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Purpose: Most studies of fundus autofluorescence (FAF) in geographic atrophy (GA) have been nonquantitative, with inadequate registration of image modalities. Furthermore, as pointed out in the recent Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT, it is unclear whether decreased FAF would be correlated exclusively with a single category of OCT-defined atrophy. We sought to determine how FAF intensity in eyes with GA correlates with structural changes of the outer retina and choroid as seen on co-registered spectral domain OCT (SD-OCT) images., Design: Retrospective cross-sectional., Participants: Twenty eyes of 11 patients with GA secondary to non-neovascular age-related macular degeneration (AMD)., Methods: Spectral domain OCT and FAF images for each eye were co-registered using MATLAB (MathWorks Inc, Natick, MA). On B-scans, the choroid, retinal pigment epithelium (RPE), photoreceptor (PR) layer, and outer nuclear layer (ONL) were segmented. Regions of interest (ROIs) including all atrophic and border regions were selected manually on the FAF scans. Regions of interest were subdivided into quartiles of FAF level to correlate with retinal thickness measurements taken along the B-scans. Mean choroid, RPE, PR, and ONL thicknesses were compared across quartiles using an analysis of variance factorial design testing for interaction effects, adjusted for repeated measures (on both eyes) with a within-subjects factor., Results: Seventeen eyes of 10 patients were selected for analysis. The mean choroidal thicknesses were not significantly different across FAF quartiles, but the overall differences in mean RPE, PR layer, and ONL thicknesses across quartiles were statistically significant (analysis of variance, P < 0.001, P < 0.001, and P = 0.015, respectively). Post hoc analysis demonstrated significant differences in thickness among quartiles 1, 2, and 3 for the RPE and PR layers (Tukey, P < 0.01 in each case). The FAF quartiles within GA did not correlate exclusively with single categories of Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration-defined atrophy., Conclusions: Not only RPE but also PR layer thickness on SD-OCT varies significantly with FAF levels in GA. This suggests that although the RPE cells are losing thickness and function, evidenced by decreased FAF from fluorophores, delicate PR cells also succumb early in the disease process. These relationships should be pursued as a possibly better-detailed mechanism in GA., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

PurposeThe purpose of the study was to investigate the association between area and presence of geographic atrophy (GA) and renal function, as measured by glomerular filtration rate (GFR).Patients and methodsWe retrospectively identified patients aged 50-90 years who were assigned an ICD-9 diagnosis code for age-related macular generation (AMD) between January 2012 and January 2016. Patients met inclusion criteria if they had at least one macular spectral domain optical coherence tomography volume scan, one provider note, and one GFR value in the electronic medical record. Images were evaluated for the presence of GA, area of GA, drusen, and subretinal drusenoid deposits (SDD) and for subfoveal choroidal thickness (CTh) by standard criteria. Imaging findings were correlated with the most recent GFR from the patient's chart.ResultsWe identified 107 patients who met our inclusion criteria (mean age=74 years, range 50-90 years). Overall, we found a significant correlation between the presence of GA and reduced GFR (P=0.002), which was maintained even after accounting for age and other confounders. No association between GFR and GA area was found. CTh was significantly lower in patients with GA (P=0.038) and those with decreased GFR (P=0.004). Within the SDD-positive population, GA was associated with reduced GFR (P=0.007) but only trended toward significance after controlling for age.ConclusionOur study findings demonstrate an association between impaired renal function and the presence, but not area, of GA within an AMD population. These findings may shed light on common pathogenic mechanisms for these two diseases.

Purpose: To evaluate diagnostic accuracy of visual acuity and fundus autofluorescence (FAF) macular geographic atrophy (GA) area for the discrimination of autosomal recessive Stargardt groups., Methods: Subjects aged <50 years old with confirmed molecular diagnoses were classified to Groups 1, 2, or 3 according to a full-field electroretinogram reference standard. Diagnostic accuracy of visual acuity and the FAF macular GA area was assessed with generalized estimating equations, receiver operating characteristic curve area under the curve, and support vector machines., Results: Ten eyes were classified as Group 1 and 7 as Group 2. The mean log minimum angle resolution (Snellen equivalent) was 0.64 (20/87) for group 1 and 0.96 (20/182) for group 2. Mean FAF macular GA area was 0.96 mm for Group 1 and 3.23 mm for Group 2. The generalized estimating equation analysis showed an 8.3% increase in odds of Group 2 classification with each 0.1-unit increase in log minimum angle resolution and a 24% increase with each 1-mm increase in FAF macular GA area. Multivariate generalized estimating equation analysis showed that only the FAF macular GA area was significant. Area under the curve was 0.79 for log minimum angle resolution and 0.89 for FAF macular GA area. The support vector machine classification accuracy was 71% for log minimum angle resolution and 82% for FAF macular GA area., Conclusion: Visual acuity and FAF macular GA area had good independent accuracy for the discrimination of groups 1 and 2, indicating that they may serve as useful diagnostic parameters.

The retinal pigment epithelium (RPE) is juxtaposed to the overlying sensory retina, and supports the function of the visual system. Among the tasks performed by the RPE are phagocytosis and processing of outer photoreceptor segments through lysosome-derived organelles. These degradation products, stored and referred to as lipofuscin granules, are composed partially of bisretinoids, which have broad fluorescence absorption and emission spectra that can be detected clinically as fundus autofluorescence with confocal scanning laser ophthalmoscopy (cSLO). Lipofuscin accumulation is associated with increasing age, but is also found in various patterns in both acquired and inherited degenerative diseases of the retina. Thus, studying its pattern of accumulation and correlating such patterns with changes in the overlying sensory retina are essential to understanding the pathophysiology and progression of retinal disease. Here, we describe a technique employed by our lab and others that uses cSLO in order to quantify the level of RPE lipofuscin in both healthy and diseased eyes.

Geographic atrophy (GA) and choroidal neovascularization (CNV), the two late forms of age-related macular degeneration, are generally considered two distinct entities. However, GA and CNV can occur simultaneously in the same eye, with GA usually occurring first. The prevalence of this combined entity is higher in histological studies than in clinical studies. No distinct systemic or genetic risk characteristics are associated with the combined GA/CNV entity, although on clinical examination and retinal imaging it can feature drusen or subretinal drusenoid deposits. GA and CNV may exist within the spectrum of a single disease, or they may be two very different diseases. Therapy with antivascular endothelial growth factor (anti-VEGF) is often successful for CNV, but some evidence suggests increased rates of GA development in eyes treated with anti-VEGF. In this article, we review the current literature regarding the epidemiology, clinical presentation, and treatment options for patients with the combined GA/CNV entity., (© 2016 S. Karger AG, Basel.)

Aim: To investigate the risk characteristics of the combined geographic atrophy (GA) and choroidal neovascularisation (CNV) phenotype of age-related macular degeneration (AMD) compared to GA or CNV., Methods: Patients with advanced AMD were identified and divided into three groups using multimodal imaging: patients with GA in at least one eye, patients with CNV in at least one eye, and patients with simultaneous GA and CNV in at least one eye. Epidemiologic and clinical factors were gathered from patient questionnaires. Genotypes for age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) were determined., Results: 42 patients with GA or CNV, and 16 patients with combined GA/CNV were identified. Patients with the combined phenotype were older (86.4 vs 81.8 years, p=0.049), and had a higher prevalence of advanced AMD in the fellow eye (81.3% vs 31.0%, p<0.001). CFH and ARMS2 risk alleles were not associated with the combined phenotype., Conclusions: The combined GA/CNV phenotype has similar epidemiologic, clinical, and genetic features as GA and CNV, but occurs at an older age and is more associated with advanced AMD in the fellow eye, suggesting that all these phenotypes are part of the same spectrum of disease and that the combined phenotype represents an even more advanced form of AMD than either GA or CNV., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To investigate genetic, environmental, and systemic risk factors in prospectively identified subjects with the age-related macular degeneration (AMD) phenotypes of (1) reticular pseudodrusen without large soft drusen and (2) large soft drusen without reticular pseudodrusen., Design: Prospective case-case comparison., Methods: In a clinical practice setting, patients with AMD were sequentially screened using clinical examination and scanning laser ophthalmoscopy imaging to prospectively identify subjects (n = 73) with the phenotypes of (1) reticular pseudodrusen without large soft drusen (n = 30) or (2) large soft drusen without reticular pseudodrusen (n = 43). Subjects were genotyped for 2 alleles associated with AMD, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH). A questionnaire was administered to collect history of smoking, hypertension, diabetes, and hyperlipidemia, as well as personal and family history of AMD., Results: The reticular pseudodrusen group was older (median age 87 vs 81 years, P = .04) and had more female subjects (83.3% vs 48.8%, P = .003), later ages of AMD onset (83 vs 70 years, P = .0005), and a greater frequency of hypertension (76.7% vs 55.8%, P = .08). No significant differences were found in the distribution of the ARMS2 risk allele (P = .4) between the reticular pseudodrusen (homozygous = 20.0%; heterozygous = 56.7%) and large soft drusen (homozygous = 19.0%; heterozygous = 42.9%) phenotypes, or in the distribution of the CHF risk allele (P = .7) between the reticular pseudodrusen (homozygous = 26.7%; heterozygous = 56.7%) and large soft drusen (homozygous = 21.4%; heterozygous = 66.7%) phenotypes., Conclusions: The reticular pseudodrusen phenotype was associated with increased age, later age of AMD onset, and female sex., (Copyright © 2014. Published by Elsevier Inc.)

Purpose: To investigate the incidence of reticular macular disease (RMD), a subphenotype of age-related macular degeneration, in multilobular geographic atrophy (GA) and its relation to GA progression., Methods: One hundred and fifty-seven eyes of 99 subjects with age-related macular degeneration, primary GA, and good quality autofluorescence, and/or infrared images were classified into unilobular GA (1 lesion) or multilobular GA (≥ 2 distinct and/or coalescent lesions). Thirty-four subjects (50 eyes) had serial imaging. The authors determined the spatiotemporal relationships of RMD to GA and GA progression rates in five macular fields., Results: 91.7% eyes (144 of 157) had multilobular GA, 95.8% of which exhibited RMD. In subjects with serial imaging, the mean GA growth rate significantly differed between the unilobular and multilobular groups (0.40 vs. 1.30 mm2/year, P < 0.001). Of the macular fields in these eyes, 77.1% of fields with RMD at baseline showed subsequent GA progression, while 53.4% of fields without RMD showed progression (P < 0.001). Percentage of fields with RMD significantly correlated with GA progression rate (P = 0.01)., Conclusion: Autofluorescence and infrared imaging demonstrates that RMD is nearly always present with multilobular GA in age-related macular degeneration. Furthermore, GA lobules frequently develop in areas of RMD, suggesting progression of a single underlying disease process.

Purpose: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes., Design: Sibling correlation study and genome-wide association study (GWAS)., Participants: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls., Methods: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts., Main Outcome Measures: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes., Results: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis)., Conclusions: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the risk of progression to advanced age-related macular degeneration (AMD) conferred by reticular pseudodrusen (RPD), an imaging presentation of reticular macular disease (RMD), in high-risk fellow eyes of subjects with AMD and unilateral choroidal neovascularization (CNV) in a large, prospective study., Design: Cohort study., Participants: Two hundred seventy-one subjects with AMD; 94 with RPD and 177 without RPD., Methods: Images from a cohort of 271 subjects with AMD in the Nutritional AMD treatment phase II (NAT 2) Study, a 3-year prospective study of subjects with unilateral CNV and large soft drusen in the fellow eye, were studied. The fellow eye, at high risk for advanced AMD developing, was the study eye. There were 5 visits per subject. Imaging at each visit consisted of color, red-free, and blue-light photography and fluorescein angiography. The images were analyzed for the presence of RPD, following disease progression throughout the 3-year study., Main Outcome Measures: The development of advanced AMD (CNV or geographic atrophy)., Results: For the 271 subjects who completed the full 3-year study, there was a significantly higher rate of advanced AMD (56% or 53/94) in fellow eyes with RPD at any visit compared with eyes without RPD (32% or 56/177; P < 0.0001, chi-square test; relative risk [RR], 1.8; 95% confidence interval [CI], 1.4-2.4). The chance of developing advanced AMD in the fellow eye in women with RPD (66%) was more than double that of women without RPD (30%; P < 0.00001; RR, 2.2; 95% CI, 1.6-3.1)., Conclusions: To the authors' knowledge, this is the first comprehensive prospective study of RMD, a distinct clinical phenotype of AMD that includes RPD. It provides strong confirmation that RMD, a disease entity with stereotypical presentations across imaging methods, is associated with a high risk of progression to advanced AMD, perhaps on an inflammatory or vascular basis. Reticular macular disease deserves wider recognition and consideration by clinicians caring for patients with AMD., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To review the current literature regarding the imaging characteristics of dry age-related macular degeneration (AMD) lesions, with a special focus on drusen and geographic atrophy imaging. We also explore the role of novel approach of hyperspectral imaging in AMD., Methods: Review of current literature as well as findings in a small group of patients imaged with hyperspectral imaging., Results: The use of optical coherence tomography, and especially fourier-domain devices, has enhanced our ability to classify various lesions of dry AMD. The increasing role of autofluorescence in characterization and prognostication in geographic atrophy is reviewed. The advances made in automated detection and multimodal imaging are highlighted, with their potential to revolutionize this area of research., Conclusions: Recent advances in retinal imaging have improved our understanding of the characteristics and prognostication of dry AMD, with an increasing role for multimodal imaging and image correlations. The potential future role of hyperspectral imaging in dry AMD is also presented herein.