Non-advanced Age-related Macular Degeneration Research Articles

In Vivo Correlation Between Macular Pigment Optical Volume and Retinal Layers Thickness.

This study aims to investigate the potential in vivo relationship between macular pigment (MP) and retinal layers thickness in healthy subjects and dry, non-advanced age-related macular degeneration (AMD). An observational, cross-sectional study was conducted. Healthy subjects >40years and patients with early or intermediate AMD were recruited. Structural OCT and macular pigment optical volume (MPOV) were collected for each subject. Retinal layers parameters were calculated based on the standard early treatment diabetic retinopathy study (ETDRS) map. Additionally, MPOV within 1°, 2°, and 9° of eccentricity was assessed and associated with retinal layers thickness and volume. Linear mixed-effects models were used to test the relationship between MP and structural OCT parameters, while adjusting for known possible confounding factors. A total of 144 eyes of 91 subjects (60.4% females) were evaluated, comprising 43% normal eyes and 57% with early/intermediate AMD. Among the retinal layers, only the outer nuclear layer (ONL) thickness and volume appeared to be associated to higher MP levels. Specifically, the central ONL thickness was identified as a significant predictor of the MPOV 1°(P = 0.04), while the parafoveal ONL thickness (inner ETDRS subfield) was identified as a significant fixed effect on the MPOV 9° (P = 0.037). Age and the presence of drusen or subretinal drusenoid deposits were also tested without showing significant correlations. Among the retinal layers examined, only the ONL thickness demonstrated a significant association with MPOV. Consequently, ONL thickness might serve as a potential biomarker related to MP levels.

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Evaluation of APOE polymorphisms and the risk for age-related macular degeneration in a Southeastern Brazilian population.

This study aimed to evaluate the role of APOE polymorphisms (rs429358 and rs7412) in the risk of age-related macular degeneration in a sample of the Southeastern Brazilian population. Seven hundred and five unrelated individuals were analyzed, 334 with age-related macular degeneration (case group), and 371 without the disease (control group). In the case group, patients were further stratified according to disease phenotypes, divided into dry and wet age-related macular degeneration, and non-advanced and advanced age-related macular degeneration. APOE polymorphisms (rs429358 and rs7412) were evaluated through polymerase chain reaction and direct sequencing. In the comparison of cases vs. controls, none of the associations reached statistical significance, considering the Bonferroni-adjusted P-value, although there was a suggestive protection for the E3/E4 genotype (OR = 0.626; P-value = 0.037) and E4 carriers (OR = 0.6515; P-value = 0.047). Statistically significant protection for both the E3/E4 genotype and E4 carriers was observed in the comparisons: advanced age-related macular degeneration vs. controls (OR = 0.3665, P-value = 0.491 × 10-3 and OR = 0.4031, P-value = 0.814 × 10-3, respectively), advanced age-related macular degeneration vs. non-advanced age-related macular degeneration (OR = 0.2529, P-value = 0.659 × 10-4 and OR = 0.2692, P-value = 0.631 × 10-4, respectively). In the comparison of wet age-related macular degeneration vs. control, protection was statistically significant only for E3/E4 (OR = 0.4052, P-value = 0.001). None of the comparisons demonstrated any significant association for E2 genotypes or E2 carriers in age-related macular degeneration risk in this study. Findings suggest a protective role of the E4 haplotype in the APOE gene in the risk for advanced and wet forms of age-related macular degeneration, in a sample of the Brazilian population. To our knowledge, this is the first Brazilian study to show the association between APOE polymorphisms and age-related macular degeneration.

An exploratory study to evaluate visual function endpoints in non-advanced age-related macular degeneration

BackgroundTo prevent irreversible vision loss in age-related macular degeneration (AMD), it is critical to detect retinal dysfunction before permanent structural loss occurs. In the current study we evaluated a series of visual function tests to identify potential endpoints to detect visual dysfunction in non-advanced AMD.MethodsA series of visual function tests were performed on 23 non-advanced AMD subjects (AREDS grade 1–4 on simplified scale) and 34 age-matched normals (AREDS grade 0). Tests included some commonly used endpoints such as ETDRS visual acuity (VA), low luminance (LL) 2.0ND ETDRS VA, MNREAD as well as newly developed tests such as the Ora-VCF™ test, Ora-tablet reading test, color sensitivity etc. Differences between the two groups were compared for each test. Test-retest repeatability and reproducibility was assessed on a subset of subjects and percent agreement was calculated.ResultsThere was no difference in standard ETDRS VA between non-advanced AMD (0.06 ± 0.02 logMAR) and normal groups (0.04 ± 0.02 logMAR) (p = 0.57). LL 2.0 ETDRS VA and MNREAD showed no difference between the groups (p > 0.05). Ora-VCF™ test was significantly worse in the non-advanced AMD group compared to normals (0.67 ± 0.07 in AMD; 0.45 ± 0.04 in normals, p = 0.005). Non-advanced AMD subjects also had significantly worse reading performance using the Ora-tablet with LL 2.0ND (114.55 ± 11.22 wpm in AMD; 145.17 ± 9.55 wpm in normals p = 0.049). No significant difference between the groups was noted using other tests. Repeatability was 82% for Ora-VCF™ test and 92% for Ora-tablet LL 2.0ND reading. Reproducibility was 89% for both Ora-VCF™ test and Ora-tablet LL 2.0ND reading.ConclusionWhile there was no significant difference between non-advanced AMD and normal groups using some current common endpoints such as ETDRS VA, LL 2.0 ETDRS VA or MNREAD, Ora-VCF™ test and Ora-tablet LL 2.0ND reading tests were able to identify significant visual dysfunction in non-advanced AMD subjects. These tests show promise as endpoints for AMD studies.

Association Between Perifoveal Drusen Burden Determined by OCT and Genetic Risk in Early and Intermediate Age-Related Macular Degeneration.

PurposeThe purpose of this study was to determine associations between macular drusen parameters derived from an automatic optical coherence tomography (OCT) algorithm, nonadvanced age-related macular degeneration (AMD) stage, and genetic variants.MethodsEyes classified as early or intermediate AMD with OCT imaging and genetic data were selected (n = 239 eyes). Drusen area and volume measurements were estimated using the Zeiss Cirrus advanced retinal pigment epithelium analysis algorithm in a perifoveal zone centered on the fovea. Associations between drusen measurements and common genetic variants in the complement and high-density lipoprotein (HDL) lipid pathways and the ARMS2/HTRA1 variant were calculated using generalized estimating equations and linear mixed models adjusting for age, sex, smoking, body mass index, and education.ResultsDrusen area ≥ the median was independently associated with a higher number of risk alleles for CFH risk score and risk variants in C3 and ARMS2/HTRA1 compared with eyes with no measurable drusen. Similar results were obtained for drusen volume. When all genes were analyzed in the same model, only CFH score and ARMS2/HTRA1 were associated with drusen measurements. HDL pathway genes were not significantly related to drusen parameters. Nonadvanced AMD stages were associated with OCT-derived drusen area and volume.ConclusionsVariants in CFH and ARMS2/HTRA1, commonly associated with advanced AMD, were independently associated with an increase in drusen burden determined by OCT in an allele dose dependent manner, in eyes with early and intermediate AMD. Biomarkers such as a quantitative classification of nonadvanced AMD and other OCT-derived subphenotypes could provide earlier anatomic endpoints for clinical trials and facilitate the development of new therapies for AMD.

Metabolomics in serum of patients with non-advanced age-related macular degeneration reveals aberrations in the glutamine pathway.

Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology.

Identification of Drusen Characteristics in Age-Related Macular Degeneration by Polarization-Sensitive Optical Coherence Tomography

PurposeTo describe qualitative characteristics of drusen in eyes with nonadvanced age-related macular degeneration (AMD) using polarization-sensitive optical coherence tomography (OCT).DesignCross-sectional study.MethodsTwenty-five eyes of 25 patients with early to intermediate (nonadvanced) AMD were imaged with polarization-sensitive OCT using macular volume scans. All individual drusen in each B-scan were manually delineated by experts certified by a reading center and graded for 6 different morphologic characteristics based on a defined classification scheme, including the presence of internal depolarizing structures and associated depolarizing foci. With the use of a custom-made software, the central B-scan of each individual druse was selected and used to analyze its location, diameter, and characteristics and assess the prevalence of the different features and relations between them.ResultsUsing the macular volume scans, 6224 individual drusen could be identified, including their position within the retina, their characteristics, and their association with any pigmentary alterations. The most common drusen type was a convex-shaped druse with homogeneous medium internal reflectivity and no depolarizing contents (55.3% of drusen). A total of 30.5% of the drusen exhibited internal depolarizing material; 0.3% presented overlying hyperreflective foci, and in 54.5% the foci were also depolarizing. Significant correlations were found between the diameter of the drusen and their distribution throughout the retina, shape, homogeneity of internal reflectivity, presence of internal depolarizing characteristics, and presence of overlying foci (P < .001 each). Significant relations were found between reflectivity, homogeneity, and polarization-sensitive internal characteristics (P < .001).ConclusionsPolarization-sensitive OCT reveals characteristic morphologic features of different druse types highlighting the pathophysiological spectrum of early to intermediate AMD.

Proof of Concept, Randomized, Placebo-Controlled Study of the Effect of Simvastatin on the Course of Age-Related Macular Degeneration

BackgroundHMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.Methodology/Principal Findings Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected.Conclusion/SignificanceSimvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.Trial RegistrationAustralian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF DRUSENOID PIGMENT EPITHELIAL DETACHMENTS

To evaluate drusenoid retinal pigment epithelial detachments (DPED) secondary to age-related macular degeneration (AMD) using spectral-domain optical coherence tomography imaging. In this prospective natural history study, eyes from patients with the diagnosis of nonexudative AMD and DPEDs were followed for at least 6 months. Eyes were scanned using the Cirrus spectral-domain optical coherence tomography instrument and the 200 × 200 A-scan raster pattern. A custom software was used to quantify volumetric changes in DPEDs and to detect the evolution and formation of geographic atrophy and choroidal neovascularization. Changes in DPED area and volume and development of the advanced forms of AMD were the main outcome. Of the 130 patients (186 eyes) with nonadvanced AMD, 11 patients (16 eyes) presented with DPEDs during the study. Mean follow-up was 18.5 months. Most DPEDs had an area exceeding 1 disk area (14 of 16 eyes) based on color fundus images with a mean area of 4.19 mm(2) (SD = 1.35) measured by spectral-domain optical coherence tomography. The mean volume at the time the DPED was diagnosed was 0.48 mm(3) (SD = 0.28). Four different patterns of progression were observed: DPEDs remained unchanged in 8 of 16 eyes (50%), DPEDs tended to increase in volume before progressing to geographic atrophy in 5 eyes (31.25%) and choroidal neovascularization in 2 eyes (12.5%), and a DPED decreased by more than 50% without progressing to geographic atrophy or choroidal neovascularization in 1 eye (6.25%). Spectral-domain optical coherence tomography imaging is able to detect subtle changes in the area and volume of DPEDs. Quantitative spectral-domain optical coherence tomography imaging of DPEDs is useful for identifying the natural history of disease progression and as a clinical tool for monitoring eyes with AMD in clinical trials.

Automatic Drusen Quantification and Risk Assessment of Age-Related Macular Degeneration on Color Fundus Images

To evaluate a machine learning algorithm that allows for computer-aided diagnosis (CAD) of nonadvanced age-related macular degeneration (AMD) by providing an accurate detection and quantification of drusen location, area, and size. Color fundus photographs of 407 eyes without AMD or with early to moderate AMD were randomly selected from a large European multicenter database. A machine learning system was developed to automatically detect and quantify drusen on each image. Based on detected drusen, the CAD software provided a risk assessment to develop advanced AMD. Evaluation of the CAD system was performed using annotations made by two blinded human graders. Free-response receiver operating characteristics (FROC) analysis showed that the proposed system approaches the performance of human observers in detecting drusen. The estimated drusen area showed excellent agreement with both observers, with mean intraclass correlation coefficients (ICC) larger than 0.85. Maximum druse diameter agreement was lower, with a maximum ICC of 0.69, but comparable to the interobserver agreement (ICC = 0.79). For automatic AMD risk assessment, the system achieved areas under the receiver operating characteristic (ROC) curve of 0.948 and 0.954, reaching similar performance as human observers. A machine learning system capable of separating high-risk from low-risk patients with nonadvanced AMD by providing accurate detection and quantification of drusen, was developed. The proposed method allows for quick and reliable diagnosis of AMD, opening the way for large dataset analysis within population studies and genotype-phenotype correlation analysis.

Carotenoids and Antioxidants in Age-Related Maculopathy Italian Study: Multifocal Electroretinogram Modifications after 1 Year

To evaluate the influence of short-term carotenoid and antioxidant supplementation on retinal function in nonadvanced age-related macular degeneration (AMD). Randomized controlled trial. Twenty-seven patients with nonadvanced AMD and visual acuity > or =0.2 logarithm of the minimum angle of resolution were enrolled and randomly divided into 2 age-similar groups: 15 patients had oral supplementation of vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), lutein (10 mg), zeaxanthin (1 mg), and astaxanthin (4 mg) (AZYR SIFI, Catania, Italy) daily for 12 months (treated AMD [T-AMD] group; mean age, 69.4+/-4.31 years; 15 eyes); 12 patients had no dietary supplementation during the same period (nontreated AMD [NT-AMD] group; mean age, 69.7+/-6.23 years; 12 eyes). At baseline, they were compared with 15 age-similar healthy controls. Multifocal electroretinograms in response to 61 M-stimuli presented to the central 20 degrees of the visual field were assessed in pretreatment (baseline) conditions and, in nonadvanced AMD patients, after 6 and 12 months. Multifocal electroretinogram response amplitude densities (RAD, nanovolt/deg(2)) of the N1-P1 component of first-order binary kernels measured from 5 retinal eccentricity areas between the fovea and midperiphery: 0 degrees to 2.5 degrees (R1), 2.5 degrees to 5 degrees (R2), 5 degrees to 10 degrees (R3), 10 degrees to 15 degrees (R4), and 15 degrees to 20 degrees (R5). At baseline, we observed highly significant reductions of N1-P1 RADs of R1 and R2 in T-AMD and NT-AMD patients when compared with healthy controls (1-way analysis of variance P<0.01). N1-P1 RADs of R3-R5 observed in T-AMD and NT-AMD were not significantly different (P>0.05) from controls. No significant differences (P>0.05) were observed in N1-P1 RADs of R1-R5 between T-AMD and NT-AMD at baseline. After 6 and 12 months of treatment, T-AMD eyes showed highly significant increases in N1-P1 RADs of R1 and R2 (P<0.01), whereas no significant (P>0.05) change was observed in N1-P1 RADs of R3-R5. No significant (P>0.05) changes were found in N1-P1 RADs of R1-R5 in NT-AMD eyes. In nonadvanced AMD eyes, a selective dysfunction in the central retina (0 degrees -5 degrees ) can be improved by the supplementation with carotenoids and antioxidants. No functional changes are present in the more peripheral (5 degrees -20 degrees ) retinal areas.

Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio.

Individuals with early or intermediate stages of age-related macular degeneration (AMD) make up a large and growing segment of our elderly population. To advise these high-risk patients regarding preventive measures, we evaluated anthropomorphic, behavioral, and medical factors associated with progression to the advanced stages of AMD associated with visual loss. The design was a prospective cohort study in a hospital-based retinal practice. The 261 participants were 60 years or older, with some sign of nonadvanced AMD and visual acuity of 20/200 or better in at least 1 eye. The average follow-up time was 4.6 years, and the total person-years of follow-up was 1198. Factors associated with rates of progression to advanced AMD were assessed by the Cox proportional hazards model. Progression to geographic atrophy and neovascular disease. Higher body mass index (calculated as weight in kilograms divided by the square of height in meters) increased the risk for progression to the advanced forms of AMD. Relative risk (RR) was 2.35 (95% confidence interval [CI], 1.27-4.34) for a body mass index of at least 30, and 2.32 (95% CI, 1.32-4.07) for a body mass index of 25 to 29, relative to the lowest category (<25) after controlling for other factors (P =.007 for trend). Higher waist circumference was associated with a 2-fold increased risk for progression (RR for the highest tertile compared with the lowest, 2.04; 95% CI, 1.12-3.72), with a significant trend for increasing risk with a greater waist circumference (P =.02). Higher waist-hip ratio also increased the risk for progression (RR, 1.84; 95% CI, 1.07-3.15) for the highest tertile compared with lowest (P =.02 for trend). More physical activity tended to be associated with a reduced rate of progression (25% reduction for 3 times per week vigorous activity vs none, P =.05 to P =.07). Relative risks for smoking ranged from 1.48 to 1.99, but were not statistically significant. Results provide new information regarding modifiable factors for individuals with the early or intermediate stages of this disease. Overall and abdominal obesity increased the risk for progression to advanced AMD, and more physical activity tended to decrease risk. These preventive measures deserve additional research and greater emphasis.