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After going into the etymology of the word “optotype”, this article covers some tasks in ancient times that required good visual acuity (VA). Around 300 BCE, Euclid formulated the existence of a visual cone with a minimal visual angle at its tip. Trials to test VA appeared AD 1754. Around that time, texts were introduced by opticians in order to be able to prescribe more reliably. In the early nineteenth century, the need for VA tests in ophthalmology resulted in German and English test charts. Numerous variants emerged after the first edition of Snellen’s optotypes in 1862 in The Netherlands. However, 100 years later there was still no standard optotype to reliably test VA. Multidisciplinary approaches between ophthalmology, linguistics, psychology and psychophysics improved optotypes and VA testing, which led to the more reliable LogMAR charts. Recent advances in aids and therapies for the blind and severely visually handicapped, necessitate further development of new and standardized VA tests.

We have known the accommodation phenomenon since 400 BC. Hypotheses about its mechanisms varied widely for two millennia. Early in the 17th century, when people became more aware of ophthalmic optics, Scheiner and Descartes were close to solving that accommodation worked by changes in the lens. Others rejected their idea, and people even denied the existence of accommodation because there was no clear proof. In the early 19th century, evidence accumulated for accommodation mechanisms studying bird, fish, insect, mammal and human eyes. On the discovery of muscle fibres in the ciliary body, attention shifted to its role in accommodation. Around 1850, came the proof that accommodation occurs by a change in the anterior lens curvature. Still for another 50 years, controversies remained about the exact changes in the lens and the precise accommodation mechanism. On looking back, this is not surprising because only late in the 20th century did it become clear that one cannot extrapolate from the multitude of accommodation mechanisms in the animal kingdom to human eyes.

After going into the etymology of the word "optotype", this article covers some tasks in ancient times that required good visual acuity (VA). Around 300 BCE, Euclid formulated the existence of a visual cone with a minimal visual angle at its tip. Trials to test VA appeared AD 1754. Around that time, texts were introduced by opticians in order to be able to prescribe more reliably. In the early nineteenth century, the need for VA tests in ophthalmology resulted in German and English test charts. Numerous variants emerged after the first edition of Snellen's optotypes in 1862 in The Netherlands. However, 100 years later there was still no standard optotype to reliably test VA. Multidisciplinary approaches between ophthalmology, linguistics, psychology and psychophysics improved optotypes and VA testing, which led to the more reliable LogMAR charts. Recent advances in aids and therapies for the blind and severely visually handicapped, necessitate further development of new and standardized VA tests.摘要: 在深入研究“视力表”的词源后, 本文阐述了几个古代需要获得视力的一些重要事件节点。大约在公元300年, Euclid 提出了“视锥”的存在, 即反映在视角尖端的最小角度。视力检查出现于公元1754年。当时, 验光师为了获得更精准的验光处方引入了视力检查。在19世纪早期, 对于眼科视力检查的需求刺激了德语和英语视力表的产生。1862年, 第一版Snellen视力表在荷兰问世后, 大量不同的版本也随之涌现。然而, 100年后依然没有标准视力表能够可靠地检测视力。眼科学、语言学、心理学、心理物理学等多学科方法改进了视力表和视力检查, 这也促使了更为可靠的LogMAR视力表的产生。在盲人和严重视力障碍患者的辅助和治疗的最新进展中, 需要进一步开发新的标准化视力检查方法。.

Importance: Treatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking. Objective: To determine long-term enlargement of GA. Design, Setting, and Participants: In this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020. Main Outcomes and Measures: Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. Results: Of 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm2(95% CI, 3.11-4.67). Enlargement rate varied widely between persons (0.02 to 4.05 mm2per year), with a mean of 1.09 mm2per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P =.01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. Conclusions and Relevance: In this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy..

Purpose To assess joint effects of genetic and modifiable factors on the 10-year progression of age-related macular degeneration (AMD). Design Individual and pooled data analyses of 2 population-based cohorts. Participants Blue Mountains Eye Study (BMES) and Rotterdam Study (RS) participants (n = 835). Methods Participants of the BMES and RS were followed up over 10 years or more. At baseline and follow-up visits, interviews using questionnaires and eye examinations with retinal photography were performed. Age-related macular degeneration was assessed by trained photographic graders and verified by retinal specialists. Genetic susceptibility to AMD meant carrying 2 or more risk alleles of the CFH or ARMS2 SNPs, or both (rs1061170 and rs10490924), relative to 0 or 1 risk allele. Discrete logistic regression models were used to investigate the joint associations of genetic susceptibility and either smoking, fish consumption, dietary intake of lutein–zeaxanthin, or combined environmental risk scores from the 3 modifiable factors with the risk of AMD progression. Odds ratios (ORs) with 95% confidence intervals (CIs) and synergy indexes are reported. Main Outcome Measure Ten-year progression of AMD, categorized as any (≥1 step) or 2-step (≥2 steps) progression on the Three Continent AMD Consortium 5-step severity scale. Results Older age, the presence of AMD genetic susceptibility, and baseline AMD status were associated strongly with AMD progression (P Conclusions Among persons with AMD genetic susceptibility and pre-existing early AMD lesions, presenting with high environmental risk scores from 3 modifiable factors (smoking, infrequent consumption of fish, low lutein–zeaxanthin intake) were associated with an increased risk of 2-step progression over 10 years.

Item does not contain fulltext Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Purpose To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe. Design Cross-sectional, population-based epidemiologic study. Participants Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women. Methods Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design. Main Outcome Measures Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0–4) and a separate category of large drusen (≥125 μm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA). Results Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (>6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27–1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele ( P = 0.89). For all early AMD (grade 1–3), there was no relationship with MDS ( P trend = 0.9). There was a weak trend ( P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest ( P = 0.05). Conclusions This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated.

To assess joint effects of genetic and modifiable factors on the 10-year progression of age-related macular degeneration (AMD).Individual and pooled data analyses of 2 population-based cohorts.Blue Mountains Eye Study (BMES) and Rotterdam Study (RS) participants (n = 835).Participants of the BMES and RS were followed up over 10 years or more. At baseline and follow-up visits, interviews using questionnaires and eye examinations with retinal photography were performed. Age-related macular degeneration was assessed by trained photographic graders and verified by retinal specialists. Genetic susceptibility to AMD meant carrying 2 or more risk alleles of the CFH or ARMS2 SNPs, or both (rs1061170 and rs10490924), relative to 0 or 1 risk allele. Discrete logistic regression models were used to investigate the joint associations of genetic susceptibility and either smoking, fish consumption, dietary intake of lutein-zeaxanthin, or combined environmental risk scores from the 3 modifiable factors with the risk of AMD progression. Odds ratios (ORs) with 95% confidence intervals (CIs) and synergy indexes are reported.Ten-year progression of AMD, categorized as any (≥1 step) or 2-step (≥2 steps) progression on the Three Continent AMD Consortium 5-step severity scale.Older age, the presence of AMD genetic susceptibility, and baseline AMD status were associated strongly with AMD progression (P0.0001). In analyses of pooled data, each additional score from the combined environmental risk scores was associated with an increased risk of 2-step progression over 10 years (OR, 1.26; 95% CI, 1.02-1.56). The copresence of AMD genetic susceptibility and combined risk score of 3 or more was associated with a substantially higher risk of 2-step progression compared with the presence of either factor alone. There was a significant synergistic effect (OR, 4.14; 95% CI, 1.07-15.95) and interaction (P = 0.025) between genetic susceptibility and environmental risk score of 3 or more.Among persons with AMD genetic susceptibility and pre-existing early AMD lesions, presenting with high environmental risk scores from 3 modifiable factors (smoking, infrequent consumption of fish, low lutein-zeaxanthin intake) were associated with an increased risk of 2-step progression over 10 years.

Worldwide, and especially in Asia, myopia is a major vision-threatening disorder. From AD 1600 on, to prevent myopia, authors warned against near work without sufficient pauses. There was an abundance of theories about the causes of myopia, the most common one being the necessity of extra convergence on nearby work with thickened extraocular muscles and elevated intraocular pressure. Ocular tenotomies against myopia were in vogue for a while. Axial lengthening of the eye in myopia was mentioned around 1700, but it took 150 years to become accepted as the most prevalent sign of high myopia. In 1864, a lucid concept of myopia and other ametropias arose through a clear separation between accommodation and refraction. Posterior staphyloma was known around 1800 and its association with myopia became evident some 30 years later. There still seems to be no generally accepted classification of myopia and particularly not of degenerative or pathologic myopia. This review focuses on myopia from 350 BC until the 21st century and on the earliest writings on the histology of eyes with posterior staphyloma. A proposal for myopia classification is given.

Item does not contain fulltext PURPOSE: To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. DESIGN: Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. METHODS: Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. RESULTS: In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the complement factor H and age-related maculopathy susceptibility 2 genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye. CONCLUSION: One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.

PURPOSE: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes.DESIGN: Population-based, cross-sectional study in a random sample aged 65 years or older from 7 European countries.PARTICIPANTS: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD.METHODS: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD).RESULTS: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD.CONCLUSIONS: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD.

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95% CI 13.6%–21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%–0.3%) and 9.8% (95% CI 6.3%–13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. Conclusion We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti–vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 x 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

PURPOSE: To describe associations of serum lipid levels and lipid pathway genes to the incidence of age-related macular degeneration (AMD). DESIGN: Meta-analysis. METHODS: SETTING: Three population-based cohorts. POPULATION: A total of 6950 participants from the Beaver Dam Eye Study (BDES), Blue Mountains Eye Study (BMES), and Rotterdam Study (RS). OBSERVATION PROCEDURES: Participants were followed over 20 years and examined at 5-year intervals. Hazard ratios associated with lipid levels per standard deviation above the mean or associated with each additional risk allele for each lipid pathway gene were calculated using random-effects inverse-weighted meta-analysis models, adjusting for known AMD risk factors. MAIN OUTCOME MEASURES: Incidence of AMD. RESULTS: The average 5-year incidences of early AMD were 8.1%, 15.1%, and 13.0% in the BDES, BMES, and RS, respectively. Substantial heterogeneity in the effect of cholesterol and lipid pathway genes on the incidence and progression of AMD was evident when the data from the 3 studies were combined in meta-analysis. After correction for multiple comparisons, we did not find a statistically significant association between any of the cholesterol measures, statin use, or serum lipid genes and any of the AMD outcomes in the meta-analysis. CONCLUSION: In a meta-analysis, there were no associations of cholesterol measures, history of statin use, or lipid pathway genes to the incidence and progression of AMD. These findings add to inconsistencies in earlier reports from our studies and others showing weak associations, no associations, or inverse associations of high-density lipoprotein cholesterol and total cholesterol with AMD. (C) 2014 by Elsevier Inc. All rights reserved.

Purpose: To describe methods to harmonize the classification of age-related macular degeneration (AMD) phenotypes across four population-based cohort studies: the Beaver Dam Eye Study (BDES), the Blue Mountains Eye Study (BMES), the Los Angeles Latino Eye Study (LALES), and the Rotterdam Study (RS). Methods: AMD grading protocols, definitions of categories, and grading forms from each study were compared to determine whether there were systematic differences in AMD severity definitions and lesion categorization among the three grading centers. Each center graded the same set of 60 images using their respective systems to determine presence and severity of AMD lesions. A common 5-step AMD severity scale and definitions of lesion measurement cutpoints and early and late AMD were developed from this exercise. Results: Applying this severity scale changed the age-sex adjusted prevalence of early AMD from 18.7% to 20.3% in BDES, from 4.7% to 14.4% in BMES, from 14.1% to 15.8% in LALES, and from 7.5% to 17.1% in RS. Age-sex adjusted prevalences of late AMD remained unchanged. Comparison of each center's grades of the 60 images converted to the consortium scale showed that exact agreement of AMD severity among centers varied from 61.0-81.4%, and one-step agreement varied from 84.7-98.3%. Conclusion: Harmonization of AMD classification reduced categorical differences in phenotypic definitions across the studies, resulted in a new 5-step AMD severity scale, and enhanced similarity of AMD prevalence among the four cohorts. Despite harmonization it may still be difficult to remove systematic differences in grading, if present

Purpose Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies. Design Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC). Participants People (n = 10 106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline. Methods Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis. Main Outcome Measures Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits. Results Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores. Conclusions Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Objective To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 ( ARMS2 ) and complement factor H ( CFH ) and to investigate potential interactions between smoking and ARMS2 . Design Population-based, cross-sectional European Eye Study in 7 countries in Europe. Participants Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling. Methods Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression. Main Outcome Measures Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status. Results Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD ( P −20 ). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models ( P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16–242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1×10 −26 (late AMD). Conclusions A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2 , and a significant gene–environment interaction with cigarette smoking was confirmed. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Contains fulltext : 167772.pdf (Publisher’s version ) (Open Access) Purpose: Reticular pseudodrusen (RPD) are considered to be a distinct feature in AMD. Population studies have studied the epidemiology of RPD using standard color fundus photographs (CFP). However, recent studies have shown that RPD are better imaged using near-infrared (NIR) imaging. We studied the epidemiology of RPD in a large population-based study using NIR and CFP. Methods: Participants aged 65+ years from the Rotterdam Study underwent ophthalmologic examination including NIR and CFP. Both images were graded for the presence of RPD and soft indistinct drusen (SID). Associations with demographic and environmental factors, 26 genetic variants, and total genetic risk score were analyzed using logistic regression analysis. Results: Reticular pseudodrusen were detected in 137 (4.9%) of 2774 study participants; of these, 92.7% were detected with NIR imaging and 38% on CFP. Most eyes with RPD showed presence of SID, whereas other drusen types coincided less frequently. Reticular pseudodrusen were significantly associated with age (odds ratio [OR] 1.21, 95% Confidence Interval [CI] 1.17-1.24) and female sex (OR 2.10, 95% CI 1.41-3.13). Environmental factors did not show a significant association with RPD. Major AMD risk variants were significantly associated with RPD and SID; however, ARMS2, C3, and VEGFA were more associated with RPD (RPD vs. SID P < 0.05). Total genetic risk score did not differ significantly (P = 0.88). Conclusion: Detection of RPD was better with NIR imaging than on CFP in a population-based setting. Presence of RPD often coincided with presence of SID; however, they showed quantitative differences in genetic risk profile.

Although ocular tissues involved in aging macula disorder (AMD) were already known in 300 BC, the last type of photoreceptors was discovered only 10 years ago. The earliest descriptions of AMD appeared around 1850. It took over 150 years, till a clearer concept of AMD was formulated and even longer to grasp its pathophysiology. The uncertainty of researchers about the pathogenesis of AMD over the last century is reflected in its changing terminology. The evolution of this terminology is provided in a table to afford the reader a better insight into explanations proposed by researchers during this quest.

Objective— N-terminal pro-B–type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage. Approach and Results— From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03–1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: −0.89 µm [−1.54 to −0.24]). This association remained unchanged after excluding participants with retinopathy signs. Conclusions— In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease.

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1 , which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies. * Abbreviations : AGS : Aicardi-Goutieres syndrome MC : mutation carrier RVCL(-S) : retinal vasculopathy with cerebral leukoencephalopathy (and systemic manifestations)

Contains fulltext : 168269.pdf (Publisher’s version ) (Open Access) Vitamin D has been linked to various cardiovascular risk factors including indices of large-vessel disease. However, it remains unclear whether vitamin D is also associated with microvascular damage. In a community-dwelling population, we studied associations between vitamin D serum levels and retinal microvascular damage defined as retinopathy signs, narrower arterioles, and wider venules.From the population-based Rotterdam Study, we included 5675 participants (age >/=45 years) with vitamin D data and gradable retinal photographs. Serum levels of vitamin D were measured using an antibody-based assay. Retinal exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages were graded on fundus photographs by experienced graders in the whole sample; retinal vascular calibers, that is, arteriolar and venular diameters, were semiautomatically measured in a subsample (n = 2973). We examined the cross-sectional association between vitamin D and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors.We found that persons with lower vitamin D levels were more likely to have retinopathy (adjusted odds ratio per standard deviation (SD) decrease of vitamin D = 1.30; 95% confidence interval (CI): = 1.12-1.49). Furthermore, lower vitamin D levels were associated with wider venular calibers (adjusted mean difference per SD decrease in vitamin D = 1.35; 95% CI = 0.64-2.06). This association was strongest among men (P for interaction = 0.023).Lower levels of vitamin D are associated with retinal microvascular damage, suggesting that the link with cardiovascular risk may partly run through changes in the microvasculature.

Objective To study associations between aspirin use and early and late aging macula disorder (AMD). Design Population-based cross-sectional European Eye Study in 7 centers from northern to southern Europe. Participants In total, 4691 participants 65 years of age and older, collected by random sampling. Methods Aspirin intake and possible confounders for AMD were ascertained by a structured questionnaire. Ophthalmic and basic systemic measurements were performed in a standardized way. The study classified AMD according to the modified International Classification System on digitized fundus images at 1 grading center. Nonfasting blood samples were analyzed in a single laboratory. Associations were analyzed by logistic regression. Main Outcome Measures Odds ratios (ORs) for AMD in aspirin users. Results Early AMD was present in 36.4% of the participants and late AMD was present in 3.3% of participants. Monthly aspirin use was reported by 1931 (41.2%), at least once weekly by 7%, and daily use by 17.3%. For daily aspirin users, the ORs, adjusted for potential confounders, showed a steady increase with increasing severity of AMD grades. These were: grade 1, 1.26 (95% confidence interval [CI], 1.08–1.46; P Conclusions Frequent aspirin use was associated with early AMD and wet late AMD, and the ORs rose with increasing frequency of consumption. This interesting observation warrants further evaluation of the associations between aspirin use and AMD. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE. To determine the associations between the use of antithrombotic drugs and incident open-angle glaucoma (OAG).METHODS. Ophthalmic examinations including measurements of the IOP and perimetry were performed at baseline and follow-up in 3939 participants of the prospective population-based Rotterdam Study who did not have OAG at baseline. The use of antithrombotic drugs was monitored continuously during follow-up. Antithrombotic drugs were stratified into anticoagulants and platelet aggregation inhibitors. Associations between incident OAG and the use of antithrombotic drugs were assessed using Cox regression; the model was adjusted for age, sex, baseline IOP and IOP-lowering treatment, family history of glaucoma, and myopia. Associations between antithrombotic drugs and IOP at follow-up were analyzed with multiple linear regression.RESULTS. During a mean follow-up of 9.8 years, 108 participants (2.7%) developed OAG. The hazard ratio for anticoagulant use was 0.90 (95% confidence interval [CI], 0.55-1.48; P = 0.69) and for platelet aggregation inhibitors 0.80 (0.53-1.21; P = 0.28). There was no trend towards a reduced or increased risk of incident OAG with prolonged anticoagulant use (P value for trend 0.84) or platelet aggregation inhibitor use (0.59). There was a significant IOP-lowering effect of anticoagulants (-0.31 mm Hg; 95% CI, -0.58 to -0.04 mm Hg; P = 0.025) but not of platelet aggregation inhibitors (P = 0.06). The IOP-lowering effect of anticoagulants disappeared after additional adjustment for the use of systemic beta-blockers.CONCLUSIONS. Use of anticoagulants or platelet aggregation inhibitors appears not to be associated with incident OAG. (Invest Ophthalmol Vis Sci. 2012;53:3801-3805) DOI:10.1167/iovs.12-9604

It is becoming increasingly difficult to get manuscripts on (ophthalmic) history accepted by medical journals. This, in spite of the fact that studying the history of disorders yields valuable insights, which can offer new approaches to solving problems of pathophysiology or delimiting disease entities. Some authors may not even be aware that a literature search is also a form of historical investigation. Drusen are a case in point. For 160 years drusen have been associated with the aging macula disorder (AMD) −sometimes under a different name-, and are a benchmark for AMD.We still do not know at the present time what role they play in AMD pathogenesis. I was surprised to find out that the association between drusen and AMD was explicitly denied 30 years after their link was first described. Otto Haab coined the name Bsenile Macular Disease^ (MD) [1] and explicitly wrote that drusen, Bquite innocent changes in old persons,^ had nothing to do with this disease [2] (Fig. 1), although three researchers had earlier linked drusen to MD. So why did Haab come to this conclusion? Was it because earlier authors could not agree on where drusen originate from or the effect they had on retinal function? Carl Wedl named drusen as colloid bodies of the choroid and thought they were incompletely developed cells, because they had no cell membrane or nucleus [3]. Frans Donders called them colloid balls surrounded by pigment, noting their preference for the macular area and concluded that drusen originate from retinal pigment epithelial (RPE) cell nuclei [4]. Heinrich Muller mentioned deposits on the inner side of the choroid that had a ball-shaped or drusenoid form and coined the word Bdruse.^ [5] He mentioned that drusen originate from focal thickenings in Bruch’s membrane. Later, the theory was formulated that drusen originate from leucocytes [6]. But we still do not know, 160 odd years on, from where exactly drusen originate . The RPE has returned as the latest candidate [7], just as Donders suggested. Who were these early authors who linked drusen with AMD? Donders designed in 1852 an improved ophthalmoscope after Helmholtz’s publication on ophthalmoscopy of the living eye. Donders was convinced that the white flecks that he had seen several times on ophthalmoscopy in eyes of old people suffering from Bsenile amblyopia^ (as loss of visual acuity in the elderly was called at that time) were not fatty metamorphoses but colloid degenerations. Around 1853 Donders started with histological examination of 38 apparently healthy eyes. Drusen rarely were absent in the eyes of persons aged 70 to 80 years. The visual acuity in these eyes had not been carefully recorded before death [4]. Using microscopy Donders noticed rods, obliquely oriented around small drusen as well as degeneration of the choriocapillaris and the RPE. Often rods and cones were absent above drusen, that sometimes compressed the retina, without expanding the retina on the vitreous side. Donders concluded that the Partly presented at the 28thmeeting of the Julius Hirschberg Gesellschaft, Bonn, Germany, October 4 2014, and at the joint Cogan – Hirschberg Society meeting, New York, USA March 28 2015.

Objective: To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study. Methods: For 2167 individuals (≥55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes. Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, β-carotene, lutein/zeaxanthin, and eicosapentaenoic/ docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P < .05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of β-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends

Objective: To determine whether lifestyle-related risk factors, such as socioeconomic status, smoking, alcohol consumption, and obesity, are associated with open-angle glaucoma (OAG).Methods: Participants from the Rotterdam Study, a prospective population-based cohort study, were considered eligible if they participated at both baseline and follow-up and if they had no OAG at baseline. All participants underwent an identical ophthalmologic examination at all visits, including intraocular pressure measurements, optic nerve head assessment, and perimetry. Lifestyle-related factors were assessed by questionnaires by trained research assistants or measured during the examinations (body mass index and waist to hip ratio). Cox proportional hazard regression analysis was applied to calculate hazard ratios.Results: Of 3939 eligible participants, 108 (2.7%) developed OAG during 9.7 years' mean follow-up. No statistically significant effect of socioeconomic status, smoking, or alcohol intake was found. In women, each unit increase in body mass index resulted in a 7% decrease in the risk of developing OAG (P=.04). There was a significant increasing effect of body mass index on intraocular pressure (PConclusions: Obesity appears to be associated with a higher intraocular pressure and a lower risk of developing OAG. These associations were only present in women. Other lifestyle-related factors, such as socioeconomic status, smoking, and alcohol consumption, were not associated with OAG.

Objective: Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.Design: Population-based setting, family-based setting, and a case-control study.Participants: The Rotterdam Study I cohort (N = 5312; mean age +/- standard deviation [SD], 68.0 +/- 8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age +/- SD, 48.3 +/- 15.2 years), and a cohort from Southampton (N = 702; mean age +/- SD, 72.5 +/- 10.7 years).Methods: After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.Main Outcome Measures: Odds ratios and AUCs of individual and combined risk alleles.Results: No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).Conclusions: A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011; 118: 2389-2397 (C) 2011 by the American Academy of Ophthalmology.

The Association for Research in Ophthalmology (ARO) was founded in 1928 by Conrad Berens, (Fig. 1) a New York ophthalmologist, to strengthen the scientific basis of ophthalmology. Initially, only clinicians with some scientific expertise attended the half-day meetings that were paired with the American Academy conventions. The fledgling ARO became more viable in the years after World War II which, despite its terrible consequences, spurred the development of visual sciences. In 1970, ARO changed to the Association for Research in Vision and Ophthalmology (ARVO), and thus ARVO seems to be, with 83 years, in the same age range in which the disorders that I am going to discuss have their highest incidence. What would Conrad Berens think of this ARVO meeting? Would he be impressed by its 13 scientific sections and its nearly 7000 abstracts or puzzled by the overlap in posters on certain topics as observed from these abstracts? He might be pleased by the fact that 44% of the 6000 ARVO members are non-MDs or be disappointed because only 2.3% of all ophthalmologists world-wide are members of ARVO. Would he get the impression that for some, vision research seems a goal in itself, instead of a search for better cures for eye disorders? Would he consider the recent separation of the Visual Section from ARVO’s main meeting a bright idea or the sequelae of blind spots in its board members? In this lecture, I will describe my transformation, perhaps somewhat similar to that of Berens’, from pure clinician to clinical researcher in ophthalmology, a field that has undergone a striking metamorphosis over the past 40 years. I will deal more at length with aging macula disorder (AMD) and open-angle glaucoma (OAG). I will analyze what might bewilder Berens about our ophthalmology advancements and will conclude my reflections by mentioning some human interactions and scientific factors that may influence progress in vision research.

PURPOSE. To determine the association between the ocular perfusion pressure (OPP; essentially the difference between the blood pressure and the intraocular pressure [IOP]) and incident open-angle glaucoma (OAG).METHODS. A subset of 3882 participants of the population-based Rotterdam Study for whom data from ophthalmic examinations at baseline and follow-up and blood pressure measurements at baseline were available, and who did not have OAG at baseline, were included. Associations between the mean, systolic and diastolic OPP, and incident OAG were assessed using Cox regression models adjusted for age and sex, with and without adjustment for IOP.RESULTS. During a mean follow-up of 9.8 years, 103 participants (2.7%) developed OAG. The association between the mean OPP and incident OAG was not significant (hazard ratio 0.995 per mm Hg increase in mean OPP; 95% confidence interval 0.971-1.019) when adjusted for IOP, but became significant if not adjusted for IOP (0.968; 0.945-0.992). The systolic and diastolic OPP showed a pattern similar to that of the mean OPP, though less significant.CONCLUSIONS. The OPP appears to be associated with incident OAG but this association seems to be due to the fact that the IOP, a strong risk factor for OAG, is part of the OPP, rather than that OPP is an independent OAG risk factor itself. (Invest Ophthalmol Vis Sci. 2011;52:6875-6881) DOI:10.1167/iovs.117376

Purpose: Diseases characterized by a continuous trait can be defined by setting a cut-off point for the disease measure in question, accepting some misclassification. The 97.5th percentile is commonly used as a cut-off point. However, it is unclear whether this percentile is the optimal cut-off point from the point of view of risk-factor analysis. The optimal cut-off point for risk-factor analysis can be found with a statistical method that minimizes the effect of misclassification. We applied this method to glaucomatous optic neuropathy. Here, the continuous trait is the cup-disc ratio. The aim of this study was to determine the optimal cup-disc ratio cut-off point for risk-factor analysis in population-based epidemiology.Methods: All participants in the population-based Rotterdam Study underwent intraocular pressure (IOP) measurements, assessment of the cup-disc ratio with the Heidelberg Retina Tomograph (HRT) and visual field testing. In the statistical method, the cup-disc ratio (the continuous trait) and the IOP (a major risk factor) were independent variables and glaucomatous visual field loss (the true glaucoma endpoint) the dependent variable in a logistic regression model. The optimal cup-disc ratio cut-off point was found by minimizing the influence of IOP in this model. Variability of the approach was assessed by using a bootstrap resampling technique.Results: Of 2444 included participants, 93 had glaucomatous visual field loss. The median optimal cup-disc ratio cut-off point was the 97.0th percentile with a 95% central range from 95.5 to 98.5.Conclusion: The optimal cup-disc ratio cut-off point for risk-factor analysis is close to the commonly used 97.5th percentile.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOe4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.650.74; P = 4.41 x 10-11) and APOe2 (OR = 1.83 for homozygote carriers; CI: 1.043.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.381.72; P = 2.8 x 10(-15)) and atrophic (OR = 1.38; CI: 1.181.61; P = 3.37 x 10(-5)) AMD but not early AMD (OR = 0.94; CI: 0.861.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond e2 and e4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology. 32:14071416, 2011. (C) 2011 Wiley Periodicals, Inc.

Purpose: To establish normative values for Heidelberg Retina Tomograph (HRT3) variables and to develop HRT3-based criteria for glaucomatous optic neuropathy for epidemiological research in a white population. Methods: Consecutive participants in the Rotterdam Study were examined with HRT and simultaneous stereoscopic fundus photography (ImageNet) in addition to other ophthalmic examinations including intraocular pressure (IOP) measurements and perimetry. Normative values for all HRT3 variables were determined in participants who met all the following criteria: no glaucomatous visual field loss (GVFL), an IOP of 21mmHg or less, no IOP lowering treatment, and a negative family history of glaucoma. Sensitivity was determined in participants with glaucomatous visual field loss at a fixed high specificity of 97.5% - a value commonly used in population-based epidemiology. Results: A total of 2516 participants were included in this study of whom 66 had glaucomatous visual field loss in at least one eye and 1680 fulfilled the criteria for contributing to the normative values. The HRT3 linear cup-disc ratio (LCDR) variable, adjusted for disc area, showed the highest sensitivity, 35%, at the required specificity of 97.5%. The 97.5th percentile of the LCDR was 0.67 for small discs (up to 1.5mm

Objectives: To test the "vascular depression" hypothesis, the authors investigated whether smaller retinal arteriolar or larger venular calibers, which are markers of cerebral microvascular disease, were associated with incident late-life depression. Methods: The authors included 3,605 participants (age >= 55 years) from the population-based Rotterdam Study with no depression at baseline (1993-1995) and fundus photographs gradable for retinal vascular caliber measurements. The authors identified persons with incident depressive symptoms and syndromes using psychiatric interviews during follow-up visits and continuous monitoring. The follow-up was complete until October 2005. Results: After a mean follow-up of 9.0 years, 555 participants developed incident depression, including 312 with depressive syndrome. Neither smaller arteriolar (age-and sex-adjusted hazard ratio: 1.01; 95% confidence interval: 0.93-1.10), nor larger venular calibers (hazard ratio: 1.02; 95% confidence interval: 0.94-1.12) were associated with incident depressive syndromes. Conclusions: Our data showed no evidence of an association between retinal vascular calibers and incident late-life depression. (Am J Geriatr Psychiatry 2010; 18: 452-456)

Pseudoxanthoma elasticum (PXE) is a systemic disorder affecting elastic tissues most markedly in skin, retina, and blood vessels. It is caused by mutations in the ABCC6 gene and is transmitted in an autosomal recessive fashion. In 1994 a new classification system for PXE was published as the result of a consensus conference. Since then the ABCC6 gene has been discovered. We propose that there is a need for a classification system incorporating all relevant systemic symptoms and signs, based on standardized clinical, histological, and molecular biological examination techniques. We re-evaluated the histopathologic PXE signs and propose a classification system with unambiguous criteria leading to a consistent diagnosis of definitive, probable, or possible PXE world-wide. We put this proposed classification forward to encourage further debate on the diagnosis of this multi-organ disorder. (c) 2010 Wiley-Liss, Inc

Purpose: To determine the 10-year incidence of glaucomatous visual field loss (GVFL) and to investigate the influence of risk factors for open-angle glaucoma on this incidence. Design: Population-based cohort study. Participants: Participants aged >55 years from the Rotterdam Study. Methods: Of the 7983 participants in the Rotterdam Study, 6806 underwent ophthalmic examinations at baseline (1990-1993). In 6723 of these 6806 participants (99%), both visual field screening and an assessment of the optic disc were performed. After exclusion of 93 participants with GVFL at baseline, 6630 participants at risk of developing GVFL remained. These participants underwent similar ophthalmic examinations during 2 follow-up visits (1997-1999 and 2002-2006). The incidence of GVFL was determined as an incidence rate and recalculated to a 10-year risk. Risk factors for open-angle glaucoma (age, gender, positive family history of glaucoma, baseline intraocular pressure (IOP), myopia, and baseline vertical cup-to-disc ratio [VCDR]) were assessed using Cox regression. The dependent variable was the development of GVFL. Main Outcome Measures: Ten-year risk and incidence rates of GVFL. Hazard ratios of the above-mentioned risk factors. Results: Of 6630 participants, 3939 (59%) completed at least 1 follow-up examination and 2571 (39%) completed both; 108 participants developed GVFL. The overall incidence rate and 10-year risk of GVFL were 2.9 per 1000 person-years (95% confidence interval [CI], 2.4-3.5) and 2.8% (2.3-3.4), respectively. The 10-year risk increased from 1.9% at age 55 to 59 years to 6.4% at age >= 80 years (P

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

Purpose: Pseudoxanthoma elasticum is an autosomal recessive disorder of elastic tissue in the skin, eyes, and cardiovascular system, caused by mutations in the ABCC6 gene. The purpose of this study was to check variability in expression within one genotype and look for pseudoxanthoma elasticum signs in heterozygotes. Methods: We examined a relatively large, in comparison with the present literature, group of adult persons homozygous or heterozygous for the c.3775delT mutation in the ABCC6 gene, front a genetically isolated population in the Netherlands. All participants filled out a questionnaire and underwent standardized dermatologic and ophthalmologic examinations with photography of skin and fundus abnormalities. Skin biopsies from affected skin or a predilection site and/or a scar were examined and compared with biopsies from controls. Results: Skin abnormalities, ophthalmologic signs, and cardiovascular problems varied greatly among the 15 homozygous participants. There was no correlation among severity of skin, eyes, or cardiovascular abnormalities. None of the 44 heterozygous participants had any sign of pseudoxanthoma elasticum on dermatologic, histopathologic, and/or ophthalmologic examination, but 32% had cardiovascular disease. Conclusion: Individuals homozygous for the c.3775delT mutation can have a highly variable phenotype. We did not find pseudoxanthoma elasticum eye or skin abnormalities in the heterozygous family members. Genet Med 2009:11(12):852-858

Purpose Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and a target for inhibition therapy in wet age-related macular degeneration (AMD). The purpose of this study was to examine whether genetic variation in the VEGF gene is associated with AMD and, especially, with its wet end stage. Design Prospective population-based cohort study. Participants Four thousand two hundred twenty-eight participants aged 55 years and older. Methods AMD was classified according to a modified International Classification System using fundus color images. Genotypes and haplotypes were determined for 3 functional VEGF single nucleotide polymorphisms (SNPs): C-2578A, G-1154A, and G-634C. Cox proportional hazards regression analyses were used to investigate possible associations between the individual SNPs and incident AMD. The Haplo.Stats program was used to test the associations between VEGF gene haplotypes and incident AMD. Main Outcome Measure AMD Results Of 4228 participants at risk for incident early and late AMD for whom blood specimens were available for VEGF genotyping, incident early AMD developed in 514 and incident late AMD developed in 89 (35 dry and 54 wet) after a mean follow-up of 7.4 years. None of the SNPs showed a significant association with incident early or late AMD, especially not with incident wet AMD. Haplotype analyses also detected no associations. Conclusions The a priori hypothesis that 3 common SNPs in the VEGF gene would be a risk factor for AMD, especially the wet form, could not be confirmed. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective Retinal vessel diameters, in particular larger venular diameters, have been associated with cerebrovascular disease. Larger retinal venular diameters may reflect cerebral ischemia. The authors investigated whether arteriolar oxygen saturation (SaO 2 ) and total cerebral blood flow (CBF), indicators of cerebral oxygen supply, are associated with retinal arteriolar or venular diameters. Design Cross-sectional study performed within the population-based Rotterdam Study. Participants Randomly selected participants aged 55 years or older (n = 696), who underwent both an eye examination and brain magnetic resonance imaging (MRI). Methods Arteriolar oxygen saturation was determined by pulse oximetry on the right index finger. Cerebral blood flow was assessed using a phase-contrast MRI sequence that measured the flow in the basilar and both internal carotid arteries. Brain volume was measured to express CBF per 100 ml brain volume. Retinal arteriolar and venular diameters were measured on digitized fundus color transparencies on 1 eye of each participant. Regression models were used to investigate the association of SaO 2 and CBF with retinal vessel diameters. Main Outcome Measures Mean retinal arteriolar and venular diameters (in micrometers). Results Lower SaO 2 was associated with larger venular diameters. Persons with SaO 2 less than 96% (n = 113) had on average 5 μm larger venular diameters compared with those with SaO 2 of 96% or more (n = 583; age- and gender-adjusted mean difference, 5.6 μm; 95% confidence interval, 1.2–10.0). Cerebral blood flow was not related to venular diameters when analyzed separately. Additional analyses showed that the association between SaO 2 and venular widening was confined to participants within the lowest tertile of CBF. No associations were found between SaO 2 or CBF and arteriolar diameters. Additional adjustment for established cardiovascular risk factors did not change the results. Conclusions An association of lower SaO 2 with larger retinal venular diameters was observed, in particular in the presence of lower CBF. These findings suggest that venular widening may reflect a lower oxygen supply, especially to the brain.

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

Objective To examine the association of sunlight exposure and antioxidant level with age-related macular degeneration (AMD). Methods Four thousand seven hundred fifty-three participants aged 65 years or older in the European Eye Study underwent fundus photography, were interviewed for adult lifetime sunlight exposure, and gave blood for antioxidant analysis. Blue light exposure was estimated by combining meteorologic and questionnaire data. Results Data on sunlight exposure and antioxidants were available in 101 individuals with neovascular AMD, 2182 with early AMD, and 2117 controls. No association was found between blue light exposure and neovascular or early AMD. Significant associations were found between blue light exposure and neovascular AMD in individuals in the quartile of lowest antioxidant level—vitamin C, zeaxanthin, vitamin E, and dietary zinc—with an odds ratio of about 1.4 for 1 standard deviation unit increase in blue light exposure. Higher odds ratios for blue light were observed with combined low antioxidant levels, especially vitamin C, zeaxanthin, and vitamin E (odds ratio, 3.7; 95% confidence interval, 1.6-8.9), which were also associated with early stages of AMD. Conclusions Although it is not possible to establish causality between sunlight exposure and neovascular AMD, our results suggest that people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients.

PURPOSE. It has been suggested that early menopause increases the risk of aging-macula disorder (AMD), the major cause of incurable blindness with a dry and wet late subtype, and that exposure to endogenous or postmenopausal exogenous estrogens reduces this risk. This study was undertaken to investigate whether genetic variations in the estrogen receptor a(ESR1) gene are associated with incident AMD. METHODS. In the Rotterdam Study, a prospective population-based cohort study of participants aged 55 years and older, associations between ESR1 PvuII-XbaI haplotypes and incident early or late AMD were studied in 4571 participants after a mean follow-up time of 7.7 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), with adjustment for the most common confounders. RESULTS. ESR1 PvuII-XbaI haplotype 1 was a risk factor for late AMD. Persons with two copies of haplotype 1 were at 3.20 (95% CI, 1.47Â?6.99) times higher risk for late AMD than noncarriers of haplotype 1, after adjustment for age and sex. This increase was more pronounced for wet AMD (hazard ratio [HR] 4.29; 95% CI, 1.47Â?12.49) after adjustment for age, sex, smoking, and complement factor H genotype. Correction for additional confounders, including age at menopause, use of hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings. CONCLUSIONS. Persons with one or two copies of ESR1 PvuII-XbaI haplotype 1 have an increased risk of late AMD, especially of the wet form.

Objective To examine whether C-reactive protein (CRP) level is a risk factor for aging macula disorder (AMD) in a general population. Methods We examined serum high-sensitivity CRP (HsCRP) levels in 4914 participants of the population-based Rotterdam Study at risk for AMD. After a mean follow-up of 7.7 years, 561 cases of early and 97 cases of late incident AMD (iAMD) were identified. We used Cox proportional hazards regression models to estimate hazard ratios and corresponding 95% confidence intervals (CIs). Results After adjustment for age and sex, hazard ratios were 1.11 (95% CI, 1.02-1.21) per standard deviation increase in HsCRP level for early iAMD and 1.28 (95% CI, 1.02-1.60) for late iAMD. Hazard ratios for early iAMD increased per quartile increase in HsCRP level as follows: second quartile, 1.19 (95% CI, 0.94-1.52); third quartile, 1.29 (95% CI, 1.01-1.64); and fourth quartile, 1.33 (95% CI, 1.05-1.70). The risk of late iAMD was higher in all upper quartiles of HsCRP. Conclusion Elevated baseline levels of HsCRP were associated with the development of early and late AMD in this large population-based cohort.

ABCC6 belongs to the adenosine triphosphate-binding cassette (ABC) gene subfamily C. This protein family is involved in a large variety of physiological processes, such as signal transduction, protein secretion, drug and antibiotic resistance, and antigen presentation [Kool et al. (1999) 59:175-182; Borst and Elferink (2002) 71:537-592]. ABCC6 is primarily and highly expressed in the liver and kidney [Kool et al. (1999) 59:175-182; Bergen et al. (2000) 25:228-2231]. The precise physiological function and natural substrate(s) transported by ABCC6 are unknown, but the protein may be involved in active transport of intracellular compounds to the extracellular environment [Kool et al. (1999) 59:175-182] [Scheffer et al. (2002) 82:515-518]. Recently, it was shown that loss of function mutations in ABCC6 cause pseudoxanthoma elasticum (PXE) [Bergen et al. (2000) 25:228-2231; Le Saux et al. (2000) 25:223-227]. PXE is an autosomal recessively inherited multi-organ disorder [Goodman et al. (1963) 42:297-334; Lebwohl et al. (1994) 30:103-107]. PXE is primarily associated with the accumulation of mineralized and fragmented elastic fibers of the connective tissue in the skin [Neldner (1988) 6:1-159], Bruch's membrane in the retina [Hu et al. (2003) 48:424-438], and vessel walls [Kornet et al. (2004) 30:1041-1048]. PXE patients usually have skin lesions and breaks in Bruch's membrane of the retina (angioid streaks). Also, a variety of cardiovascular complications has been observed [Hu et al. (2003) 48:424-438]. Recently, a mouse model for PXE was created by targeted disruption of Abcc6 [Gorgels et al. (2005) 14:1763-1773; Klement et al. (2005) 25:8299-8310], which may be useful to elucidate the precise function of Abcc6 and to develop experimental therapies.

Objective: To investigate cross-sectional associations among blood pressures (BPs), arterial stiffness, and open-angle glaucoma (OAG). Methods: Study participants came from the population-based Rotterdam Study. The baseline examination phase took place after an extensive home interview from March 20, 1990, to June 17, 1993, and the third phase between March 19, 1997, and December 16, 1999. Cases were classified into high-tension OAG (htOAG) and normal-tension OAG (ntOAG), according to an intraocular pressure greater than 21 mm Hg or 21 mm Hg or less. Pulse pressure was the difference between systolic and diastolic BP. Diastolic perfusion pressure was the difference between diastolic BP and the intraocular pressure; indicators of arterial stiffness were carotid-femoral pulse wave velocity and carotid distensibility. Associations were evaluated with logistic regression analysis, adjusted for age, sex, body mass index, smoking, diabetes mellitus, serum cholesterol level, and BP-lowering treatment. Results: A total of 5317 participants were included in this study. In participants with a higher pulse pressure, the prevalence of htOAG was elevated (odds ratio [OR] per standard deviation, 1.32; 95% confidence interval [CI], 1.03-1.69). In persons treated for systemic hypertension, low diastolic perfusion pressure (