [SD] age = 71.7 years [5.9]), FD% was higher in early AMD (mean [SD] = 54.0% [5.5], N = 122) and intermediate AMD (59.8% [7.4], N = 92), compared to normal (52.1% [5.3], N = 196) eyes. Among visual functions evaluated, RMDA showed the strongest association with FD% (r = 0.35, P < 0.0001), followed by contrast sensitivity (r = -0.22, P < 0.0001). Eyes with SDD had worse FD% (58.3% [7.4], N = 87), compared to eyes without SDD (53.4% [6.0], N = 323, P = < 0.0001). Choriocapillaris FD% were associated with AMD severity and with impaired vision, especially RMDA. Reduced metabolic transport and exchange across the choriocapillaris-Bruch's membrane retinal pigment epithelium (RPE) complex, a causal factor for high-risk soft drusen formation, also may impair photoreceptor sustenance from the circulation. This includes retinoid resupply, essential to dynamic rod function.

Critical Dependence on Area in Relationship between ARMS2/HTRA1 Genotype and Faster Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report Number 33

To analyze ARMS2/HTRA1 as a risk factor for faster geographic atrophy (GA) enlargement according to (1) GA area and (2) contiguous enlargement versus progression to multifocality. Age-Related Eye Disease Study 2 (AREDS2) cohort analysis. Eyes with GA: 546 eyes of 406 participants. Geographic atrophy area was measured from color fundus photographs at annual visits. Mixed-model regression of square root of GA area and proportional hazards regression of progression to multifocality were analyzed by ARMS2 genotype. Change in square root GA area and progression to multifocality. Geographic atrophy enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.224 mm/year (95% CI, 0.195-0.252 mm/year), 0.298 mm/year (95% CI, 0.271-0.324 mm/year), and 0.317 mm/year (95% CI, 0.279-0.355 mm/year), for 0 to 2 risk alleles, respectively. However, a significant interaction (P= 0.011) was observed between genotype and baseline area. In eyes with very small area (< 1.9 mm2), enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.193 mm/year (95% CI, 0.162-0.225 mm/year) versus 0.304 mm/year (95% CI, 0.280-0.329 mm/year) for 0 versus 1 to 2 risk alleles, respectively. With moderately small (1.9-3.8 mm2) or medium to large (≥ 3.8 mm2) area, enlargement was not significantly faster with ARMS2 risk alleles (P= 0.66 and P= 0.70, respectively). In nonmultifocal GA, enlargement was significantly faster with ARMS2 risk alleles (P= 0.001) at 0.175 mm/year (95% CI, 0.142-0.209 mm/year), 0.226 mm/year (95% CI, 0.193-0.259 mm/year), and 0.287 mm/year (95% CI, 0.237-0.337 mm/year) with 0 to 2 risk alleles, respectively. ARMS2 genotype was not associated significantly with progression to multifocal GA. The relationship between ARMS2/HTRA1 genotype and faster GA enlargement depends critically on GA area: risk alleles represent a strong risk factor for faster enlargement only in eyes with very small area. They increase the growth rate more through contiguous enlargement than progression to multifocality. ARMS2/HTRA1 genotype is more important in increasing risk of progression to GA and initial GA enlargement (contiguously) than in subsequent enlargement or progression to multifocality. These findings may explain some discrepancies between previous studies and have implications for both research and clinical practice. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Family History of Age-Related Macular Degeneration and Genetics Predict Progression to Advanced Age-Related Macular Degeneration Adjusting for Macular Status, Demographic, and Lifestyle Factors

To determine if a family history of age-related macular degeneration (AMD) and genetic variants identify eyes at higher risk for progression to advanced AMD (AAMD), after controlling for baseline demographics, behavioral factors, and macular status. Prospective, longitudinal cohort study. Eyes were classified using the Age-Related Eye Disease Study severity scale. Non-genetic and genetic predictors for progression to AAMD, geographic atrophy, and neovascular disease were evaluated. Cox proportional hazards models using the eye as the unit of analysis were used to calculate hazard ratios (HRs), accounting for correlated data. Discrimination between progressing and non-progressing eyes was assessed using C-statistics and net reclassification improvement (NRI). Among 4910 eyes, 863 progressed to AAMD over 12 years. Baseline AMD severity scale and status of the fellow eye were important predictors; genes provided additional discrimination. A family history of AMD also independently predicted progression after accounting for genetic and other covariates: 1 family member versus none (HR 1.21 [95% confidence interval {CI} 1.02-1.43]; P=0.03); ≥2 family members versus none (HR 1.55 [95% CI 1.26-1.90]; P < 0.001). A composite risk score calculated using β estimates of both non-genetic and significant genetic factors predicted progression to AAMD (HR 5.57; 90th vs 10th percentile; area under the receiver operating characteristic curve [AUC] = 0.92), providing superior fit compared with other models, including one with only ocular variables (NRI=0.34; P < 0.001; AUC = 0.87, ΔAUC 0.05 ± 0.005; P < 0.001). Genetic variants and family history provided additional discrimination for predicting progression to AAMD, after accounting for baseline macular status and other covariates.

Plasma Metabolites Associated with OCT Features of Age-Related Macular Degeneration

The most widely used classifications of age-related macular degeneration (AMD) and its severity stages still rely on color fundus photographs (CFPs). However, AMD has a wide phenotypic variability that remains poorly understood and is better characterized by OCT. We and others have shown that patients with AMD have a distinct plasma metabolomic profile compared with controls. However, all studies to date have been performed solely based on CFP classifications. This study aimed to assess if plasma metabolomic profiles are associated with OCT features commonly seen in AMD. Prospectively designed, cross-sectional study. Subjects with a diagnosis of AMD and a control group (> 50 years old) from Boston, United States, and Coimbra, Portugal. All participants were imaged with CFP, used for AMD staging (Age-Related Eye Disease Study 2 classification scheme), and with spectral domain OCT (Spectralis, Heidelberg). OCT images were graded by 2 independent graders for the presence of characteristic AMD features, according to a predefined protocol. Fasting blood samples were collected for metabolomic profiling (using nontargeted high-resolution mass spectrometry by Metabolon Inc). Analyses were conducted using logistic regression models including the worst eye of each patient (AREDS2 classification) and adjusting for confounding factors. Each cohort (United States and Portugal) was analyzed separately and then results were combined by meta-analyses. False discovery rate (FDR) was used to account for multiple comparisons. Plasma metabolite levels associated with OCT features. We included data on 468 patients, 374 with AMD and 94 controls, and on 725 named endogenous metabolites. Meta-analysis identified significant associations (FDR < 0.05) between plasma metabolites and 3 OCT features: hyperreflective foci (6), atrophy (6), and ellipsoid zone disruption (3). Most associations were seen with amino acids, and all but 1 metabolite presented specific associations with the OCT features assessed. To our knowledge, we show for the first time that plasma metabolites have associations with specific OCT features seen in AMD. Our results support that the wide spectrum of presentations of AMD likely include different pathophysiologic mechanisms by identifying specific pathways associated with each OCT feature. Proprietary or commercial disclosure may be found after the references.

Biologically Guided Optimization of Test Target Location for Rod-mediated Dark Adaptation in Age-related Macular Degeneration: Alabama Study on Early Age-related Macular Degeneration 2 Baseline.

We evaluate the impact of test target location in assessing rod-mediated dark adaptation (RMDA) along the transition from normal aging to intermediate age-related macular degeneration (AMD). We consider whether RMDA slows because the test locations are near mechanisms leading to or resulting from high-risk extracellular deposits. Soft drusen cluster under the fovea and extend to the inner ring of the ETDRS grid where rods are sparse. Subretinal drusenoid deposits (SDDs) appear first in the outer superior subfield of the ETDRS grid where rod photoreceptors are maximal and spread toward the fovea without covering it. Cross-sectional. Adults ≥ 60 years with normal older maculas, early AMD, or intermediate AMD as defined by the Age-Related Eye Disease Study (AREDS) 9-step and Beckman grading systems. In 1 eye per participant, RMDA was assessed at 5° and at 12° in the superior retina. Subretinal drusenoid deposit presence was identified with multi-modal imaging. Rod intercept time (RIT) as a measure of RMDA rate at 5° and 12°. In 438 eyes of 438 persons, RIT was significantly longer (i.e., RMDA is slower) at 5° than at 12° for each AMD severity group. Differences among groups were bigger at 5° than at 12°. At 5°, SDD presence was associated with longer RIT as compared to SDD absence at early and intermediate AMD but not in normal eyes. At 12°, SDD presence was associated with longer RIT in intermediate AMD only, and not in normal or early AMD eyes. Findings were similar in eyes stratified by AREDS 9-step and Beckman systems. We probed RMDA in relation to current models of deposit-driven AMD progression organized around photoreceptor topography. In eyes with SDD, slowed RMDA occurs at 5° where these deposits typically do not appear until later in AMD. Even in eyes lacking detectable SDD, RMDA at 5° is slower than at 12°. The effect at 5° may be attributed to mechanisms associated with the accumulation of soft drusen and precursors under the macula lutea throughout adulthood. These data will facilitate the design of efficient clinical trials for interventions that aim to delay AMD progression.

Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration.

To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Prospective, longitudinal study. Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Analyses were performed using the Seddon Longitudinal Cohort Study (N=2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N=2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Progression to AAMD, GA, or NV. In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P<0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P=0.049). CFI carriers were more likely to have a family history of AMD (P for trend=0.035) and a higher baseline AMD grade (P<0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR]=1.91; 95% confidence interval [CI]=1.03, 3.52) but not NV (OR=0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs.<25; OR=5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR=1.1; 95% CI=0.9, 1.3), with P_interaction=0.011. Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Proprietary or commercial disclosure may be found after the references.

Macular and Plasma Xanthophylls Are Higher in Age-related Macular Degeneration than in Normal Aging: Alabama Study on Early Age-related Macular Degeneration 2 Baseline.

Quantification of retinal xanthophyll carotenoids in eyes with and without age-related macular degeneration (AMD) via macular pigment optical volume (MPOV), a metric for xanthophyll abundance from dual wavelength autofluorescence, plus correlations to plasma levels, could clarify the role of lutein (L) and zeaxanthin (Z) in health, AMD progression, and supplementation strategies. Cross-sectional observational study (NCT04112667). Adults ≥ 60 years from a comprehensive ophthalmology clinic, with healthy maculas or maculas meeting fundus criteria for early or intermediate AMD. Macular health and supplement use was assessed by the Age-related Eye Disease Study (AREDS) 9-step scale and self-report, respectively. Macular pigment optical volume was measured from dual wavelength autofluorescence emissions (Spectralis, Heidelberg Engineering). Non-fasting blood draws were assayed for L and Z using high-performance liquid chromatography. Associations among plasma xanthophylls and MPOV were assessed adjusting for age. Age-related macular degeneration presence and severity, MPOV in fovea-centered regions of radius 2.0° and 9.0°; plasma L and Z (μM/ml). Of 809 eyes from 434 persons (89% aged 60-79, 61% female), 53.3% eyes were normal, 28.2% early AMD, and 18.5% intermediate AMD. Macular pigment optical volume 2° and 9° were similar in phakic and pseudophakic eyes, which were combined for analysis. Macular pigment optical volume 2° and 9° and plasma L and Z were higher in early AMD than normal and higher still in intermediate AMD (P<0.0001). For all participants, higher plasma L was correlated with higher MPOV 2° (Spearman correlation coefficient [Rs]=0.49; P < 0.0001). These correlations were significant (P<0.0001) but lower in normal (Rs=0.37) than early and intermediate AMD (Rs=0.52 and 0.51, respectively). Results were similar for MPOV 9°. Plasma Z, MPOV 2°, and MPOV 9° followed this same pattern of associations. Associations were not affected by supplement use or smoking status. A moderate positive correlation of MPOV with plasma L and Z comports with regulated xanthophyll bioavailability and a hypothesized role for xanthophyll transfer in soft drusen biology. An assumption that xanthophylls are low in AMD retina underlies supplementation strategies to reduce progression risk, which our data do not support. Whether higher xanthophyll levels in AMD are due to supplement use cannot be determined in this study.

Deep-GA-Net for Accurate and Explainable Detection of Geographic Atrophy on OCT Scans

To propose Deep-GA-Net, a 3-dimensional (3D) deep learning network with 3D attention layer, for the detection of geographic atrophy (GA) on spectral domain OCT (SD-OCT) scans, explain its decision making, and compare it with existing methods. Deep learning model development. Three hundred eleven participants from the Age-Related Eye Disease Study 2 Ancillary SD-OCT Study. A dataset of 1284 SD-OCT scans from 311 participants was used to develop Deep-GA-Net. Cross-validation was used to evaluate Deep-GA-Net, where each testing set contained no participant from the corresponding training set. En face heatmaps and important regions at the B-scan level were used to visualize theoutputs of Deep-GA-Net, and 3 ophthalmologists graded the presence or absence of GA in them to assess the explainability (i.e., understandability and interpretability) of its detections. Accuracy, area under receiver operating characteristic curve (AUC), area under precision-recall curve (APR). Compared with other networks, Deep-GA-Net achieved the best metrics, with accuracy of 0.93, AUC of 0.94, and APR of 0.91, and received the best gradings of 0.98 and 0.68 on the en face heatmap and B-scan grading tasks, respectively. Deep-GA-Net was able to detect GA accurately from SD-OCT scans. The visualizations of Deep-GA-Net were more explainable, as suggested by 3 ophthalmologists. The code and pretrained models are publicly available at https://github.com/ncbi/Deep-GA-Net. The author(s) have no proprietary or commercial interest in any materials discussed in this article.