Self-rated eyesight among healthy older Australians: Baseline results of the ASPREE Longitudinal Study of Older Persons.

BACKGROUND: We aimed to describe the self-reported level of eyesight amongst a cohort of relatively healthy older Australian adults, and to investigate associations between poorer self-rated eyesight and demographic, health, and functional characteristics METHODS: The ASPirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) study was embedded in a multisite trial which recruited independently living Australians from general practices (2010-2014). Self-rated eyesight was recorded on a paper-based questionnaire as Excellent, Good, Fair, Poor, Very poor, or Completely blind at the baseline study wave RESULTS: Data from 14 592 participants (aged 70-95 years, 54.61% female) were included in this cross-sectional analysis. Eighty percent of participants reported excellent or good eyesight (n = 11 677). People with complete blindness were precluded from enrolling but 299 participants (2.0%) reported poor or very poor eyesight, and 2616 rated their eyesight as fair (17.9%). Lower levels of eyesight were associated with being older, female, fewer years of formal education, a primary language other than English, smoking, and self-reported macular degeneration, glaucoma, retinopathy, cataracts, and hearing problems (each p ≤ 0.021). People with lower levels of eyesight had a higher number of falls, frailty characteristics, and depressive symptoms, and lower mental and physical health functioning scores (each p < 0.001) CONCLUSIONS: Whilst most of these healthy older Australians reported good or excellent eyesight, a notable minority reported poor or very poor eyesight, and this was associated with a range of poorer health measures. These findings support the need for additional resources to prevent vision loss and associated sequelae.

Plasma levels of amyloid beta and other proinflammatory mediators in patients with age-related macular degeneration.

PURPOSE: To investigate the plasma levels of amyloid beta (Aß) and select inflammatory mediators in patients with various stages of AMD compared to that of age-matched controls, and discern a relationship to disease severity. METHODS: Plasma samples were obtained from AMD subjects at various stages of disease-early (drusen only), geographic atrophy (GA), neovascular AMD (CNV)-and from controls of similar age without AMD. Samples were analyzed using a commercially available ELISA kit (sixteen cytokines) or LC/MS/MS (Aß isotypes). Descriptive statistics were compiled on all analytes. Analysis of covariance (ANCOVA) was conducted to compare each analyte across AMD groups while adjusting for sex and age of the patients, and in comparison to the control group. Receiver operating characteristics plots were generated for the strongest predictor variables. RESULTS: Levels of alternative spliced CC3 proteins were significantly different between controls and CNV groups (p < 0.05), with median levels almost twice higher in CNV than in controls. There was an increasing trend for plasma levels of Αß isotypes across AMD progressive stages (p values ranged from 0.052 to 0.0012) (ANCOVA). When adjusted for multiple comparisons analysis, plasma Aß 1-42 levels, and its ratio with Aß 1-40 were the most significantly associated with late AMD stages. Consistently with the ANCOVA results for Αß isotypes, the ROC curve showed a moderate prediction (AUC = - ~ 0.78) of AMD vs control using the Aß 1-42 isotype. CONCLUSION: Plasma Aß 1-42 may have utility as a systemic biomarker for AMD.

Age-related macular degeneration phenotypes associated with mutually exclusive homozygous risk variants in CFH and HTRA1 genes.

PURPOSE: To determine age-related macular degeneration (AMD) phenotypes associated with mutually exclusive homozygotic risk variants in rs1061170 (CFH) and rs11200638 (HTRA1). METHODS: Nested case-control study of 2,982 eyes (2,129 control, 809 drusen ≥125 µm, 44 advanced AMD) homozygous for CFH [TT or CC] and HTRA1 [GG or AA] were analyzed using logistic regression and generalized estimating equations specifically regards to homozygous risk variants in one but homozygous no-risk in the other gene. RESULTS: In early AMD, [CFH HTRA1] and [CFH HTRA1] were associated with central drusen (odds ratio [95% confidence interval] = 4.13 [2.97-5.73] and 3.65 [1.88-7.09], respectively). However, only [CFH HTRA1] was associated with central drusen occupying ≥50% area (13.9 [2.97-64.7]). In advanced AMD, [CFH HTRA1] was associated with geographic atrophy (4.04 [1.57-10.4]), whereas [CFH HTRA1] was associated with neovascular AMD (36.5 [8.3-160.9]). In doubly homozygous risk groups [CFH HTRA1], odds ratios were multiplicative. CONCLUSION: Central but not peripheral drusen location was strongly associated with both [CFH HTRA1] and [CFH HTRA1]. Only [CFH HTRA1] was significantly associated with increased central drusen area.

Can genetic associations change with age? CFH and age-related macular degeneration.

Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86. A difference in genotype frequencies was seen across age groups, where the low-risk homozygote prevalence rose with each increasing age group. Associations with early AMD were strongly modified by age for three of the four SNPs (interaction P-value: 0.01-0.00003). An inverse association between the high-risk homozygote for each SNP and early AMD was observed in the younger age groups [odds ratios (OR) range 0.37-0.48 for age <55], reversing to a positive association with increasing age (OR 1.87-2.8 for age >75). The direction of associations for this gene change was from inverse to risk with increasing age. These findings have important implications for predictive models for AMD and potentially other age-related diseases which extrapolate risks from older cohorts, as they assume homogeneity of association by age, which might not exist.

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.

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

Younger siblings, C-reactive protein, and risk of age-related macular degeneration.

In this study, we examined the relationship between exposure to siblings and 1) the risk of age-related macular degeneration (AMD) and 2) C-reactive protein levels. We retrospectively analyzed pooled cross-sectional data from 2 studies: the Cardiovascular Health and Age-Related Maculopathy Study (2001-2002) and the Age-Related Maculopathy Statin Study (2004-2006). Associations between number of siblings and AMD were assessed by using multinomial logistic regression. Associations between number of siblings and C-reactive protein levels were examined by using a generalized linear model for γ distribution. A higher number of younger siblings was associated with significantly lower odds of early AMD in those with a family history of AMD (odds ratio = 0.2, 95% confidence interval: 0.1, 0.8) (P = 0.022) but was unrelated to AMD for those who had no family history of the disease (odds ratio = 1.0, 95% confidence interval: 0.9, 1.2) (P = 0.874). A higher number of younger siblings correlated with lower C-reactive protein levels (ß = -0.19, 95% confidence interval: -0.38, -0.01) (P = 0.036). This supports the theory that immune modulation contributes to AMD pathogenesis and suggests that exposure to younger siblings might be protective when there is a family history of AMD.

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.

Apolipoprotein E gene associations in age-related macular degeneration: the Melbourne Collaborative Cohort Study.

The apolipoprotein E gene (APOE) has been found to be associated with age-related macular degeneration (AMD). Reported associations have been questioned, as they are opposite those for Alzheimer's disease and cardiovascular disease. The authors examined associations between APOE genotype and AMD using a case-control study (2,287 cases and 2,287 controls individually matched on age, sex, and country of origin) nested within Melbourne Collaborative Cohort Study participants aged 48-86 years at AMD detection. The odds ratio for early AMD among participants with ε2-containing genotypes (ε2ε2/ε2ε3/ε2ε4) was 1.32 (95% confidence interval (CI): 1.11, 1.58; P = 0.002) versus persons with genotype ε3ε3. Associations with early AMD varied by smoking status; ε2-containing genotypes were positively associated with early AMD for never and previous smokers (never smokers: odds ratio (OR) = 1.40, 95% CI: 1.12, 1.76 (P = 0.003); previous smokers: OR = 1.39, 95% CI: 1.00, 1.93 (P = 0.05)) but not for current smokers (OR = 0.66, 95% CI: 0.34, 1.30 (P = 0.2; interaction P = 0.05). The ε4-containing genotype group (ε3ε4/ε4ε4) had an inverse association with early AMD among current smokers only (OR = 0.41, 95% CI: 0.22, 0.77 (P = 0.005)). These results highlight the importance of stratifying by smoking status in elderly populations. Smokers who survive to old age may be more likely to possess unknown genotypes which modify exposure-disease associations.

20/20--Alcohol and age-related macular degeneration: the Melbourne Collaborative Cohort Study.

Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol intake using 20,963 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). Participants' alcohol consumption was determined from a structured interview at baseline. At follow-up from 2003 to 2007, digital macula photographs of both eyes were taken and evaluated for early and late AMD signs. Drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD (odds ratio = 1.21, 95% confidence interval: 1.06, 1.38; P = 0.004) when compared with those who reported no alcohol intake at baseline, having adjusted for sex, age, smoking, country of birth, education, physical activity, and energy from food. This positive association was apparent for wine, beer, and spirits. The estimates were similar for both sexes. The odds ratio for those drinking more than 20 g of alcohol per day for late AMD was 1.44 (95% confidence interval: 0.85, 2.45; P = 0.17). These results show a modest association between alcohol consumption and increased AMD risk.

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.

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

PURPOSE: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression. METHODS: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants. RESULTS: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors. CONCLUSIONS: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.

Age Related Macular Degeneration and Total Hip Replacement Due to Osteoarthritis or Fracture: Melbourne Collaborative Cohort Study.

Osteoarthritis is the leading cause of total hip replacement, accounting for more than 80% of all total hip replacements. Emerging evidence suggests that osteoarthritis has a chronic inflammatory component to its pathogenesis similar to age-related macular degeneration. We evaluated the association between age-related macular degeneration and total hip replacement as proxy for severe osteoarthritis or fractured neck of femur in the Melbourne Collaborative Cohort Study. 20,744 participants had complete data on both age-related macular degeneration assessed from colour fundus photographs taken during 2003-2007 and total hip replacement. Total hip replacements due to hip osteoarthritis and fractured neck of femur during 2001-2011 were identified by linking the cohort records to the Australian Orthopedic Association National Joint Replacement Registry. Logistic regression was used to examine the association between age-related macular degeneration and risk of total hip replacement due to osteoarthritis and fracture separately, adjusted for confounders. There were 791 cases of total hip replacement for osteoarthritis and 102 cases of total hip replacement due to fractured neck of femur. After adjustment for age, sex, body mass index, smoking, and grouped country of birth, intermediate age-related macular degeneration was directly associated with total hip replacement for osteoarthritis (odds ratio 1.22, 95% CI 1.00-1.49). Late age-related macular degeneration was directly associated with total hip replacement due to fractured neck of femur (odds ratio 5.21, 95% CI2.25-12.02). The association between intermediate age-related macular degeneration and an increased 10-year incidence of total hip replacement due to osteoarthritis suggests the possibility of similar inflammatory processes underlying both chronic diseases. The association of late age-related macular degeneration with an increased 10-year incidence of total hip replacement due to fractured neck of femur may be due to an increased prevalence of fractures in those with poor central vision associated with the late complications of age-related macular degeneration.

Age-related macular degeneration in ethnically diverse Australia: Melbourne Collaborative Cohort Study.

PURPOSE: To determine and compare the prevalence of age-related macular degeneration (AMD) in older Australians of Anglo-Celtic and Southern European origin. METHODS: A total of 21,132 participants of the Melbourne Collaborative Cohort Study, aged 47-86 years, were assessed for AMD in 2003-2007 with non-mydriatic fundus photography. Of these, 14% were born in Southern Europe (Greece, Italy or Malta), with the remaining 86% of Anglo-Celtic origin, born in Australia, the United Kingdom or New Zealand. RESULTS: Overall, 2694 participants (12.7%) had early stages of AMD, defined as either one or more drusen ≥ 125 µm (with or without pigmentary abnormalities) or one or more drusen 63-124 µm with pigmentary abnormalities in a 6000-µm diameter grading grid, in the absence of late AMD in either eye. A total of 122 participants (0.6%) had late AMD, defined as either geographic atrophy or neovascular AMD. In logistic regression analysis, adjusted for age, sex, smoking, education and physical activity, Southern Europeans compared to Anglo-Celts had a higher prevalence of the early stages of AMD (odds ratio, OR, 1.15, 95% confidence interval, CI, 1.00-1.34), and lower prevalence of late AMD (OR 0.36, 95% CI 0.17-0.78). CONCLUSIONS: Australians of Southern European origin have a higher prevalence of the early stages of AMD and lower prevalence of late AMD compared to those of Anglo-Celtic origin. Although AMD prevalence in the older age group(s) of Southern Europeans could be underestimated due to disparity in participation rates, it is likely that both lifestyle and genetic factors play their parts in differential AMD prevalence in these ethnic groups.

Does aspirin increase the risk of age-related macular degeneration?

This commentary on the review by Christen and Chew discusses the controversy surrounding aspirin use and its association with age-related macular degeneration (AMD). We address the strength of evidence between low-dose aspirin use and AMD and also discuss the risks and benefits of aspirin use in primary versus secondary prevention of cardiovascular diseases in these cases. We also highlight an ongoing randomized controlled trial in this area.

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. 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.

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.

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 participant's 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.

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)-ß1, 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-ß1 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-ß1 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.