Oral protein kinase c ß inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study 2.

PURPOSE: To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study and Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C ß inhibitor trials. METHODS: Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity ≥45 letters (∼20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in ≥1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (≥15-letter loss sustained for the last 6 months of study). RESULTS: In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A ≥15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a ≥15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified. CONCLUSION: Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema.

Evaluation of the age-related eye disease study clinical lens grading system AREDS report No. 31.

PURPOSE: To examine the grading (interrater) reliability of the Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System (ARLNS). DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: One hundred fifty volunteers (284 eyes). METHODS: Participants with lens opacities of varying severity were independently graded at the slit lamp for cataract severity by 2 examiners (retinal or anterior segment specialists) using the ARLNS, which employs 3 standard photographs of increasing severity for classifying each of the 3 major types of opacity. Lens photographs were taken and graded at a reading center using the more detailed AREDS System for Classifying Cataracts from photographs. MAIN OUTCOME MEASURES: The Pearson correlation, weighted-kappa, and limits-of-agreement statistics were used to assess the interrater agreement of the gradings. RESULTS: Examinations were performed on 284 lenses (150 participants). Tests of interrater reliability between pairs of clinicians showed substantial agreement between clinicians for cortical and posterior subcapsular opacities and moderate agreement for nuclear opacities. A similar pattern and strength of agreement was present when comparing scores of retinal versus anterior segment specialists. Interrater agreement between clinical and reading center gradings was not as great as inter-clinician agreement. CONCLUSIONS: Interrater agreements were in the moderate to substantial range for the clinical assessment of lens opacities. Inherent differences in cataract classification systems that rely on slit lamp vs photographic assessments of lens opacities may explain some of the disagreement noted between slit lamp and photographic gradings. Given the interrater reliability statistics for clinicians and the simplicity of the grading procedure, ARLNS is presented for use in studies requiring a simple, inexpensive method for detecting the presence and severity of the major types of lens opacities. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Effects of multivitamin/mineral supplementation on plasma levels of nutrients. Report No. 4 of the Italian-American clinical trial of nutritional supplements and age-related cataract.

The use of multivitamin-mineral supplements has become increasingly common, but whether the use of such supplements improves micronutrient status remains still unclear. The objective of this report is to investigate how a long-term vitamin-mineral supplementation following the US Recommended Daily Intake (RDI) affected the plasma levels of selected nutrients in a subset (No. = 407) of participants in the Italian-American Clinical Trial of Nutritional Supplements and Age-related Cataract (CTNS). The CTNS was a double-blind, single centre, controlled clinical trial of 1020 participants aged 55-75 years randomized to a daily tablet of Centrum(R) or placebo. A representative sample of 40% of the 1020 subjects, whom plasma level of selected vitamins was determined at the baseline, was retested throughout the treatment period that averaged 9.0 +/- 2.4 years. Participants assigned to Centrum(R) showed a significant increase (p < 0.005) in mean/median plasma levels of vitamin E, beta-carotene, folate, and vitamin B12, and an improved riboflavin status when compared with participants assigned to placebo. Differences concerning vitamin C were statistically less relevant and those concerning vitamin A were at a borderline level. In the treated group the effect of supplementation on plasma levels of vitamins A, E, and C, and on the glutathione reductase activation coefficient was significantly higher in participants with lower nutritional status at baseline.

Dietary compound score and risk of age-related macular degeneration in the age-related eye disease study.

PURPOSE: Because foods provide many nutrients that may interact to modify risk for multifactorial diseases such as age-related macular degeneration (AMD), we sought to develop a composite scoring system to summarize the combined effect of multiple dietary nutrients on AMD risk. This has not been done previously. DESIGN: Cross-sectional study. PARTICIPANTS: From the 4003 participants in the Age-Related Eye Disease Study (AREDS), there were 7,934 eyes included in this study. METHODS: Considering dietary intakes of vitamins C and E, zinc, lutein/zeaxanthin, docosahexaenoic acid, eicosapentaenoic acid, and low-dietary glycemic index (dGI) from AREDS baseline information, we assigned each nutrient a percentile rank score then summed them into a compound score for each participant. Using eye as the unit of analysis, we evaluated the association between the compound score and risk of prevalent AMD. Validation, fitness, and performance of the model were evaluated using bootstrapping techniques, adjusted quasi-likelihood under the independence model criterion, and the c-index, respectively. MAIN OUTCOME MEASURES: Stereoscopic fundus photographs of the macula were taken and graded at baseline using the AREDS protocol and AMD Classification System. RESULTS: Our results showed that higher compound scores were associated with lower risk for early AMD, indicated by drusen, and advanced AMD. Validation analyses indicated that these relationships are robust (the average 50-time bootstrapping per quartile odds ratios = 0.727, 0.827, and 0.753, respectively, for drusen, and 0.616, 0.536, and 0.572, respectively, for advanced AMD). Model selection analyses suggested that the compound score should be included, but that measures of dietary beta-carotene should not be included. CONCLUSIONS: We found that consuming diets that provide low dGI and higher intakes of these nutrients were associated with the greatest reduction in risk for prevalent drusen and advanced AMD, whereas dietary beta-carotene did not affect these relationships. These findings warrant further prospective studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Risk of advanced age-related macular degeneration after cataract surgery in the Age-Related Eye Disease Study: AREDS report 25.

PURPOSE: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). METHODS: 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. MAIN OUTCOME MEASURES: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). RESULTS: 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. CONCLUSIONS: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema.

PURPOSE: To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters. METHODS: In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. RESULTS: Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). CONCLUSIONS: The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).

The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.

OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3.

OBJECTIVE: To evaluate the effect of a multivitamin/mineral supplement on development or progression of age-related lens opacities. DESIGN: Randomized, double-masked, single center, placebo-controlled clinical trial. PARTICIPANTS: One thousand twenty participants, 55 to 75 years old and with early or no cataract, were randomly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo. METHODS: Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts. MAIN OUTCOME MEASURES: The primary outcome was a prespecified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity (VA) loss from baseline > or =15 letters. RESULTS: Participants were observed for an average of 9.0+/-2.4 years. There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68-0.98; P = 0.03). Nuclear events were significantly less common (HR, 0.66; 95% CI, 0.50-0.88; P = 0.004) and PSC events significantly more common (HR, 2.00; 95% CI, 1.35-2.98; P<0.001) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo. No statistically significant treatment effects were seen for cortical opacities, moderate VA loss, or cataract surgery. CONCLUSIONS: Lens events were less common in participants who took the multivitamin/mineral formulation, but treatment had opposite effects on the development or progression of nuclear and PSC opacities, the 2 most visually important opacity subtypes.

Dietary carbohydrate and the progression of age-related macular degeneration: a prospective study from the Age-Related Eye Disease Study.

BACKGROUND: Cross-sectional studies indicate that diets that provide a higher dietary glycemic index (dGI) are associated with a greater risk of age-related macular degeneration (AMD). No prospective studies have addressed this issue. OBJECTIVE: The objective was to prospectively evaluate the effect of baseline dGI on the progression of AMD. DESIGN: dGI was calculated as the weighted average of GIs from foods and was evaluated as being above or below the sex median (women: 77.9; men: 79.3) for 3977 participants aged 55-80 y (58% women) in the Age-Related Eye Disease Study. The 7232 eligible eyes without advanced AMD were classified into 1 of 3 AMD categories: group 1 (nonextensive small drusen), group 2 (intermediate drusen, extensive small drusen, or pigmentary abnormalities), or group 3 (large drusen or extensive intermediate drusen). With the use of multifailure Cox proportional-hazards regression, we modeled the time to the maximal progression to evaluate the relation between dGI and the risk of AMD. RESULTS: Overall, the multivariate-adjusted risk of progression over 8 y of follow-up (x: 5.4 y) was significantly higher (risk ratio: 1.10; 95% CI: 1.00, 1.20; P = 0.047) in the high-dGI group than in the low-dGI group. The risk of progression for groups 1, 2, and 3 eyes was 5%, 8%, and 17% greater, respectively (P for trend < 0.001). The latter gives an estimate that 7.8% of new advanced AMD cases would be prevented in 5 y if people consumed the low-dGI diet. CONCLUSION: Persons at risk of AMD progression, especially those at high risk of advanced AMD, may benefit from consuming a smaller amount of refined carbohydrates.

The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22.

OBJECTIVE: To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol, and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with < 15 small drusen). Nutrient intake was estimated from a self-administered semiquantitative food frequency questionnaire at enrollment. Intake values were energy adjusted and classified by quintiles. The relationship between diet and AMD status was assessed using logistic regression analyses. RESULTS: Dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.93), geographic atrophy (OR, 0.45; 95% CI, 0.24-0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56-0.96), comparing the highest vs lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients were not independently related to AMD. CONCLUSION: Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen.

Association between dietary glycemic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study.

BACKGROUND: Age-related macular degeneration (AMD) is the major cause of irreversible blindness. AMD appears to share several carbohydrate-related mechanisms and risk factors with diabetes-related diseases, including retinopathy and cardiovascular disease (CVD); however, to date, only one small study has addressed this issue. OBJECTIVE: The objective was to test the hypothesis that dietary glycemic index (dGI), which has been related to the risk of diabetes and CVD, is associated with the risk and severity of AMD in nondiabetic elderly populations. DESIGN: Dietary information was obtained from 4099 participants aged 55-80 y (56% women) in the Age-Related Eye Disease Study (AREDS). A total of 8125 eligible eyes at baseline were classified into 1 of 5 AMD groups according to the size and extent of drusen, the presence of geographic atrophy, and neovascular changes. We used a generalized estimating approach to evaluate the relations between dGI and risk and severity of AMD with eyes as the unit of analysis. RESULTS: Compared with eyes in the first quintile of dGI, eyes in the fourth and fifth quintiles had a significantly or suggestively higher risk of large drusen, geographic atrophy, and neovascularization. The multivariate-adjusted odds ratios (95% CIs) for the highest quintile were 1.42 (1.09, 1.84), 1.78 (0.81, 3.90), and 1.41 (0.95, 2.08), respectively, of which only the odds ratio for large drusen was significant. A significant positive relation between dGI and severity of AMD was also noted (P for trend < 0.001). There was a 49% increase in the risk of advanced AMD (geographic atrophy plus neovascularization) for persons with a dGI higher than the sex median (women: >or=77.9; men: >or=79.3). This result indicated that 20% of prevalent cases of AMD would have been eliminated if the AREDS participants consumed diets with a dGI below the median. CONCLUSION: The association between dGI and AMD from the AREDS cross-sectional analysis at baseline suggests that a reduction in the dGI, a modifiable risk factor, may provide a means of diminishing the risk of AMD.

The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.

OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.

OBJECTIVE: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes. DESIGN: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial. PARTICIPANTS: Six hundred eighty-five patients randomized at 70 clinical sites. METHODS: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye. MAIN OUTCOME MEASURE: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy. RESULTS: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008). CONCLUSION: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Centrum use and progression of age-related cataract in the Age-Related Eye Disease Study: a propensity score approach. AREDS report No. 21.

PURPOSE: To evaluate the effect of the multivitamin Centrum on the development and progression of age-related lens opacities. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Four thousand five hundred ninety individuals with at least one natural lens and photographic follow-up (median, 6.3 years) were assessed for development or progression of lens opacities. MAIN OUTCOME MEASURES: Progression of "any" lens opacity or type-specific opacity was ascertained from lens photographs taken at baseline and at annual visits beginning at year 2. METHODS: The Age-Related Eye Disease Study (AREDS) showed no statistically significant effect of a high-dose antioxidant formulation on progression of lens opacities. Centrum also was provided to approximately two thirds of the study participants. Because Centrum use was elective, a logistic regression model of baseline characteristics was used to generate a propensity score for Centrum use. Repeated-measures logistic regression, adjusted for propensity score and other covariates, was used to evaluate associations of Centrum use and lens opacity. RESULTS: Centrum use, adjusted for propensity score and other covariates, was associated with a reduction in "any" lens opacity progression (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.72-0.98, P = 0.025). Results for individual lens opacity types suggested that Centrum use was protective for nuclear opacity events (OR = 0.75, 95% CI = 0.61-0.91, P = 0.004). CONCLUSION: Observational data from the AREDS and other studies suggest that use of a multivitamin may delay the progression of lens opacities. A National Eye Institute-sponsored clinical trial scheduled for completion in 2007 will provide additional data on Centrum use and cataract development.

Dietary carbohydrate intake and glycemic index in relation to cortical and nuclear lens opacities in the Age-Related Eye Disease Study.

BACKGROUND: Little is known about the association between dietary carbohydrates and cataract in nondiabetic persons. OBJECTIVE: The aim was to test whether recent dietary carbohydrate intakes or glycemic index (GI; a measure of carbohydrate intake quality) was associated with the presence of cortical or nuclear opacities. DESIGN: A modified Block food-frequency questionnaire was used to obtain dietary information from 3377 participants (aged 60-80 y; 56% were women) in the Age-Related Eye Disease Study (AREDS). Lens status was evaluated by using the AREDS System for Classifying Cataracts. Associations were examined for eyes with only a single, or pure, type of lens opacity by using the generalized estimating approach to logistic regression to account for the lack of independence between the eyes of a person. RESULTS: For participants in the highest quartile, dietary GI was associated with a higher prevalence of all pure nuclear opacities [grade >2; odds ratio (OR): 1.29; 95% CI: 1.04, 1.59; P for trend = 0.02] and moderate nuclear opacities (grade > or =4; OR: 1.43; 95% CI: 0.96, 2.14; P for trend = 0.052). The OR in a comparison of the highest with the lowest quartile of intake was 1.27 (95% CI: 0.99, 1.63; P for trend = 0.09) for cortical opacities of any severity (>0% of area opaque), and the OR increased somewhat for moderate cortical opacities (>5% of area opaque; OR: 1.71; 95% CI: 1.00, 2.95; P for trend = 0.056). CONCLUSIONS: Results from the cross-sectional analysis of AREDS baseline data suggest that dietary glycemic quality and dietary carbohydrate quantity may be associated with prevalent nuclear and cortical opacities, respectively.

C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration.

OBJECTIVE: We investigated whether age-related macular degeneration risk factors are associated with high-sensitivity C-reactive protein (CRP) and homocysteine (HCY), systemic biomarkers for cardiovascular disease. METHODS: Subjects with a range of age-related macular maculopathies or no maculopathy at two centers in the United States were evaluated. Risk factors and biomarkers were assessed by questionnaire, direct measurement, or analyses of blood specimens. RESULTS: Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake were associated with lower serum CRP levels, whereas serum vitamin E, smoking, and increased body mass index were associated with increased CRP. Serum vitamin E, serum alpha-carotene, and dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY, whereas hypertension was associated with increased HCY. CONCLUSIONS: C-reactive protein and HCY levels are related to traditional dietary and behavioral factors associated with age-related macular degeneration.

Evaluation of plasma homocysteine and risk of age-related macular degeneration.

PURPOSE: To assess the relationship between plasma levels of homocysteine and age-related macular degeneration (AMD). DESIGN: Cross-sectional, case-control study. METHODS: Fasting plasma homocysteine levels were measured at two centers in 934 individuals who were participating in an ancillary study of the Age-Related Eye Disease Study. There were 547 cases and 387 control subjects, who were determined by fundus photography. Conditional logistic regression analyses were conducted to assess the association of homocysteine with AMD. RESULTS: Median values of homocysteine were higher among advanced AMD cases (9.51 mmol/l) compared with persons with no AMD (8.81 mmol/l; P = .01). Values of >12 mmol/l vs < or =12 mmol/l were also associated with an increased risk of AMD (P = .023), when controlled for other covariates. CONCLUSION: Results are consistent with a possible small, independent association between higher homocysteine levels and AMD. Homocysteine may be a modifiable risk factor for AMD.

The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17.

OBJECTIVE: To develop a fundus photographic severity scale for age-related macular degeneration (AMD). METHODS: In the Age-Related Eye Disease Study, stereoscopic color fundus photographs were taken at baseline, at the 2-year follow-up visit, and annually thereafter. Photographs were graded for drusen characteristics (size, type, area), pigmentary abnormalities (increased pigment, depigmentation, geographic atrophy), and presence of abnormalities characteristic of neovascular AMD (retinal pigment epithelial detachment, serous or hemorrhagic sensory retinal detachment, subretinal or sub-retinal pigment epithelial hemorrhage, subretinal fibrous tissue). Advanced AMD was defined as presence of 1 or more neovascular AMD abnormalities, photocoagulation for AMD, or geographic atrophy involving the center of the macula. We explored associations among right eyes of 3212 participants between severity of drusen characteristics and pigmentary abnormalities at baseline and development of advanced AMD within 5 years of follow-up. RESULTS: A 9-step severity scale that combines a 6-step drusen area scale with a 5-step pigmentary abnormality scale was developed, on which the 5-year risk of advanced AMD increased progressively from less than 1% in step 1 to about 50% in step 9. Among the 334 eyes that had at least a 3-step progression on the scale between the baseline and 5-year visits, almost half showed stepwise progression through intervening severity levels at intervening visits. Replicate gradings showed agreement within 1 step on the scale in 87% of eyes. CONCLUSIONS: The scale provides convenient risk categories and has acceptable reproducibility. Progression along it may prove to be useful as a surrogate for progression to advanced AMD.

A simplified severity scale for age-related macular degeneration: AREDS Report No. 18.

OBJECTIVE: To develop a simplified clinical scale defining risk categories for development of advanced age-related macular degeneration (AMD). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19.

PURPOSE: To describe the association of demographic, behavioral, medical, and nonretinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA) in the Age-Related Eye Disease Study (AREDS), a randomized trial of antioxidants and zinc supplementation prophylaxis for development of advanced AMD. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Of individuals with early or intermediate AMD at baseline with a median follow-up of 6.3 years, 788 were at risk of developing advanced AMD in one eye (the fellow eye had advanced AMD), and 2506 were at risk in both eyes. METHODS: The incidence of neovascular AMD and CGA was assessed from stereoscopic color fundus photographs taken at baseline and at annual visits beginning at year 2. MAIN OUTCOME MEASURES: Neovascular AMD was defined as photocoagulation for choroidal neovascularization, or photographic documentation at the reading center of any of the following: nondrusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and subretinal fibrosis. Central geographic atrophy was defined as geographic atrophy involving the center of the macula. RESULTS: In multivariable models, in persons at risk of advanced AMD in both eyes, while controlling for age, gender, and AREDS treatment group, the following variables were statistically significantly associated with the incidence of neovascular AMD: race (odds ratio [OR], white vs. black, 6.77; 95% confidence interval [CI], 1.24-36.9) and larger amount smoked (OR, >10 vs. < or =10 pack-years [a pack-year is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09). The following were statistically significantly associated with the incidence of CGA: less education (OR, high school graduate or less vs. college graduate, 1.75; 95% CI, 1.10-2.78), greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65), larger amount smoked (OR, >10 pack-years vs. < or =10 pack-years, 1.82; 95% CI, 1.25-2.65), and antacid use (OR, 0.29; 95% CI, 0.09-0.91). In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31), and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59). CONCLUSIONS: Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD, and suggest other associations (e.g., use of antacids and antiinflammatory medications) that warrant further study. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. .