Advanced Advanced Age-related Macular Degeneration Research Articles

Risk Assessment Model for Development of Advanced Age-Related Macular Degeneration

To design a risk assessment model for development of advanced age-related macular degeneration (AMD) incorporating phenotypic, demographic, environmental, and genetic risk factors. We evaluated longitudinal data from 2846 participants in the Age-Related Eye Disease Study. At baseline, these individuals had all levels of AMD, ranging from none to unilateral advanced AMD (neovascular or geographic atrophy). Follow-up averaged 9.3 years. We performed a Cox proportional hazards analysis with demographic, environmental, phenotypic, and genetic covariates and constructed a risk assessment model for development of advanced AMD. Performance of the model was evaluated using the C statistic and the Brier score and externally validated in participants in the Complications of Age-Related Macular Degeneration Prevention Trial. The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. The model did well on performance measures, with very good discrimination (C statistic = 0.872) and excellent calibration and overall performance (Brier score at 5 years = 0.08). Successful external validation was performed, and a risk assessment tool was designed for use with or without the genetic component. We constructed a risk assessment model for development of advanced AMD. The model performed well on measures of discrimination, calibration, and overall performance and was successfully externally validated. This risk assessment tool is available for online use.

Association of Variants in theLIPCandABCA1Genes with Intermediate and Large Drusen and Advanced Age-Related Macular Degeneration

Intermediate and large drusen usually precede advanced age-related macular degeneration (AMD). There is little information about which genes influence drusen accumulation. Discovery of genetic variants associated with drusen may lead to prevention and treatments of AMD in its early stages. A total of 3066 subjects were evaluated on the basis of ocular examinations and fundus photography and categorized as control (n = 221), intermediate drusen (n = 814), large drusen (n = 949), or advanced AMD (n = 1082). SNPs in the previously identified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and ABCA1 in the high-density lipoprotein (HDL) cholesterol pathway were genotyped. Associations between stage of AMD and SNPs were assessed using logistic regression. Controlling for age, sex, education, smoking, body mass index, and antioxidant treatment, the number of minor (T) alleles of the genes LIPC and ABCA1 were significantly associated with a reduced risk of intermediate drusen (LIPC [P trend = 0.045], ABCA1 [P = 4.4 × 10(-3)]), large drusen (LIPC [P = 0.041], ABCA1 [P = 7.7 × 10(-4)]), and advanced AMD (LIPC [P = 1.8 × 10(-3)], ABCA1 [P = 3 × 10(-4)]). After further adjustment for known genetic factors, the protective effect of the TT genotype was significant for intermediate drusen (LIPC [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.33-0.94], ABCA1 [OR, 0.48; 95% CI, 0.27-0.85]), large drusen (LIPC [OR, 0.58; 95% CI, 0.34-0.98)], ABCA1 [OR, 0.41; 95% CI, 0.23-0.74)]), and advanced AMD (LIPC [OR, 0.39; 95% CI, 0.21-0.74)], ABCA1 [OR, 0.35; 95% CI, 0.17-0.71)]). CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD. LIPC and ABCA1 are related to intermediate and large drusen, as well as advanced AMD. CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD. Genes may have varying effects on different stages of AMD.

A Prospective Study of Reticular Macular Disease

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. Cohort study. Two hundred seventy-one subjects with AMD; 94 with RPD and 177 without RPD. 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. The development of advanced AMD (CNV or geographic atrophy). 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). 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. Proprietary or commercial disclosure may be found after the references.

Genetic association study of age-related macular degeneration in the Spanish population

To investigate new genetic risk factors and replicate reported associations with advanced age-related macular degeneration (AMD) in a prospective case-control study developed with a Spanish cohort. Three hundred and fifty-three unrelated patients with advanced AMD (225 with atrophic AMD, 57 with neovascular AMD, and 71 with mixed AMD) and 282 age-matched controls were included. Functional and tagging SNPs in 55 candidate genes were genotyped using the SNPlex™ genotyping system. Single SNP and haplotype association analysis were performed to determine possible genetic associations; interaction effects between SNPs were also investigated. In agreement with previous reports, ARMS2 and CFH genes were strongly associated with AMD in the studied Spanish population. Moreover, both loci influenced risk independently giving support to different pathways implicated in AMD pathogenesis. No evidence for association of advanced AMD with other previous reported susceptibility genes, such as CST3, CX3CR1, FBLN5, HMCN1, PON1, SOD2, TLR4, VEGF and VLDLR, was detected. However, two additional genes appear to be candidate markers for the development of advanced AMD. A variant located at the 3' UTR of the FGF2 gene (rs6820411) was highly associated with atrophic AMD, and the functional SNP rs3112831 at ABCA4 showed a marginal association with the disease. We performed a large gene association study in advanced AMD in a Spanish population. Our findings show that CFH and ARMS2 genes seem to be the principal risk loci contributing independently to AMD in our cohort. We report new significant associations that could also influence the development of advanced AMD. These findings should be confirmed in further studies with larger cohorts.

Serum Lipid Biomarkers and Hepatic Lipase Gene Associations with Age-Related Macular Degeneration

A genetic variant in the high-density lipoprotein (HDL) cholesterol pathway, hepatic lipase (LIPC), was discovered to be associated with advanced age-related macular degeneration (AMD) in a genome-wide association study. In this study, we evaluated whether LIPC is associated with serum lipids, and whether this gene and serum lipids are independently associated with AMD. Case-control study. A total of 458 participants from the Progression Study of Macular Degeneration and the Age-Related Eye Disease Ancillary Biomarker Study, including 318 advanced AMD cases with either geographic atrophy (n = 123) or neovascular disease (n = 195) and 140 controls. Participants were genotyped for 8 variants associated with AMD: 2 CFH variants, C2, CFB, C3, CFI, the ARMS2/HTRA1 gene region, and LIPC. Fasting blood specimens were obtained at study onset, and serum levels of total cholesterol, low-density lipoprotein (LDL), HDL, and triglycerides were determined. Logistic and linear regression were used to evaluate associations between serum lipids, LIPC genotype, and AMD. LIPC and serum lipid associations with AMD. The minor T allele of the LIPC gene was associated with a reduced risk of AMD (odds ratio, 0.4; 95% confidence interval, 0.2-0.9; P = 0.01, trend for number of T alleles, controlling for age and gender). Mean level of HDL was lower (P = 0.05) and mean level of LDL (P = 0.03) was higher in cases of advanced AMD compared with controls. Higher total cholesterol and LDL levels were associated with increased risk of AMD, with P for trend = 0.01 for both, in models controlling for environmental and genetic covariates. The T allele of LIPC was associated with higher levels of HDL, although LIPC was associated with advanced AMD independent of HDL level. The HDL-raising allele of the LIPC gene (T) was associated with a reduced risk of AMD. Higher total cholesterol and LDL levels were associated with increased risk, whereas higher HDL levels tended to reduce the risk of AMD. The specific mechanisms underlying the association between AMD and LIPC require further investigation.

Four-Year Incidence and Progression of Age-Related Macular Degeneration: The Los Angeles Latino Eye Study

To estimate 4-year incidence and progression of early and advanced age-related macular degeneration (AMD). Population-based cohort study. A comprehensive ophthalmologic examination including stereoscopic fundus photography was performed on adult Latinos at baseline and follow-up. Photographs were graded using a modified Wisconsin Age-Related Maculopathy Grading System. For estimations of incidence and progression of AMD, the Age Related Eye Disease Study Scale was used. Main outcome measures are incidence and progression of early AMD (drusen type, drusen size, and retinal pigmentary abnormalities) and advanced AMD (exudative AMD and geographic atrophy). A total of 4658 of 6100 subjects (76%) completed the follow-up examination. The 4-year incidence of early AMD was 7.5% (95% CI: 6.7, 8.4) and advanced AMD was 0.2% (95% CI: 0.1, 0.4). Progression of any AMD occurred in 9.2% (95% CI: 8.3, 10.1) of at-risk participants. Incidence and progression increased with age. Incidence of early AMD in the second eye (11.2%) was higher than incidence in the first eye (6.9%). Baseline presence of soft indistinct large drusen >or=250 microm in diameter was more likely to predict the 4-year incidence of pigmentary abnormalities, geographic atrophy, and exudative AMD than smaller or hard or soft distinct drusen. Age-specific incidence and progression of AMD in Latinos are lower than in non-Hispanic whites. While incident early AMD is more often unilateral, the risk of its development in the second is higher than in the first eye. Older people and those with soft indistinct large drusen had a higher risk of developing advanced AMD compared to those who were younger and did not have soft indistinct large drusen.

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( LIPC )

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.

Overall Diet Quality and Age-Related Macular Degeneration

Purpose: To examine overall diet quality in relation to advanced age-related macular degeneration (AMD).Methods: This case-control study identified 437 advanced AMD patients and 259 unrelated controls using stereoscopic color fundus photographs. Participants were predominantly non-Hispanic White men and women from North Carolina and Tennessee. A 97-item Block food frequency questionnaire was used to gather diet information, and overall diet quality was measured using the Healthy Eating Index (HEI) and Alternate Healthy Eating Index (AHEI).Results: Participants in the highest quartile of diet quality had significantly reduced odds of AMD according to the AHEI score (0.54, 95% confidence interval 0.30–0.99) and non-significantly reduced odds of AMD according to the HEI (0.75, 0.41–1.38). Odds of AMD were also 51% lower in the highest quartile of fish intake compared to the lowest quartile (odds ratio = 0.49, 0.26–0.90).Conclusions: We found that advanced AMD was significantly related to overall diet quality. The AHEI score may be a useful instrument for assessing AMD risk due to diet, and it could potentially be improved by incorporating more specific information regarding micronutrient intake.

Statin Use and the Incidence of Advanced Age-related Macular Degeneration in the Complications of Age-related Macular Degeneration Prevention Trial

To evaluate the impact of statin use on the incidence of advanced age-related macular degeneration (AMD) and its components, choroidal neovascularization (CNV) and geographic atrophy (GA), among patients with bilateral large drusen. Cohort study within a multicenter, randomized, clinical trial. Patients enrolled in the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Eligibility criteria for the clinical trial required that participants have >or=10 large (>125 microm) drusen and visual acuity >or=20/40 in each eye. Patients scheduled for their final CAPT visit after May 2005 were interviewed on their history of use of cholesterol-lowering medications, including statins. Trained readers identified CNV and end point GA (>1 Macular Photocoagulation Study disc area of GA) based on review of fluorescein angiograms and fundus photographs taken at annual follow-up visits and when patients reported symptoms. The risk ratio for participants developing CNV or developing GA associated with statin use was estimated with time-dependent Cox proportional hazards models. Development of advanced AMD, CNV, and end point GA. Among 764 patients eligible for the interview, 744 (97.4%) patients completed the interview on medication use. Statin use was reported by 296 (39.8%) of those interviewed, with the majority, 187 (63.2%) of the 296, beginning use after enrollment in CAPT. Among 744 patients, advanced AMD developed in 332 (22.5%) eyes of 242 (32.5%) patients, CNV in 222 (15%) eyes of 176 (23.7%) patients, and GA in 114 (7.7%) eyes of 80 (10.8%) patients. With adjustment for other risk factors, the estimated risk ratio for eyes (95% confidence interval) associated with statin use was 1.15 (0.87-1.52) for advanced AMD, 1.35 (0.99-1.83) for CNV, and 0.80 (0.46-1.39) for GA. The CAPT data are not consistent with a strong protective effect (risk ratio, <or=0.85) of statins on the development of advanced AMD among patients with bilateral large drusen.

Description of the Age-Related Eye Disease Study 9-Step Severity Scale Applied to Participants in the Complications of Age-related Macular Degeneration Prevention Trial

To describe characteristics of the Age-Related Eye Disease Study (AREDS) 9-step severity scale applied to participants in the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Eligibility criteria for CAPT required 10 or more large (>or=125 microm) drusen in each eye. Readers graded baseline photographs from all participants and all follow-up photographs from 402 untreated eyes. Drusen and pigment characteristics were used to assign the AREDS scale score. Choroidal neovascularization was identified from fluorescein angiograms. Geographic atrophy involving the macular center was identified from color photographs. Among 1001 untreated eyes, 90% were at steps 5 to 7 at baseline. The 5-year incidence of advanced age-related macular degeneration (AMD) increased with each step from 8% (step 4) to 40% (steps 8 and 9 combined). These rates were similar to those reported in AREDS. Among 261 eyes with all 5 annual photograph gradings available and without progression to advanced AMD, 55% of eyes had scores that indicated improvement at least once. Before progression to advanced AMD, only 32% of 141 eyes either went through step 8 or 9 or had an increase of 2 or more steps from baseline. The AREDS 9-step severity scale was predictive of development of advanced AMD. The AREDS scale has deficiencies as a surrogate outcome for progression to advanced AMD.

RISK FACTORS FOR SECOND EYE PROGRESSION TO ADVANCED AGE-RELATED MACULAR DEGENERATION

To identify characteristics predictive of progression to advanced age-related macular degeneration (AMD) in second (fellow) eyes of participants in the Submacular Surgery Trials (SST) who had unilateral neovascular AMD at study entry. Review of baseline fluorescein angiograms confirmed the absence of advanced AMD in 370 fellow eyes. All participants were eligible for 2 years of follow-up; follow-up angiograms of eyes at risk were evaluated to estimate incidence rates of advanced AMD. Baseline nonocular and ocular AMD characteristics were evaluated to identify those that predicted development of advanced AMD. Of 110 eyes that progressed to advanced AMD, choroidal neovascularization (CNV) developed in 98 eyes and foveal geographic atrophy (GA) in 15 eyes. No nonocular characteristic (age, gender, history of hypertension or smoking) or ocular feature of the study eye at baseline (lesion composition, lesion size, or visual acuity) was predictive of progression to advanced AMD in this cohort. Multivariate analysis identified three baseline fellow eye ocular features that had a significant and independent relationship with progression to advanced AMD: drusen size, focal hyperpigmentation, and nonfoveal GA. Recognition of factors that predict advanced AMD in the second eye may identify those individuals at greater risk of progression so that treatment can be provided before vision is severely compromised.

Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements?

Background:Recent information suggests that the Age-Related Eye Disease Study (AREDS) supplement, enhanced intake of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and reducing dietary glycaemic index (dGI) are protective against...

Risk of Advanced Age-Related Macular Degeneration after Cataract Surgery in the Age-Related Eye Disease Study: AREDS Report 25

To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. Cohort study. Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

CFH and LOC387715/ARMS2 Genotypes and Treatment with Antioxidants and Zinc for Age-Related Macular Degeneration

To determine if CFH and LOC387715/ARMS2 genotypes influence treatment response to AREDS-type nutritional supplementation with antioxidants and zinc. Retrospective analysis of participants in a randomized, controlled clinical trial, the Age-Related Eye Disease Study (AREDS). Eight hundred seventy-six AREDS study participants who were considered at high risk for developing advanced age-related macular degeneration (AMD). Using DNA extracted from venous blood of 876 white participants in AREDS categories 3 and 4, that is, those considered to be at high risk for progression to advanced AMD, the authors genotyped for the single nucleotide polymorphisms in the CFH (Y402H, rs1061170) and LOC387715/ARMS2 (A69S, rs10490924) genes. The authors performed adjusted unconditional logistic regression analysis and assessed interactions of these genotypes to determine the relationship between CFH and LOC387715/ARMS2 genotype and treatment with antioxidants plus zinc. Interaction between genetic variants and treatment response as determined by progression from high-risk to advanced AMD. Progression occurred in 264 of 876 patients from AREDS category 3 (intermediate AMD) to category 4 or 5 (unilateral or bilateral advanced AMD, respectively), or from category 4 to category 5. A treatment interaction was observed between the CFH Y402H genotype and supplementation with antioxidants plus zinc (CC; P = 0.03). An interaction (P = 0.004) was observed in the AREDS treatment groups taking zinc when compared with the groups taking no zinc, but not in groups taking antioxidants compared with those taking no antioxidants (P = 0.59). There were no significant treatment interactions observed with LOC387715/ARMS2. The findings of this study indicate that an individual's response to AREDS supplements may be related to CFH genotype. This could have clinical relevance by predicting treatment outcome and potentially preventing unwanted side effects in those who may not benefit. Corroboration of these analyses is needed before considering modification of current management. This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment.

Cardiovascular Risk Factors and Age-related Macular Degeneration: The Los Angeles Latino Eye Study

To assess the association of cardiovascular risk factors and ocular perfusion pressure with early and advanced age-related macular degeneration (AMD) in Latinos. Population-based, cross-sectional study. Data were collected from a population-based sample of self-identified adult Latinos using standardized protocols for assessing blood pressure and intraocular pressure (IOP) measurement and stereoscopic macular photography. Hypertension was defined as either a history of hypertension or systolic blood pressure (SBP) > 140 mm Hg +/- diastolic blood pressure (DBP) > or = 85 mm Hg. Ocular perfusion pressure (OPP) was defined as the difference between mean arterial blood pressure and IOP. AMD was diagnosed from photographic grading by masked trained graders. Logistic regression was used to assess associations. Gradable retinal photographs were available in 5,875 participants. After adjusting for age, gender, and cigarette smoking, higher DBP and uncontrolled diastolic hypertension were associated with exudative AMD (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1 to 2.8; and OR, 3.3; CI, 1.2 to 9.3, respectively). Higher OPP was associated with a decreased risk of geographic atrophy (GA) (OR, 0.4 per 10 mm Hg; CI, 0.3 to 0.5). Low pulse pressure was associated with a lower risk of exudative AMD (OR, 0.2; CI, 0.1 to 0.6). Obesity was associated with increased retinal pigment (OR, 1.6; CI, 1.0 to 2.3). These data suggest that in Latinos cardiovascular risk factors may play a role in advanced AMD. Given that Latinos have a high prevalence of cardiovascular risk factors, an intervention aimed at reducing these risk factors may also have a beneficial impact on the risk of having early and advanced AMD.

Population-Based Study of Early Age-Related Macular Degeneration: Role of the Complement Factor H Y402H Polymorphism in Bilateral but Not Unilateral Disease

Recently, a strong association has been observed for the complement factor H (CFH) Tyr402His polymorphism with early and advanced age-related macular degeneration (AMD) in independent non-Hispanic White, clinic-based, case-control studies. These studies suggest the CFH His402 allele is a major risk allele in early and advanced AMD, explaining 43% to 70% of all AMD in older adults. We utilized a population-based case-control study design of early AMD among Latinos/Hispanics to evaluate the CFH Tyr402His polymorphism for an association with early AMD phenotypes. Retrospective population-based case-control study. This study cohort consists of 285 early AMD cases and 570 controls matched on age, birthplace, and smoking status. Genotype determination was performed by allele-specific digestion of polymerase chain reaction products. Complement factor H Tyr402His polymorphism. We observed no overall statistically significant association with early AMD among Latinos. However, a subset of early AMD cases that have bilateral, not unilateral, intermediate-to-large soft macular drusen were 1.7 times more likely to carry either the homozygous or heterozygous His402 genotype. Our data suggest that the CFH Tyr402His is not a major risk factor for overall early AMD in this Latino population, but may play a role in susceptibility to phenotypes of early AMD likely to progress to late AMD.

A Simplified Severity Scale for Age-Related Macular Degeneration

To develop a simplified clinical scale defining risk categories for development of advanced age-related macular degeneration (AMD). Following development of a detailed scale for individual eyes based on gradings of fundus photographs in the Age-Related Eye Disease Study, rates of progression to advanced AMD were assessed in cross-tabulations of presence or absence in each eye of 2 easily identified retinal abnormalities, drusen and pigment abnormalities. Large drusen and any pigment changes were particularly predictive of developing advanced AMD. The scoring system developed for patients assigns to each eye 1 risk factor for the presence of 1 or more large (> or = 125 microm, width of a large vein at disc margin) drusen and 1 risk factor for the presence of any pigment abnormality. Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases in this easily remembered sequence: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%. For persons with no large drusen, presence of intermediate drusen in both eyes is counted as 1 risk factor. This simplified scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less demanding photographic procedures than used in the Age-Related Eye Disease Study.

Responsiveness of the National Eye Institute Visual Function Questionnaire to Progression to Advanced Age-Related Macular Degeneration, Vision Loss, and Lens Opacity

To describe the ability of the National Eye Institute Visual Function Questionnaire (NEI-VFQ) to detect meaningful change over time (responsiveness) to the primary Age-Related Eye Disease Study outcomes. The 25-item NEI-VFQ plus appendix was administered at 2 visits at 1- to 4-year intervals to 4119 participants in the Age-Related Eye Disease Study. Events evaluated were progression to advanced age-related macular degeneration (AMD), visual acuity (VA) loss of at least 15 letters, and lens opacity progression. Responsiveness was measured by the t statistic, effect size (ES), responsiveness statistic, and area under the receiver operating characteristic curve. Variance components were used to estimate the contributions of events to variability of the NEI-VFQ score. Overall NEI-VFQ score was responsive to AMD progression (t = 14.0; P< .001; ES = 0.81) and VA (t = 16.2; P< .001; ES = 0.74). Mean changes ranged from 11 to 25 points for the subscales of general vision, near and distance activities, social functioning, mental health, role difficulties, dependency, and driving. The NEI-VFQ was unresponsive to lens opacity progression, although when the event occurred in the eye with the best vision at the first administration, the lens opacity ES was moderate for the color vision (ES = 0.62) and driving subscales (ES = 0.66). Progression to advanced AMD and VA loss contributed significantly to the variation in the mean difference in overall VFQ score. Changes in the NEI-VFQ overall and subscale scores of 10 points or more are associated with clinically significant changes in vision and AMD. This finding may assist the design of interventional studies of AMD and VA loss that include the NEI-VFQ as an outcome measure.

Optic disk appearance in advanced age-related macular degeneration

Purpose To describe and quantify the appearance of the optic disk in patients with advanced age-related macular degeneration (ARMD). Design Retrospective comparative study. Methods A total of 316 charts were reviewed. From these, 45 subjects with advanced ARMD (defined as geographic atrophy or disciform scar) in at least one eye were enrolled. Patients with glaucoma or glaucoma visual field defects were excluded. The probability of glaucomatous optic nerve damage was scored by evaluation of stereoscopic optic disk photographs in a masked fashion, according to a predefined evaluation scale and measured with confocal ophthalmoscopy (Heidelberg Retinal Tomograph; HRT). The area of macular involvement was measured in units of disk area. The optic disk evaluation scores and HRT measurements of a group of eyes with a large area of ARMD were compared with their fellow eyes with smaller areas of ARMD. The correlations between the area of macular involvement with the optic disk evaluation scores and HRT measurements were analyzed. Main outcome measures The optic disk evaluation scores and the HRT measurements between study groups. Results Eyes with larger areas of ARMD had optic disks that were more likely to be classified as glaucomatous by clinical evaluation (3.45 ± 0.23 vs 3.05 ± 0.18, P = .015) and by HRT imaging analysis (−0.995 ± 0.423 vs −0.376 ± 0.249, P = .030) than the fellow eyes with smaller areas of ARMD. For eyes with six or more disk areas of ARMD, larger areas of ARMD correlated with a higher cup/disk ratio ( P = .022), smaller neuroretinal rim area ( P = .022), and glaucomatous classification ( P = .040) with HRT discriminant function analysis. Conclusions Eyes with large areas of geographic or diskiform ARMD have optic disk structural alterations that resemble glaucomatous optic neuropathy. This should be taken into consideration when evaluating patients with ARMD for glaucomatous damage.

AREDS—Two Years Later

Objective: To estimate the potential public health impact of the findings of the Age-Related Eye Disease Study (AREDS) on reducing the number of persons developing advanced age-related macular degeneration (AMD) during the next 5 years in the United States. Methods: The AREDS clinical trial provides estimates of AMD progression rates and of reduction in risk of developing advanced AMD when a high-dose nutritional supplement of antioxidants and zinc is used. These results are applied to estimates of the US population at risk, to estimate the number of people who would potentially avoid advanced AMD during 5 years if those at risk were to take a supplement such as that used in AREDS. Results: An estimated 8 million persons at least 55 years old in the United States have monocular or binocular intermediate AMD or monocular advanced AMD. They are considered to be at high risk for advanced AMD and are those for whom the AREDS formulation should be considered. Of these people, 1.3 million would develop advanced AMD if no treatment were given to reduce their risk. If all of these people at risk received supplements such as those used in AREDS, more than 300000 (95% confidence interval, 158000-487000) of them would avoid advanced AMD and any associated vision loss during the next 5 years. Conclusion: If people at high risk for advanced AMD received supplements such as those suggested by AREDS results, the potential impact on public health in the United States would be considerable during the next 5 years.