Age-Related Eye Disease Study Classification Research Articles

Age-related macular degeneration discordance in monozygotic twin pairs.

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

Association Between Fatty Acid Intakes and Age-Related Macular Degeneration in a Japanese Population: JPHC-NEXT Eye Study

To determine the associations between fatty acid intakes and the prevalence of age-related macular degeneration (AMD) under a population-based cross-sectional study. Residents of Chikusei City aged ≥40 years underwent systemic and eye screening. AMD was graded according to a modified version of the Age-Related Eye Disease Study classification. Dietary intake was assessed using a food frequency questionnaire and was adjusted for total energy intake. Altogether, 10,788 eyes of 5394 participants, 2116 men (mean [standard deviation (SD)] age, 62.4 [9.4] years) and 3278 women (60.6 [9.5] years), were included. The mean daily total fat intakes were 52.8 g and 59.0 g in men and women, respectively. After adjustments for potential confounders, saturated fatty acid (SFA) intake was inversely associated with the prevalence of any AMD in men (for each energy-adjusted 1-SD increase: odds ratio [OR], 0.86; 95% confidence interval [CI], 0.74-1.00). Significant trends were found for decreasing odds ratios of AMD with increasing SFA, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake (P for trend = 0.02, 0.04, and 0.04, respectively). In women, only a significant association was observed between the second quartile of linolenic acid intake and the prevalence of any AMD (OR, 0.78; 95% CI, 0.62-0.99). We found an inverse association of SFA intake and a weak inverse association of MUFA and PUFA intakes with the prevalence of any AMD in a Japanese population. Adequate fatty acid intake may be necessary to prevent or decelerate AMD.

Assessing the quality of life in age-related macular degeneration patients: a cross-sectional study in Kazakhstan.

The goal of this study was to assess Vision-Related Quality of Life (VRQoL) in patients with Age-Related Macular Degeneration (AMD) and identify its significant predictors. 458 AMD patients from four eye clinics in three major cities of Kazakhstan were recruited for this study. Data were collected using a structured questionnaire on sociodemographic and visual information and the National Eye Institute-VisualFunction Questionnaire-39 (NEI-VFQ-39). The study sample included 181 male patients who were 64.9 years on average (SD±8.4), and 277 female patients who were 68.7 years on average (SD±10.7). The majority of patients had stage 2 (43.7%) or stage 3 (40.2%) AMD according to the Age-Related Eye Disease Study (AREDS) classification. The mean (SD) NEI-VFQ-39 total score was 58.0 (23.8), range (9.8 - 100). The multiple linear regression model showed that the VRQoL of AMD patients correlated with the AMD stage according to the AREDS classification, age of the patients, visual acuity, number of years since the AMD diagnosis, and the city of residence. AMD causes severe vision impairment and daily functioning problems, reducing the quality of life of patients. To diagnose and treat degenerative eye disorders at an early stage, it is essential to inform patients about regular ophthalmological checkups to diagnose and treat degenerative eye disorders at an early stage.

Association between age-related macular degeneration and 25(OH) vitamin D levels in the Turkish population.

Age-related macular degeneration is the most common cause of blindness in developed countries, and several factors have been attributed for its etiology. This study was conducted to explore the relationship between serum vitamin D levels and age-related macular degeneration. We retrospectively analyzed the data of 114 patients with age-related macular degeneration. A total of 102 patients who did not have any other diseases than refractive error were allocated to the control group. The best-corrected visual acuity, fundus findings, and spectral domain optical coherence tomography findings were analyzed. Patients were allocated to groups based on the Age-related Eye Disease Study classification. Serum 25(OH) vitamin D levels were measured. The central foveal thickness and the subfoveal choroidal thickness were measured by optical coherence tomography. The 25(OH) vitamin D levels in age- and gender-matched patients with age-related macular degeneration and in healthy subjects were 14.6 ± 9.8 and 29.14 ± 15.1 ng/ml, respectively. The age-related macular degeneration group had significantly lower vitamin D levels than the control group (p>0.001). The subfoveal choroidal thickness was lower in patients with age-related macular degeneration (p>0.001). The 25(OH) vitamin D level showed a weak positive correlation with choroidal thickness (r=0.357, p=0.01). When the level of 25(OH) vitamin D was evaluated according to the stages of age-related macular degeneration, it was found to be lower in the advanced-stage disease (p=0.01). The risk for the development of choroid neovascular membrane and subretinal fibrosis was found to increase with decreased vitamin D levels. Significantly decreased levels of 25(OH) vitamin D in advanced-stage age-related macular degeneration suggest a significant correlation existing between vitamin D deficiency and age-related macular degeneration development. Further studies are required to examine whether vitamin D supplementation has an effect on the development and progression of age-related macular degeneration.

Genomic-Metabolomic Associations Support the Role of LIPC and Glycerophospholipids in Age-Related Macular Degeneration.

Purpose:Large-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP–metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs.Design:Cross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal).Participants:Patients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years).Methods:Age-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR).Main Outcome Measures:Plasma metabolite levels associated with AMD risk SNPs.Results:After quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (β = 0.016−0.083; FDR q-value < 1.14 × 10−2), which corresponded to 5 metabolites and 2 genes: ASPM and LIPC. Polymorphisms in the LIPC gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the ASPM gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score–metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome.Conclusions:This study demonstrated that genomic–metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the LIPC gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.

Association of Drusen Phenotype in Age-Related Macular Degeneration from Human Eye-Bank Eyes to Disease Stage and Cause of Death

To stage maculopathy, assess and quantify drusen, determine drusen subtype frequency, and compare subtypes with age-related macular degeneration (AMD) stage and cause of death using an eye-bank model of AMD. Cross-sectional study. Two thousand ninety-two human eyes from 1067 eye-bank donors, selected from a population at risk for AMD. We analyzed donor eye tissue images (2005-2020) using both the 4- and 9-step Minnesota Grading System (MGS), an AMD grading system for eye-bank eyes corresponding to the Age-Related Eye Disease Study classification. The 9-step MGS quantifies total drusen area, hyperpigmentation, and depigmentation. We analyzed reticular pseudodrusen (RPD), basal laminar drusen (BLD), and calcified drusen (CaD) frequency within this population and explored associations with AMD stage, donor age, gender, and cause of death. Statistical analyses were performed using Wilcoxon rank-sum and chi-square tests. Testing encompassed staging eye-bank eyes using MGS analysis. Drusen subtype frequency associations with AMD stage and cause of death. We detected RPD in 228 (13%), BLD in 131 (7%), and CaD in 84 (5%) of the examined eyes (n=1777). All subtypes were associated with advanced AMD (RPD: odds ratio [OR], 3.4 [95% confidence interval (CI), 2.5-4.5; P < 0.0001]; BLD: OR, 2.2 [95% CI, 1.5-3.2; P < 0.0001]; and CaD: OR, 39.1 [95% CI, 16.8-91.0; P< 0.0001]). Only the RPD subtype was associated statistically with cardiovascular death when compared with those without cardiovascular death (48% vs. 32%; OR, 2.0 [95% CI, 1.4-2.9]; P= 0.0002). In a large group of eye-bank eyes selected from a population at risk for AMD and graded using the 4-step and 9-step MGS, RPD, BLD, and especially CaD were associated strongly with advanced AMD. The RPD subtype was associated with a cardiovascular cause of death and may represent an ophthalmologic biomarker for cardiovascular disease.

Comparison of choriocapillary flow density between fellow eyes of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration

BackgroundTo compare the choriocapillary flow density (CFD) among the fellow eyes of polypoidal choroidal vasculopathy (PCV), neovascular age-related macular degeneration (nAMD), and healthy controls using spectral-domain optical coherence angiography tomography (SD-OCTA).MethodsThis is a cross-sectional study that includes the fellow eyes of 38 patients with unilateral PCV, 36 patients with unilateral nAMD, and 36 eyes from 36 healthy volunteers. The PCV group was further classified into polypoidal CNV (P-CNV) and typical PCV (T-PCV) for subgroup analysis. The age, subfoveal choroidal thickness (SFCT), Age-Related Eye Disease Study (AREDS) classification, and fellow eye diagnosis were acquired. All subjects underwent SD-OCTA with a 6.0-mm scan pattern. Circles with radius of 1.00, 1.50, and 3.00 mm were manually selected in the choriocapillaris (CC) slab, and the CFD was calculated as the percentage of the flow area to the whole selected area as CFD-1.00, 1.50, and 3.00, respectively. Univariate and multivariate analysis were performed to study the correlation between the aforementioned factors with CFD.ResultsThe mean CFD-1.00, 1.50, and 3.00 of the nAMD group were 61.51, 63.18, and 66.20, respectively; these were significantly lower than those of the PCV group (65.90, 66.89, and 67.94; P < 0.001, P < 0.001, and P = 0.010; respectively) and control group (66.28, 66.96, and 68.42; P < 0.001, P < 0.001, and P = 0.001, respectively), and no difference was detected between the PCV and control group or between PCV subtypes. The AREDS classification and fellow eye diagnosis were correlated with CFD in univariate analysis; however, only the fellow eye diagnosis showed a significant correlation after multiple linear regression.ConclusionsThe CFD of nAMD fellow eyes was significantly lower than that of PCV and control eyes, and no difference was detected between PCV and control group, indicating that CC loss plays a different role in the early pathogenesis of nAMD and PCV.

Novel Association of High C-Reactive Protein Levels and A69S at Risk Alleles in Wet Age-Related Macular Degeneration Women.

To explore the relationship between plasma C-reactive protein (CRP) levels, the main ARMS2 gene single nucleotide polymorphism (SNP), and gender in patients with neovascular age-related macular degeneration (wet AMD). Our study included 131 patients with wetAMD [age-related eye disease study (AREDS) category 4] and 153 control participants (AREDS category 1) from two Spanish retinal units. CRP levels were determined on blood samples by high-sensitivity ELISA assay. According to their CRP level, subjects were categorized into three well-established CRP categories: low (<1.00 mg/L, L-CRP), moderate (1-2.99 mg/L, M-CRP), and high (>3.00 mg/L, H-CRP). Genomic DNA was extracted from oral swabs using QIAcube (Qiagen, Hilden, Germany) and the A69S; rs10490924 of ARMS2 gene was genotyped by allelic discrimination with validated TaqMan assays (Applied Biosystems, Foster City, CA, USA). Univariate and multivariate logistic regression adjusted for age was used to analyze the genomic frequencies and to calculate odds ratio (OR) using SNPStats software. Considering CRP risk categories, H-CRP group showed a significant [OR 4.0 (1.9-8.3)] association with wetAMD compared to L-CRP group. The risk genotypes of A69S (TT) SNPs showed an association with wetAMD risk [OR 14.0 (4.8-40.8)]. Interestingly, the gender stratification of the CRP categories showed a significant increase in CRP levels in wetAMD women compared with control women [OR 6.9 (2.2-22.3)] and with wetAMD men [OR 4.6 (1.3-16.9)]. In addition, the subgroup analysis of CRP within A69S genotype and gender showed a link in women between the A69S and CRP levels in the AMD group compared to controls [OR 4.2 (1.4-12.6)]. Our study shows, for the first time, that a different genetic association related with gender could contribute to AMD risk. As a consequence, the risk of female gender in the different CRP levels and A69S SNP frequencies could be taken into consideration to the established risk relationship of high levels of CRP and its association with risk A69S genotype.

Peripheral Changes Associated With Delayed Dark Adaptation in Age-related Macular Degeneration

To study the association between peripheral changes in age-related macular degeneration (AMD) and dark adaptation (DA). Prospective, cross-sectional study. We recruited patients with AMD and a control group (>50 years) without any vitreoretinal disease. Ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) were obtained, and were assessed by 2 graders for the presence of several peripheral changes in perimacular, midperipheral, and far-peripheral zones. All participants were also imaged with 7-field color fundus photographs used for AMD staging (Age-Related Eye Disease Study classification system). Both eyes of study participants were tested with a dark adaptation (DA) extended protocol (20minutes). Multilevel mixed-effect models (accounting for correlated outcomes between 2 eyes) were used for analyses. We included 128 eyes (n= 72 patients), 75% with AMD and the remainder controls. The presence of reticular pigmentary changes in the midperipheral (ß= 4.3, P= .012) and far-peripheral zones (ß= 8.4, P< .001) was associated with delayed rod-intercept times (RITs), even after adjusting for confounding factors. The presence, number, and extent of peripheral classic drusen did not show a similar association (P ≥ .148). The presence of a mottled decreased FAF pattern in the midperipheral zone was also associated with prolonged RITs (β= 4.4, P= .031). Our results suggest an association between DA and the presence of peripheral reticular pigmentary changes, as well as the presence of a peripheral mottled decreased FAF pattern. This provides new insights on the clinical significance of peripheral changes in AMD, and their contribution to impairments on DA.

MMP-2 Rs24386 (C-->T) gene polymorphism and the phenotype of age-related macular degeneration.

To examine the MMP-2 (-1306 C/T) gene polymorphism and the phenotype characterized by soft and hard drusen of early age-related macular degeneration (AMD) and geographic atrophy of late AMD form. The study enrolled 850 investigations (290 AMD patients with soft and hard drusen, 34 with geographic atrophy and a random sample of the population n=526). Early AMD was classified according to the International Classification and Grading System. For geographic atrophy diagnosis the Age-Related Eye Disease Study classification was used. The potential association with single nucleotide polymorphisms on MMP-2 Rs243865 was evaluated for all patients, adjusted for age and sex. The genotyping test of MMP-2 Rs243865 (C-->T) was conducted using the real-time polymerase chain reaction method. MMP-2 (-1306 C/T) C/C genotype was more frequently detected in AMD patients with hard drusen than the soft drusen or control group (66.43% vs 53.74%, vs 54.94%, P=0.047). Logistic regression analysis showed that the MMP-2 (-1306) C/C genotype increased the likelihood to develop hard drusen in AMD patients (OR=1.7, 95% CI: 1.06-2.74; P=0.028). No association between MMP-2 (-1306 C/T) gene polymorphism in patients with atrophic AMD and control group was found (54.94%, 37.64%, 7.41% vs 50%, 38.24%, 11.76%; P=0.6). The MMP-2 Rs24386 (C-->T) polymorphism is found to be associated with the development of hard drusen in patients with AMD.

Human Plasma Metabolomics Study across All Stages of Age-Related Macular Degeneration Identifies Potential Lipid Biomarkers

To characterize the plasma metabolomic profile of patients with age-related macular degeneration (AMD) using mass spectrometry (MS). Cross-sectional observational study. We prospectively recruited participants with a diagnosis of AMD and a control group (>50years of age) without any vitreoretinal disease. All participants underwent color fundus photography, used for AMD diagnosis and staging, according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and plasma was analyzed by Metabolon, Inc. (Durham, NC), using ultrahigh-performance liquid chromatography (UPLC) and high-resolution MS. Metabolon's hardware and software were used to identify peaks and control quality. Principal component analysis and multivariate regression were performed to assess differences in the metabolomic profiles of AMD patients versus controls, while controlling for potential confounders. For biological interpretation, pathway enrichment analysis of significant metabolites was performed using MetaboAnalyst. The primary outcome measures were levels of plasma metabolites in participants with AMD compared with controls and among different AMD severity stages. We included 90 participants with AMD (30 with early AMD, 30 with intermediate AMD, and 30 with late AMD) and 30 controls. Using UPLC and MS, 878 biochemicals were identified. Multivariate logistic regression identified 87 metabolites with levels that differed significantly between AMD patients and controls. Most of these metabolites (82.8%; n= 72), including the most significant metabolites, belonged to the lipid pathways. Analysis of variance revealed that of the 87 metabolites, 48 (55.2%) also were significantly different across thedifferent stages of AMD. A significant enrichment of the glycerophospholipids pathway was identified (P=4.7× 10-9) among these metabolites. Participants with AMD have altered plasma metabolomic profiles compared with controls. Our data suggest that the most significant metabolites map to the glycerophospholipid pathway. These findings have the potential to improve our understanding of AMD pathogenesis, to support the development of plasma-based metabolomics biomarkers of AMD, and to identify novel targets for treatment of this blinding disease.

Cost-effectiveness of age-related macular degeneration study supplements in the UK: combined trial and real-world outcomes data

AimsTo evaluate the cost-effectiveness of Age-Related Eye Disease Study (AREDS) 1 & 2 supplements in patients with either bilateral intermediate age-related macular degeneration, AREDS category 3, or unilateral neovascular age-related...

NUTRITIONAL SUPPLEMENTATION IN AGE-RELATED MACULAR DEGENERATION.

To evaluate the rate of adherence to prescribed nutritional supplementation in patients affected by age-related macular degeneration, in an Italian tertiary referral tertiary center. Patients with age-related macular degeneration, age-related eye disease study Categories 3 and 4, were recruited and underwent an 11-item questionnaire. The study included a total of 193 patients meeting the age-related eye disease study nutritional supplementation criteria (174 patients with age-related eye disease study Category 4 and 19 with Category 3). Seventy-seven (40%) were taking oral supplementation, 70 of whom (90%) 1 tablet/day. Oral supplementation was recommended by the personal ophthalmologist in 85 patients (44%), including all those currently receiving it. Eight patients of 85 (9.4%) rejected supplementation despite it being recommended, mostly because they were already taking other medicines. Ninety-four patients (48%) claimed they had not received any information from their ophthalmologist. Our data reveal that Italian patients with age-related eye disease study Categories 3 and 4 have a low adherence to nutritional supplementation. In 65% of cases, patients were not adequately informed by their ophthalmologist of the potential benefits of oral supplementation for age-related macular degeneration; indeed, 108 patients (56%) were not even aware such nutritional treatments are available. Ophthalmologists should be aware of the importance of giving advice to persons with age-related macular degeneration regarding the benefits of oral supplements.

Imaging of Melanin Disruption in Age-Related Macular Degeneration Using Multispectral Imaging.

To investigate whether multispectral imaging (MSI) is able to obtain a noninvasive view of melanin disruption associated with age-related macular degeneration (AMD), which could support early diagnosis and potential treatment strategies. A single retinal center, retrospective, observational, image analysis study of MSI images of 43 patients was done to determine the extent of melanin pigment exhibited in association with AMD, based on the Age-Related Eye Disease Study classification and grading scale. Corresponding fundus photos were also graded for 12 of the eyes. Fifty-one of 61 eyes (84%) of 43 patients with AMD were determined to have melanin disruption in their MSI images in at least the central and/or one of four inner ETDRS areas. There was a relationship between severity of disease and the degree of melanin disruption. The sensitivity of fundus photography for melanin pigment as compared to MSI was only 62.5%, with three false-negatives. A direct, noninvasive, unobstructed view of melanin disruption associated with AMD can be observed using MSI.

Macular Ganglion Cell Complex and Retinal Nerve Fiber Layer Comparison in Different Stages of Age-Related Macular Degeneration

To employ optical coherence tomography (OCT) to analyze the morphologic changes in the inner retina in different categories of age-related macular degeneration (AMD). Observational cross-sectional study. Single-center study. Inclusion criteria were age over 50, diagnosis of Age-Related Eye Disease Study (AREDS) category 2 and 3, naïve neovascular AMD, and atrophic AMD. Healthy patients of similar age acted as a control group. Primary outcome measures were the changes in ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Secondary outcomes included modifications of rim area and cup-to-disc ratio. One hundred and thirty eyes of 130 patients were recruited: 26 eyes for AREDS category 2, 26 for AREDS category 3, 26 for neovascular AMD, 26 with atrophic AMD, and 26 controls. Mean peripapillary RNFL thickness was significantly lower in neovascular AMD, compared to controls (P= .004); peripapillary RNFL did not significantly vary among AREDS category 2 and 3 and atrophic AMD groups, compared to controls. Mean GCC thickness was higher in the control group, becoming progressively thinner up to neovascular and atrophic AMD groups (P < .0001). Rim area was significantly thinner in the neovascular AMD group compared with controls (P= .047); cup-to-disc ratio was higher in the neovascular AMD group compared with the control group (P= .047). This study demonstrates that eyes with neovascular AMD display reduced RNFL and GCC thickness. RNFL is partially spared in atrophic advanced AMD. The identification of alteration in RNFL and GCC thickness may reveal useful for future therapeutic implications.

The Effect of Intensive Education on Concordance with the Age-Related Eye Disease Study (AREDS) Recommendations in a Tertiary Referral Practice

Background/Aims: The Age-Related Eye Disease Study (AREDS) showed that supplementation with their formula led to a significant decrease in progression of age-related macular degeneration (AMD). This study aims to assess the effect of different education protocols on concordance with the trial recommendations in two retinal clinics. Methods: A prospective controlled survey of concordance with the AREDS recommendations in two retinal clinics was administered to 330 patients with AREDS category 3 or 4 AMD. The results were evaluated to assess the effect of differing levels of patient education. In clinic 1, there was a formal policy of giving the patient both verbal and written instructions and verbal repetition of these instructions from each staff member on each patient visit; in clinic 2, there was no specific education policy. Results: Clinic 1 had a concordance rate of 81.6% and clinic 2 of 44.1%. There were no significant differences in the patient demographics between the two clinics. Conclusion: A high concordance rate can be achieved in clinical practice with rigorous patient education that includes a policy of having continual repetition of instructions.

Quantitative Analysis of Cone Photoreceptor Distribution and Its Relationship with Axial Length, Age, and Early Age-Related Macular Degeneration

PurposeIt has not been clarified whether early age-related macular degeneration (AMD) is associated with cone photoreceptor distribution. We used adaptive optics fundus camera to examine cone photoreceptors in the macular area of aged patients and quantitatively analyzed its relationship between the presence of early AMD and cone distribution.MethodsSixty cases aged 50 or older were studied. The eyes were examined with funduscopy and spectral-domain optical coherence tomography to exclude the eyes with any abnormalities at two sites of measurement, 2° superior and 5° temporal to the fovea. High-resolution retinal images with cone photoreceptor mosaic were obtained with adaptive optics fundus camera (rtx1, Imagine Eyes, France). After adjusting for axial length, cone packing density was calculated and the relationship with age, axial length, or severity of early AMD based on the age-related eye disease study (AREDS) classification was analyzed.ResultsPatient’s age ranged from 50 to 77, and axial length from 21.7 to 27.5 mm. Mean density in metric units and that in angular units were 24,900 cells/mm2, 2,170 cells/deg2 at 2° superior, and 18,500 cells/mm2, 1,570 cels/deg2 at 5° temporal, respectively. Axial length was significantly correlated with the density calculated in metric units, but not with that in angular units. Age was significantly correlated with the density both in metric and angular units at 2° superior. There was no significant difference in the density in metric and angular units between the eyes with AREDS category one and those with categories two or three.ConclusionAxial length and age were significantly correlated with parafoveal cone photoreceptor distribution. The results do not support that early AMD might influence cone photoreceptor density in the area without drusen or pigment abnormalities.

CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration

The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. Genetic analysis of a randomized, prospective clinical trial. White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995). Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. The effect of inherited gene polymorphisms on treatment group-specific rate of progression to advanced AMD. Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy.

Long-Term Effects of Vitamins C and E, β-Carotene, and Zinc on Age-related Macular Degeneration: AREDS Report No. 35

To describe the long-term effects (10 years) of the Age-Related Eye Disease Study (AREDS) formulation of high-dose antioxidants and zinc supplement on progression of age-related macular degeneration (AMD). Multicenter, randomized, controlled, clinical trial followed by an epidemiologic follow-up study. We enrolled 4757 participants with varying severity of AMD in the clinical trial; 3549 surviving participants consented to the follow-up study. Participants were randomly assigned to antioxidants C, E, and β-carotene and/or zinc versus placebo during the clinical trial. For participants with intermediate or advanced AMD in 1 eye, the AREDS formulation delayed the progression to advanced AMD. Participants were then enrolled in a follow-up study. Eye examinations were conducted with annual fundus photographs and best-corrected visual acuity assessments. Medical histories and mortality were obtained for safety monitoring. Repeated measures logistic regression was used in the primary analyses. Photographic assessment of progression to, or history of treatment for, advanced AMD (neovascular [NV] or central geographic atrophy [CGA]), and moderate visual acuity loss from baseline (≥15 letters). Comparison of the participants originally assigned to placebo in AREDS categories 3 and 4 at baseline with those originally assigned to AREDS formulation at 10 years demonstrated a significant (P<0.001) odds reduction in the risk of developing advanced AMD or the development of NV AMD (odds ratio [OR], 0.66, 95% confidence interval [CI], 0.53-0.83 and OR, 0.60; 95% CI, 0.47-0. 78, respectively). No significant reduction (P = 0.93) was seen for the CGA (OR, 1.02; 95% CI, 0.71-1.45). A significant reduction (P = 0.002) for the development of moderate vision loss was seen (OR 0.71; 95% CI, 0.57-0.88). No adverse effects were associated with the AREDS formulation. Mortality was reduced in participants assigned to zinc, especially death from circulatory diseases. Five years after the clinical trial ended, the beneficial effects of the AREDS formulation persisted for development of NV AMD but not for CGA. These results are consistent with the original recommendations that persons with intermediate or advanced AMD in 1 eye should consider taking the AREDS formulation. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

The Short-term Effects of Antioxidant and Zinc Supplements on Oxidative Stress Biomarker Levels in Plasma: A Pilot Investigation

To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy. Prospective interventional case series. Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped 2 weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on study day 2. Blood was drawn on study days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined. Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet (P = .034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls. This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.