Dietary Nutrient Intake and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2.

PURPOSE: To analyze associations between the dietary intake of multiple nutrients and risk of progression to late age-related macular degeneration (AMD), its subtypes, and large drusen. DESIGN: Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline among AREDS participants (n = 4504) and AREDS2 participants (n = 3738) totaled 14 135 eyes. Mean age was 71.0 years (standard deviation, 6.7 years), and 56.5% of patients were women. METHODS: Fundus photographs were collected at annual study visits and graded centrally for late AMD. Dietary intake of multiple nutrients was calculated from food frequency questionnaires. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen. RESULTS: Over median follow-up of 10.2 years, of the 14 135 eyes, 32.7% progressed to late AMD. For 9 nutrients, intake quintiles 4 or 5 (vs. 1) were associated significantly (P ≤ 0.0005) with decreased risk of late AMD: vitamin A, vitamin B6, vitamin C, folate, ß-carotene, lutein and zeaxanthin, magnesium, copper, and alcohol. For 3 nutrients, quintiles 4 or 5 were associated significantly with increased risk: saturated fatty acid, monounsaturated fatty acid, and oleic acid. Similar results were observed for GA. Regarding neovascular AMD, 9 nutrients were associated nominally with decreased risk-vitamin A, vitamin B6, ß-carotene, lutein and zeaxanthin, magnesium, copper, docosahexaenoic acid, omega-3 fatty acid, and alcohol-and 3 nutrients were associated with increased risk-saturated fatty acid, monounsaturated fatty acid, and oleic acid. In separate analyses (n = 5399 eyes of 3164 AREDS participants), 12 nutrients were associated nominally with decreased risk of large drusen. CONCLUSIONS: Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD. These associations are stronger for GA than for neovascular AMD. The same nutrients also tend to show protective associations against large drusen development. Strong genetic interactions exist for some nutrient-genotype combinations, particularly omega-3 fatty acids and CFH. These data may justify further research into underlying mechanisms and randomized trials of supplementation.

Fundus autofluorescence and retinal sensitivity in fellow eyes of age-related macular degeneration in Japan.

PURPOSE: Abnormal fundus autofluorescence (FAF) potentially precedes onset of late age-related macular degeneration (AMD) in Caucasian patients. Many differences exist between Asian and Caucasian patients regarding AMD types and severity, gender, and genetic backgrounds. We investigated the characteristics of abnormal FAF and retinal sensitivity in the fellow eyes of Japanese patients with unilateral neovascular AMD. METHODS: Sixty-six patients with unilateral neovascular AMD and abnormal FAF in the fellow eye were enrolled in this multicenter, prospective, observational study. The best-corrected visual acuity, fundus photographs, FAF images, and retinal sensitivity on microperimetry were measured periodically for 12 months. The FAF images were classified into eight patterns based on the International Fundus Autofluorescence Classification Group. The points measured by microperimetry were superimposed onto the FAF images and fundus photographs and classified as "within," "close," and "distant," based on the distance from the abnormal FAF and other findings. The relationship between the location of the baseline abnormal FAF and retinal sensitivity was investigated. RESULTS: In Japanese patients, patchy (33.3%) and focally increased (30.3%) patterns predominated in the abnormal FAF. Intermediate-to-large drusen was associated predominantly with hyperfluorescence and hypofluorescence. Neovascular AMD developed within 1 year in six (9.1%) eyes, the mean baseline retinal sensitivity of which was 12.8 ± 4.7 dB, significantly (p<0.002) lower than the other eyes. In 44 of the other 60 eyes, microperimetry was measurable at baseline and month 12 and the mean retinal sensitivity improved significantly from 13.5 ± 4.4 to 13.9 ± 4.8 dB (p<0.001), possibly associated with lifestyle changes (e.g., smoking cessation, antioxidant and zinc supplementation). The mean retinal sensitivities of points within and close to the abnormal FAF were 9.9 and 11.7 dB, respectively, which were significantly lower than the 14.0 dB of the points distant from the abnormal FAF. CONCLUSION: In Japanese patients, patchy and focally increased patterns predominated in the abnormal FAF. The retinal sensitivity was lower close to/within the abnormal FAF. FAF and microperimetry are useful to assess macular function before development of neovascular AMD or geographic atrophy.

A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.

Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36.

IMPORTANCE: Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials. OBJECTIVE: To describe 10-year progression rates to intermediate or advanced AMD. DESIGN, SETTING, AND PARTICIPANTS: We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years. EXPOSURE: Treatment with antioxidant vitamins and minerals. MAIN OUTCOMES AND MEASURES: Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits. RESULTS: The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P = .005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200. CONCLUSIONS AND RELEVANCE: The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations.

Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.

IMPORTANCE: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.

Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 study.

OBJECTIVE: To evaluate the efficacy of docosahexaenoic acid (DHA)-enriched oral supplementation in preventing exudative age-related macular degeneration (AMD). DESIGN: The Nutritional AMD Treatment 2 study was a randomized, placebo-controlled, double-blind, parallel, comparative study. PARTICIPANTS: Two hundred sixty-three patients 55 years of age or older and younger than 85 years with early lesions of age-related maculopathy and visual acuity better than 0.4 logarithm of minimum angle of resolution units in the study eye and neovascular AMD in the fellow eye. METHODS: Patients were assigned randomly to receive either 840 mg/day DHA and 270 mg/day eicosapentaenoic acid (EPA) from fish oil capsules or the placebo (olive oil capsules) for 3 years. MAIN OUTCOME MEASURES: The primary outcome measure was time to occurrence of choroidal neovascularization (CNV) in the study eye. Secondary outcome measures in the study eye were: incidence of CNV developing in patients, changes in visual acuity, occurrence and progression of drusen, and changes in EPA plus DHA level in red blood cell membrane (RBCM). RESULTS: Time to occurrence and incidence of CNV in the study eye were not significantly different between the DHA group (19.5±10.9 months and 28.4%, respectively) and the placebo group (18.7±10.6 months and 25.6%, respectively). In the DHA group, EPA plus DHA levels increased significantly in RBCM (+70%; P<0.001), suggesting that DHA easily penetrated cells, but this occurred unexpectedly also in the placebo group (+9%; P = 0.007). In the DHA-allocated group, patients steadily achieving the highest tertile of EPA plus DHA levels in RBCM had significantly lower risk (-68%; P = 0.047; hazard ratio, 0.32; 95% confidence interval, 0.10-0.99) of CNV developing over 3 years. No marked changes from baseline in best-corrected visual acuity, drusen progression, or geographic atrophy in the study eye were observed throughout the study in either group. CONCLUSIONS: In patients with unilateral exudative AMD, 3 years of oral DHA-enriched supplementation had the same effect on CNV incidence in the second eye as did the placebo. However, RBCM fatty acid measurements revealed that CNV incidence was significantly reduced in DHA-supplemented patients showing a steadily high EPA plus DHA index over 3 years. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

[Complex diagnosis of the early macular changes due to AMD]. / Kompleksowa diagnostyka wczesnych zmian w plamce w przebiegu zwyrodnienia plamki zwiazanego z wiekiem.

We demonstrated diagnostic cases of the early macular changes due to AMD, which caused central visual field disturbances. The aim of the study was to systemize the management in patients with macular lesions due to the age related macular degeneration, frequency determination and statement of the performed additional tests range. Patients reported central visual field distortions. We performed visual acuity testing, stereoscopic eye fundus examination, and PHP (macular visual field testing), which objectified distortions symptoms. Based on that tests and fellow eye condition, decision about OCT and FA and ICG performance were made. Further management was determined according to the results of that examinations: follow-up with vitamins and microelements supplementation or PDT. Our analysis confirm, that to monitor early macular changes due to AMD, follow-up examinations in 2-3 months interval are indicated: visual acuity testing, stereoscopic eye fundus examination and macular lesions modeling in PHP In difficult cases or in more advanced lesions FA, OCT and ICG were performed.

The VECAT study: methodology and statistical power for measurement of age-related macular features. Vitamin E, Cataract, and Age-related Maculopathy Study.

PURPOSES: (1) To develop the methodology for the grading of macular one-frame stereoslides and to assess the reliability of the system. (2) To determine the prevalence of soft drusen (> 63 microm) and pigment abnormalities synonymous with age-related maculopathy (ARM) at baseline, in a clinical trial of volunteers aged between 55 and 80 years of age. (3) To ascertain the power of the study to detect the 4-year incidence and progression of ARM in vitamin E versus placebo treated participants, given the baseline prevalence. METHODS: The 1204 participants enrolled in the Vitamin E, Cataract, and Age-related Maculopathy Study (VECAT) had colour stereoslides of their fundus taken using the Nidek 3-DX mydriatic fundus camera. The stereoslides were graded by two masked graders according to the "International Classification System for ARM and AMD". Assessment of inter- and intra-observer reliability was carried out on a regular basis on 15% of randomly selected slides. Anticipated rates of incidence and progression were based on results reported by the Beaver Dam Eye Study and the Chesapeake Bay Waterman Study. Power estimations were determined using the "nQuery Advisor" software program. Analyses were carried out on the worse affected eye. RESULTS: Inter-observer reliability was moderate to substantial (Kappa 0.5-0.88) whilst intra-observer agreement was high (0.6-1.0). The prevalence of any soft drusen was 32%. Significant associations were found between soft large indistinct drusen, hypopigmentation, hyperpigmentation and age (p = 0.0001, 0.024 and 0.0001, respectively). The study has at least 87% power to detect an odds ratio equal to two for the progression of soft distinct, soft indistinct, hyperpigmentation and hypopigmentation. CONCLUSIONS: The VECAT study methodology appears to be highly reliable and to have sufficient power to detect the differences in the four-year progression of soft distinct and indistinct drusen and pigment abnormalities between the treatment groups.