Aims To assess associations between features of age-related macular degeneration (AMD) and mortality. Methods A total of 21 129 participants from the Melbourne Collaborative Cohort Study aged 47-85 years (60% female) were assessed for AMD (2003-2007). Mortality data to December 31, 2012 were obtained through linkage with the National Death Index. Associations were assessed using Cox regression, adjusting for age, sex, smoking, region of birth, education, physical activity, diet and alcohol. Results Late AMD was identified in 122 (0.6%) participants, including those with choroidal neovascularisation (n = 55, 0.3%), geographic atrophy (n = 87, 0.4%) and reticular pseudodrusen (n = 87, 0.4%). After a median follow-up period of 8.1 years, 1669 (8%) participants had died, including those from cardiovascular diseases (386), tobacco-related cancers (179), and neurodegenerative disease (157). There was evidence of an increased rate of all-cause mortality for those with choroidal neovascularisation (Hazard Ratio (HR) 1.71 95% CI 1.06-2.76) and geographic atrophy (HR 1.46 95% CI 0.99-2.16). Choroidal neovascularisation was also associated with an increased rate of cardiovascular mortality (HR 3.16 95% CI 1.62-6.15) and geographic atrophy was associated with an increased rate of death from tobacco-related cancer (HR 2.86 95% CI 1.15-7.09). Weak evidence was also present for an association between choroidal neovascularisation and death from neurodegenerative disease (HR 2.49 95% CI 0.79-7.85). Neither reticular pseudodrusen nor the earlier stages of AMD were associated with mortality. Conclusions Late AMD is associated with an increased rate of all-cause mortality. Choroidal neovascularisation and geographic atrophy were associated with death from cardiovascular disease and tobacco-related cancer, respectively.

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.

PURPOSE:The relationship between clinical severity of age-related macular degeneration (AMD) and macular function has not been well established. In this study, we investigated the correlation between clinical severity and functional deficits as detected by static and flicker perimetry. METHODS:This cross-sectional study consisted of 279 AMD subjects and 24 control participants. AMD subjects were allocated into 1 of 10 AMD severity groups depending on the status of the designated study eye and the fellow eye, as assessed by color fundus photographs. Visual acuity, and static and flicker perimetry were tested on one eye during the same session. The geometric means, SDs, and percentage of abnormal eyes of static and flicker sensitivity of each AMD severity group were determined and compared. RESULTS:The pattern of change in sensitivity and percentage of abnormal eyes for static perimetry across all AMD severity groups were similar to flicker perimetry. Eyes with drusen > 125 μm (P[static] = 0.018, P[flicker] = 0.024), drusenoid epithelial detachment (P[static and flicker] < 0.001) and noncentral geographic atrophy (GA; P[static and flicker] < 0.001) had significant reductions in static and flicker sensitivities compared to normal eyes. Static (β-coefficient -1.59, 95% confidence interval [CI] -4.78-1.60) and flicker (β-coefficient -1.29, 95% CI -4.66-2.08) sensitivities declined at a similar rate in eyes that showed clinical signs of progression. CONCLUSIONS:Static and flicker perimetry were affected similarly across the spectrum of AMD severity, and methods appeared to be valid techniques for assessing retinal sensitivity in AMD once drusen > 125 μm are present, but before the development of late AMD.

PURPOSE:To investigate the potential influences that affect visual acuity (VA) outcome in a clinic-based cohort of age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) treatment for choroidal neovascularization. DESIGN:Prospective interventional case series. METHODS:Patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were prospectively recruited. A detailed questionnaire was given to patients at time of enrollment, to collect information relating to demographics, history of visual symptoms, visual acuity (VA), and treatment scheduling. Delay from symptoms to treatment ("Treatment delay") was measured in terms of weeks and analyzed in tertiles. Information pertaining to treatment outcomes was collected over a 6-month period. RESULTS:One hundred eighty-five eyes of 185 patients were recruited into the study. Longer delay from first symptoms suggestive of CNV to first injection was a significant predictor (P=.015) of poorer treatment outcome, when controlling for age, sex, and baseline VA. Patients with a delay in treatment of 21 weeks or more compared to a delay of 7 weeks or less had an odds ratio of 2.62 (1.20, 5.68) for worsening vision after treatment. CONCLUSIONS:Patients experiencing a longer delay between their first symptoms of CNV and their first anti-VEGF treatment have a significantly lower chance of improving vision at 6 months following anti-VEGF therapy. It is critical that this information reach those at potential vision loss from AMD, in order that prompt treatment may be instituted, to maximize the benefits of anti-VEGF treatment.

OBJECTIVE To investigate the longitudinal changes in flicker perimetry in patients with age-related macular degeneration (AMD) as the condition progresses from early AMD to geographic atrophy (GA) or choroidal neovascularization (CNV). METHODS Patients with AMD and control subjects were recruited from a longitudinal study of retinal function in early AMD consisting of 187 participants. Only those who completed at least 4 consecutive, 6-monthly flicker perimetry tests were selected for this study. Study groups consisted of everyone who went on to develop GA (n = 16) or CNV (n = 5), controls (n = 24), and the high-risk, early- AMD participants whose eyes did not progress to GA or CNV (drusen >125 μm; n = 18). The flicker sensitivity was determined, and its rate of change during the 18 months before the clinical detection of late AMD was calculated. RESULTS Eyes that went on to develop GA or CNV had a significantly reduced mean (SD) flicker sensitivity in the months before clinical detection of GA (15.8 [5.6] dB) or CNV (19.1 [3.8] dB) compared with control eyes (22.9 [3.0] dB) (P < .001) and with eyes that did not progress to GA or CNV (21.4 [3.4] dB) (P < .001). The rate of change in flicker sensitivity was significantly increased in GA eyes (-0.07 dB/mo) (P < .001) but not in CNV eyes (0.006 dB/mo) (P = .56) compared with the control eyes (-0.003 dB/mo). CONCLUSIONS Flicker sensitivity is reduced in eyes that go on to develop late AMD. The rate of change in flicker sensitivities over time was particularly useful in predicting eyes and areas within the eye that subsequently develop GA.

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

PURPOSE Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately 30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene. METHODS One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients. RESULTS The presence of the APOE ε4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the ε2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE ε4 allele had an odds ratio (OR) of 4.04 (95% confidence interval [CI], 1.11-14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61-10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis. CONCLUSIONS In patients with neovascular AMD, the presence of the APOE ε4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the ε2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF.

PURPOSE. In vitro and in vivo animal studies suggest that dietary carbohydrates play a role in cataractogenesis. Few epidemiologic studies have been conducted to evaluate this association. The objective of this study was to examine the cross-sectional associations between total carbohydrate intake, dietary glycemic index (dGI), and the risk of cortical and nuclear cataracts.METHODS. After excluding 864 persons from 2473 eligible participants, 1609 eligible nondiabetic participants (mean age, 57.6 years, 55.9% female) in the Melbourne Visual Impairment Project (VIP) were enrolled. Dietary information derived from a semiquantitative food-frequency questionnaire and cataract status graded by the Wilmer protocol (cortical cataract: opacity >= 4/16; nuclear cataract grade >= 2) were collected. With the use of the generalized estimating approach to logistic regression to account for the lack of independence between the eyes of an individual, the associations between dietary carbohydrates and risk of cataract in eyes with no or a single type (pure) of cataract were examined.RESULTS. Multivariate adjustment showed that pure cortical cataract (197 eyes) was significantly associated with total carbohydrate intake (odds ratio [OR] comparing the highest quartile with the lowest quartile = 3.19, 95% confidence interval [CI] = 1.10 -9.27; P-trend = 0.017). The OR for nuclear cataract (366 eyes) comparing the third quartile of dGI with the first quartile (OR = 1.64, 95% CI = 1.02-2.65) was significant, but there was not a consistent dose-response association (P-trend = 0.75).CONCLUSIONS. Carbohydrate intake may be optimized to prolong eye lens function. Because of the high proportion of subjects with missing covariates, these results warrant further study. (Invest Ophthalmol Vis Sci. 2010; 51: 2897-2905) DOI:10.1167/iovs.08-2824