Khin Zaw Aung

Visual function tests as potential biomarkers in age-related macular degeneration.

PURPOSE To evaluate the potential of psychophysical assessments of retinal function to provide diagnostic biomarkers of early age-related macular degeneration (AMD). METHODS Unilateral visual function was assessed in 221 participants (72.86 ± 9.94 years; 67% women) with early AMD (visual acuity better than 20/60) and 109 controls (73.07 ± 10.32 years; 65% women). Psychophysical assessment included steady state thresholds (4- and 14-Hz flicker and red and blue color) and dynamic tests (photostress recovery [PSR] and dark adaptation [DA]). All test parameters were compared in terms of their diagnostic capacity (sensitivity and specificity), reproducibility, and clinical applicability (test duration and participants perception of test difficulty). AMD status was determined by digital photography, according to the International Classification and Grading System. RESULTS All functional measurements were significantly worse, on average, in the AMD group than in the control group (P < 0.001). Static and dynamic parameters showed weak correlations (range, 0.003-0.225). Rod recovery in DA and cone recovery in PSR had the best diagnostic capacity (area under curve [AUC], receiver operating characteristic [ROC] analysis, 0.93 ± 0.016 and 0.85 ± 0.021, respectively). Considering diagnostic capacity together with test reproducibility and clinical applicability, the 14-Hz flicker gave the best outcome, followed by PSR. Combination of these two tests detected 71% of abnormal early AMD cases. CONCLUSIONS All the visual function tests had good diagnostic capacity. Combination of the 14-Hz flicker thresholds and dynamics of the PSR test provided optimal quantitative assessment of retinal function in early AMD, suggesting that this set is a potentially useful clinical tool for following progression of early AMD and assessing the efficacy of interventions.

Abdominal Obesity and Age-related Macular Degeneration

Evidence for an association between age-related macular degeneration (AMD) and obesity is inconsistent. The authors examined associations between adiposity and AMD prevalence using 21,287 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). For men, each increase of 0.1 in waist/hip ratio (~1 standard deviation) was associated with a 13% increase in the odds of early AMD (odds ratio = 1.13, 95% confidence interval: 1.01, 1.26; P = 0.03) and a 75% increase in the odds of late AMD (odds ratio = 1.75, 95% confidence interval: 1.11, 2.76; P = 0.02). No other adiposity measure was associated with early AMD for men. Smoking status modified the relation between waist/hip ratio and early AMD (P = 0.05), with no association for former smokers. For women, there were inverse associations with early AMD for all adiposity measures (odds ratios = 0.89-0.93; P = 0.002-0.02), but no associations were observed for late AMD. This study confirms abdominal obesity as an AMD risk factor for men despite a survivorship effect from competing risks in morbidity and mortality. The inverse associations for women may reflect weaker true positive associations with AMD that are insufficient to overcome the survivorship effect. New data are provided on complex interactions between environmental exposures and AMD risk.

The prevalence and risk factors of epiretinal membranes: the Melbourne Collaborative Cohort Study.

Purpose: To determine the prevalence of epiretinal membranes (ERMs) in Melbourne, Australia and its risk factors in this population. Methods: The Melbourne Collaborative Cohort Study is a prospective study investigating the role of diet and life style in the causation of common chronic diseases. Eighty-six percent of participants were of Northern European origin born in Australia or United Kingdom and 14% were migrants from Greece or Italy (Southern European origin). Nonmydriatic digital retinal photography was implemented at Melbourne Collaborative Cohort Study follow-up. The ERMs were recorded as cellophane macular reflex without retinal folds or preretinal macular fibrosis (PMF) with retinal folds. Results: A total of 22,406 participants had retinal photography, 95% (n = 21,241) were eligible for ERM grading. The ERM prevalence were 8.9% (1,882); cellophane macular reflex, 4.9% (1,047); and preretinal macular fibrosis, 3.9% (835). After adjustment for age, sex, level of education, smoking status, level of cholesterol, body mass index, waist-to-hip ratio, waist measurement, blood pressure, diabetes, and stroke, increasing age and Southern European ethnicity was significantly associated with ERMs. Overall, in Southern Europeans, ERMs odd ratio was 1.97 (95% confidence intervals, 1.67–2.31), P < 0.001; preretinal macular fibrosis was 1.82 (95% confidence intervals, 1.43–2.31), P < 0.001; and cellophane macular reflex was 1.93 (1.57–2.38), P < 0.001. Conclusion: In an older Australian population, the prevalence of ERMs was 8.9% and was almost two times higher in participants of Southern European origin than Northern European origin.

Reticular Pseudodrusen and Their Association with Age-Related Macular Degeneration: The Melbourne Collaborative Cohort Study.

PURPOSE To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. DESIGN Community-based cohort study in Melbourne, Victoria, Australia. PARTICIPANTS A total of 21,130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. METHODS Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. MAIN OUTCOME MEASURES Detection of RPD based on color fundus photographs. RESULTS Prevalence of RPD was 0.41% (87 of 21,130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P < 0.001). Increasing age, female gender, being a current smoker, as well as focal pigmentary abnormalities and large drusen (>125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53-442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26-310), intermediate AMD (OR, 33; 95% CI, 14-77), and early AMD (OR, 12; 95% CI, 5-31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P < 0.05). CONCLUSIONS Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.

Red Meat and Chicken Consumption and Its Association With Age-related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among older people, and diet has been postulated to alter risk of AMD. To evaluate associations between red meat and chicken intake and AMD, the authors conducted a cohort study of 6,734 persons aged 58-69 years in 1990-1994 in Melbourne, Australia. Meat intake was estimated from a food frequency questionnaire at baseline. At follow-up (2003-2006), bilateral digital macular photographs were taken and evaluated for AMD (1,680 cases of early AMD, 77 cases of late AMD). Logistic regression was used to estimate odds ratios, adjusted for age, smoking, and other potential confounders. Higher red meat intake was positively associated with early AMD; the odds ratio for consumption of red meat > or =10 times/week versus <5 times/week was 1.47 (95% confidence interval: 1.21, 1.79; P-trend < 0.001). Similar trends toward increasing prevalence of early AMD were seen with higher intakes of fresh and processed red meat. Conversely, consumption of chicken > or =3.5 times/week versus <1.5 times/week was inversely associated with late AMD (odds ratio = 0.43, 95% confidence interval: 0.20, 0.91; P-trend = 0.007). These results suggest that different meats may differently affect AMD risk and may be a target for lifestyle modification.

Dietary Patterns and Their Associations with Age-Related Macular Degeneration The Melbourne Collaborative Cohort Study

OBJECTIVE To evaluate the association between dietary patterns and age-related macular degeneration (AMD). DESIGN Food frequency data were collected from Melbourne Collaborative Cohort Study (MCCS) participants at the baseline study in 1990-1994. During follow-up in 2003-2007, retinal photographs were taken and evaluated for AMD. PARTICIPANTS At baseline, 41514 participants aged 40 to 70 years and born in Australia or New Zealand (69%), or who had migrated from the United Kingdom, Italy, Greece, or Malta (31%) were recruited. Of these, 21132 were assessed for AMD prevalence at follow-up. METHODS Principal component analysis was used to identify dietary patterns (Factors F1-6) among the food items. Logistic regression was used to assess associations of dietary patterns with AMD. MAIN OUTCOME MEASURES Odds ratios (ORs) for early stages and advanced AMD in association with dietary patterns. RESULTS A total of 2508 participants (12.8%) had early stages of AMD, and 108 participants (0.6%) had advanced AMD. Six factors characterized by predominant intakes of fruits (F1); vegetables (F2); grains, fish, steamed or boiled chicken, vegetables, and nuts (F3); red meat (F4); processed foods comprising cakes, sweet biscuits, and desserts (F5); and salad (F6) were identified. Higher F3 scores were associated with a lower prevalence of advanced AMD (fourth vs. first quartile) (OR, 0.49; 95% confidence interval [CI], 0.28-0.87), whereas F4 scores greater than the median were associated with a higher prevalence of advanced AMD (OR, 1.46; 95% CI, 1.0-2.17). CONCLUSIONS Rather than specific individual food items, these factors represent a broader picture of food consumption. A dietary pattern high in fruits, vegetables, chicken, and nuts and a pattern low in red meat seems to be associated with a lower prevalence of advanced AMD. No particular food pattern seemed to be associated with the prevalence of the earliest stages of AMD.

Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

Background HMG 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/Significance Simvastatin 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 Registration Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

The prevalence estimates of macular telangiectasia type 2: the Melbourne Collaborative Cohort Study.

Purpose: The purpose of this study was to determine the prevalence estimates of macular telangiectasia type 2 in an Australian population based on nonmydriatic digital fundus photography. Methods: Participants of the Melbourne Collaborative Cohort Study, initiated to investigate risk factors for common aging diseases, had nonmydriatic digital macular images taken from both eyes and graded for any macular abnormalities. Prevalence of the features suggestive of macular telangiectasia type 2 was assessed. Results: Macular images from the 22,062 subjects with a mean age of 64.96 years (range, 47–85 years) were assessed. Of these images, 43,234 images were gradable (21,708 images of the right eye and 21,526 images of the left eye). Using only the grading features of the macular images taken by the nonmydriatic digital fundus photography, 5 subjects with signs consistent with bilateral macular telangiectasia type 2 in this population were found by the authors. Based on the Gass-Blodi staging of this disease, all (5) were determined to be in stages 2 and 3. Conclusion: In an Australian population, the prevalence estimates of macular telangiectasia type 2 were found to be 1 of 22,062 to 5 of 22,062 or 5 to 23 cases per 100,000 people in which disease was at least at stages 2 and 3.

Relationship between Clinical Macular Changes and Retinal Function in Age-Related Macular Degeneration

PURPOSE The aim of this study was to investigate the relationship between clinical macular changes and retinal function in age-related macular degeneration (AMD). METHODS We recruited 357 participants with visual acuity of better than 20/60 in the study eye, including 64 individuals with normal fundi and 293 AMD participants classified into 12 subgroups based upon the International Classification and Grading System. Visual function in the study eye was assessed using two steady-state tests (achromatic 14 Hz flicker [F14Hz] and isoluminant blue color [BCT]) and two adaptation measurements (cone photo-stress recovery rate [CRR] and rod dark adaptation recovery rate [RRR]). The groups were compared on their average psychophysical measurements and ranked according to functional deficiency. RESULTS Both adaptation parameters were significantly abnormal when only hard and/or intermediate drusen were evident (compared to controls, P < 0.023) and yielded considerably worse outcomes in cases with more advanced fundus changes (P < 0.001), but provided limited ability to discriminate between these cases (linear trend, CRR t = 0.68, P = 0.50 and RRR t = 1.76, P = 0.08). Steady-state measurements, however, declined gradually along the entire hierarchy of fundus changes (linear trend, F14Hz t = 10.16, P < 0.001 and BCT t = 11.19, P < 0.001) with F14Hz being able to detect significant functional change as early as in the intermediate drusen group, when compared to controls (P = 0.003). CONCLUSIONS Steady state thresholds (F14Hz and BCT) and clinical signs showed significant concordance across the spectrum of early AMD fundus changes. This suggests that these tests may be an effective tool for monitoring progression of AMD to supplement clinical grading.

Identification of urinary biomarkers for age-related macular degeneration

PURPOSE Age-related macular degeneration (AMD) can be considered as a chronic low-grade systemic inflammatory disease. This study was undertaken to test the associations of AMD with the urinary proinflammatory cytokines transforming growth factor (TGF)-β1, macrophage chemoattractant protein (MCP)-1 and C3a-desArg, as potential noninvasive biomarkers for monitoring AMD. METHODS A cross-sectional study of 103 AMD cases, comprising early AMD (n = 51), geographic atrophy (GA; n = 19), or choroidal neovascularization (CNV; 33), and 54 unrelated controls, aged 73 ± 9 years, who attended the Royal Victorian Eye and Ear Hospital and private practice in Victoria, Australia. AMD status was determined from the bilateral retinal digital photographs and through angiography and optical coherence tomography images when confirmation of CNV was needed. Serum and urine cytokine levels were measured by immunoassay and the rs1061170 (Y402H) single-nucleotide polymorphism of the complement factor H (CFH) gene was determined. RESULTS Multivariate logistic regression analyses demonstrated significant associations of urinary TGF-β1 levels (odds ratio [95% confidence interval]: OR = 1.24 [1.02-1.50]; P < 0.031) and MCP-1 levels (OR = 1.07 [1.02-1.12]; P < 0.008), in early AMD, and also MCP-1 levels with GA (OR = 1.10 [1.03-1.17]; P < 0.003). There was no correlation between urinary and serum cytokine levels. Individuals with one or more copies of the C allele (Y402H) were 2.5 times more likely to have urinary MCP-1 above median levels (P < 0.040). CONCLUSIONS This study demonstrates a novel finding of an association between elevated urinary cytokines TGF-β1 and MCP-1 and AMD. Further development of a urinary biomarker profile could provide a practical tool for detection of early AMD, progression monitoring, and assessment of treatment efficacy.