Subfoveal choroidal thickness at age 9 years in relation to clinical and perinatal characteristics in the population-based Generation R Study.

PURPOSE: To assess the association between clinical and perinatal characteristics and subfoveal choroidal thickness in 9-year-old children. METHODS: The study included data from the population-based Generation R cohort, whose participants underwent cycloplegic refractometry, ocular biometry, height, weight and subfoveal choroidal thickness measurements using a swept-source optical coherence tomography (SS-OCT) instrument. Birth parameters were obtained using medical records. Statistical analyses were performed using multivariate regression models adjusted for age, ethnicity and sex. RESULTS: A total of 1018 children (52.5% girls, 47.5% boys) with a mean age of 9.9 ± 0.3 years and a mean cycloplegic spherical equivalent refraction of 0.80 ± 1.1 D in boys and 0.81 ± 1.4 in girls were eligible for analysis. The subfoveal choroid was 17 µm thicker in girls (298 ± 60.6 µm) than in boys (281 ± 55.0 µm; p < 0.001), a difference of 9.1 µm persisting after adjustment for age, ethnicity and axial length (p = 0.017). Subfoveal choroidal thickness decreased with increasing ocular axial length (-16.2 µm/mm, 95% CI -21.2 to -12.4, p < 0.001) and with increasing myopic refraction (-10.0 µm/D, 95% CI 6.8-13.1; p < 0.001, adjusted for age, ethnicity, axial length and sex) while it increased with increasing body height (1.3 µm/cm, 95% CI 0.8 to 1.9, p < 0.001). Additionally, choroidal thickness increased with increasing birthweight (13.0 µm/kg; 95% CI 0.006-0.020; p < 0.001) and increasing size for gestational age (8.2 µm/kg; 95% CI 4.6-11.8; p < 0.001). Smoking up until the time that pregnancy became known was associated with a thinner choroid (p = 0.016). There was no detectable effect of alcohol consumption. The distributions of axial length, refraction and choroidal thickness were narrower than in older populations. CONCLUSION: The subfoveal choroid was thicker in girls than in boys, and higher body height, higher birthweight and larger size for gestational age were associated with a thicker subfoveal choroid. The implications of these findings for myopia development need further evaluation in longitudinal studies.

CAMK2-Dependent Signaling in Neurons Is Essential for Survival.

Ca2+/calmodulin-dependent protein kinase II (CAMK2) is a key player in synaptic plasticity and memory formation. Mutations in Camk2a or Camk2b cause intellectual disability in humans, and severe plasticity and learning deficits in mice, indicating unique functions for each isoform. However, considering the high homology between CAMK2A and CAMK2B, it is conceivable that for critical functions, one isoform compensates for the absence of the other, and that the full functional spectrum of neuronal CAMK2 remains to be revealed.Here we show that germline as well as adult deletion of both CAMK2 isoforms in male or female mice is lethal. Moreover, Ca2+-dependent activity as well as autonomous activity of CAMK2 is essential for survival. Loss of both CAMK2 isoforms abolished LTP, whereas synaptic transmission remained intact. The double-mutants showed no gross morphological changes of the brain, and in contrast to the long-considered role for CAMK2 in the structural organization of the postsynaptic density (PSD), deletion of both CAMK2 isoforms did not affect the biochemical composition of the PSD. Together, these results reveal an essential role for CAMK2 signaling in early postnatal development as well as the mature brain, and indicate that the full spectrum of CAMK2 requirements cannot be revealed in the single mutants because of partial overlapping functions of CAMK2A and CAMK2B.SIGNIFICANCE STATEMENT CAMK2A and CAMK2B have been studied for over 30 years for their role in neuronal functioning. However, most studies were performed using single knock-out mice. Because the two isoforms show high homology with respect to structure and function, it is likely that some redundancy exists between the two isoforms, meaning that for critical functions CAMK2B compensates for the absence of CAMK2A and vice versa, leaving these functions to uncover. In this study, we generated Camk2a/Camk2b double-mutant mice, and observed that loss of CAMK2, as well as the loss of Ca2+-dependent and Ca2+-independent activity of CAMK2 is lethal. These results indicate that despite 30 years of research the full spectrum of CAMK2 functioning in neurons remains to be unraveled.

Intake of Vegetables, Fruit, and Fish is Beneficial for Age-Related Macular Degeneration.

PURPOSE: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. DESIGN: Prospective population-based cohort study. METHODS: Four thousand two hundred and two participants from the Rotterdam Study ≥55 years of age who were free of AMD at baseline were included and followed up for 9.1 ± 5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox proportional hazards models that were adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. RESULTS: Seven hundred fifty-four people developed incident AMD. Intake of the recommended amounts of vegetables (≥200 g/day), fruit (2×/day), and fish (2×/week) were 30.6%, 54.9%, and 12.5%, respectively. In particular, the intake of fish (2×/week) decreased the risk of incident AMD (hazard ratio 0.76 [95% confidence interval 0.60-0.97]). Intake of the recommended amounts of all 3 food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (hazard ratio 0.58 [95% confidence interval 0.36-0.93]). Younger age, higher income, and not smoking were associated with this food pattern, but the risk-lowering effects remained significant after additional adjustment for these factors. CONCLUSION: A diet of 200 grams per day of vegetables, fruit two times per day, and fish two times per week is associated with a significantly reduced risk of AMD.

The European Eye Epidemiology spectral-domain optical coherence tomography classification of macular diseases for epidemiological studies.

PURPOSE: The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. METHODS: A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. RESULTS: Definitions and classifications are proposed for the structure assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. CONCLUSION: The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies.

Quality of life: fractionated stereotactic radiotherapy versus enucleation treatment in uveal melanoma patients.

PURPOSE: To report the quality of life and visual functioning in uveal melanoma patients treated with enucleation or fractionated stereotactic radiation therapy (fSRT). METHODS: Uveal melanoma (UM) patients treated with fSRT (n = 65) or enucleation (n = 48) participated in this prospective study. Questionnaires to measure anxiety (State-Trait Anxiety Inventory), subjective distress (Impact of Event Scale) and quality of life (EORTC-QLQ-C30 and National Eye Institute Visual Function Questionnaire (VFQ-25)) were obtained before treatment and 2, 6, 12, 24, 36 and 48 months after treatment. RESULTS: Less peripheral vision was observed until 3 years (p = 0.026) posttreatment in enucleated patients compared to irradiated patients. From 2 months until 3 years posttreatment irradiated patients increase in role functioning-score (p = 0.005), while enucleated patients decrease in score (p = 0.012). Regardless of their treatment, for all patients we measured a reduction in physical functioning (p = 0.035), insomnia (p < 0.001) and in state anxiety from pretreatment until 2 years posttreatment (p < 0.001). An increase in pain overall (p = 0.023) and in emotional functioning is observed 1 year posttreatment (p < 0.001). At baseline, patients with metastases (independent of their treatment) have more subjective distress (p = 0.037) than patients without metastases. The mean 'global health score' overall, without effect of time, was 76.4 (SD: 13.6). CONCLUSION: Enucleated patients had more difficulty working or performing household tasks 2 months posttreatment compared to irradiated patients. Enucleated patients had diminished peripheral vision until 3 years compared to irradiated patients. Overall quality of life is not significantly different between both treatment groups.

The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data.

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

Antiplatelet and Anticoagulant Drugs Do Not Affect Visual Outcome in Neovascular Age-Related Macular Degeneration in the BRAMD Trial.

PURPOSE: To determine if use of antiplatelet or anticoagulant (AP/AC) medication influences visual acuity in patients with active neovascular age-related macular degeneration (N-AMD). DESIGN: Retrospective analysis of data from a randomized controlled trial. METHODS: Setting: Multicenter. STUDY POPULATION: Total of 330 patients with active N-AMD from the BRAMD study, a comparative trial between bevacizumab and ranibizumab in the Netherlands. OBSERVATION PROCEDURES: Patients underwent an extensive ophthalmic examination. Visual acuity was categorized into functional vision (best-corrected visual acuity [BCVA] ≥ 0.5), visual impairment (BCVA < 0.5), and severe visual impairment (BCVA < 0.3). Fundus photographs were graded for presence of retinal or subretinal hemorrhages. Information on AP/AC medication was obtained through interview. Logistic regression analysis was used to determine associations between AP/AC medication and outcomes. Frequency of hemorrhages in users and non-users stratified for visual acuity categories was analyzed with ANCOVA. MAIN OUTCOME MEASURES: BCVA and presence of hemorrhages. RESULTS: In total, 40.9% of the patients used AP/AC medication, of which 73.3% was aspirin. AP/AC use was not associated with visual impairment (adjusted odds ratio [OR] 0.79; 95% confidence interval [CI] 0.43-1.44) or severe visual impairment (adjusted OR 0.75; 95% CI 0.40-1.43). Patients on AP/AC presented with comparable frequencies of hemorrhages (27% vs 32%, P = .32, respectively). Similar results were found when analyses were restricted to aspirin users only. CONCLUSION: In our study, use of AP/AC medication was associated neither with visual decline nor with the occurrence of hemorrhages in patients with active N-AMD.

Joint Contribution of Genetic Susceptibility and Modifiable Factors to the Progression of Age-Related Macular Degeneration over 10 Years: The Three Continent AMD Consortium Report.

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 < 0.0001). 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. 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.

Retinal neurodegeneration and brain MRI markers: the Rotterdam Study.

We investigated the association of specific retinal sublayer thicknesses on optical coherence tomography (OCT) with brain magnetic resonance imaging (MRI) markers. We included 2124 persons (mean age 67.0 years; 56% women) from the Rotterdam Study who had gradable retinal OCT images and brain MRI scans. Thickness of retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer were measured on OCT images. Volumetric, microstructural, and focal markers of brain tissue were assessed on MRI. We found that thinner RNFL, GCL, and inner plexiform layer were associated with smaller gray-matter and white-matter volume. Furthermore, we found that thinner RNFL and GCL were associated with worse white-matter microstructure. No association was found between retinal sublayer thickness and white-matter lesion volumes, cerebral microbleeds, or lacunar infarcts. Markers of retinal neurodegeneration are associated with markers of cerebral atrophy, suggesting that retinal OCT may provide information on neurodegeneration in the brain.

Development of Refractive Errors-What Can We Learn From Inherited Retinal Dystrophies?

PURPOSE: It is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein. DESIGN: Case-control study. METHODS: Study Population: Total of 302 patients with IRD from 2 ophthalmogenetic centers in the Netherlands. Reference Population: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (N = 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression. RESULTS: Bipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P < .0001; SE -6.86 diopters (D) (standard deviation [SD] 6.38), followed by cone-dominated dystrophies (OR high myopia 19.5, P < .0001; OR high hyperopia 10.7, P = .033; SE -3.10 D [SD 4.49]); rod dominated dystrophies (OR high myopia 10.1, P < .0001; OR high hyperopia 9.7, P = .001; SE -2.27 D [SD 4.65]), and retinal pigment epithelium (RPE)-related dystrophies (OR low myopia 2.7; P = .001; OR high hyperopia 5.8; P = .025; SE -0.10 D [SD 3.09]). Mutations in RPGR (SE -7.63 D [SD 3.31]) and CACNA1F (SE -5.33 D [SD 3.10]) coincided with the highest degree of myopia and in CABP4 (SE 4.81 D [SD 0.35]) with the highest degree of hyperopia. CONCLUSIONS: Refractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development.

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future.

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.

Five-year progression of unilateral age-related macular degeneration to bilateral involvement: the Three Continent AMD Consortium report.

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.

Association of Axial Length With Risk of Uncorrectable Visual Impairment for Europeans With Myopia.

IMPORTANCE: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with structural changes of the retina and the globe because of elongation of the eye axis. How axial length-a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth-and myopia relate to the development of visual impairment over time is unknown. OBJECTIVES: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016. MAIN OUTCOMES AND MEASURES: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia. RESULTS: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from -25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of -6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of -6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high-risk areas. CONCLUSIONS AND RELEVANCE: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population.

Epidemiology of Reticular Pseudodrusen in Age-Related Macular Degeneration: The Rotterdam Study.

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.

Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.

Automated Segmentability Index for Layer Segmentation of Macular SD-OCT Images.

PURPOSE: To automatically identify which spectral-domain optical coherence tomography (SD-OCT) scans will provide reliable automated layer segmentations for more accurate layer thickness analyses in population studies. METHODS: Six hundred ninety macular SD-OCT image volumes (6.0 × 6.0 × 2.3 mm3) were obtained from one eyes of 690 subjects (74.6 ± 9.7 [mean ± SD] years, 37.8% of males) randomly selected from the population-based Rotterdam Study. The dataset consisted of 420 OCT volumes with successful automated retinal nerve fiber layer (RNFL) segmentations obtained from our previously reported graph-based segmentation method and 270 volumes with failed segmentations. To evaluate the reliability of the layer segmentations, we have developed a new metric, segmentability index SI, which is obtained from a random forest regressor based on 12 features using OCT voxel intensities, edge-based costs, and on-surface costs. The SI was compared with well-known quality indices, quality index (QI), and maximum tissue contrast index (mTCI), using receiver operating characteristic (ROC) analysis. RESULTS: The 95% confidence interval (CI) and the area under the curve (AUC) for the QI are 0.621 to 0.805 with AUC 0.713, for the mTCI 0.673 to 0.838 with AUC 0.756, and for the SI 0.784 to 0.920 with AUC 0.852. The SI AUC is significantly larger than either the QI or mTCI AUC (P < 0.01). CONCLUSIONS: The segmentability index SI is well suited to identify SD-OCT scans for which successful automated intraretinal layer segmentations can be expected. TRANSLATIONAL RELEVANCE: Interpreting the quantification of SD-OCT images requires the underlying segmentation to be reliable, but standard SD-OCT quality metrics do not predict which segmentations are reliable and which are not. The segmentability index SI presented in this study does allow reliable segmentations to be identified, which is important for more accurate layer thickness analyses in research and population studies.

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Ophthalmic epidemiology in Europe: the "European Eye Epidemiology" (E3) consortium.

The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case-control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in individual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological samples, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.

Characterizing the Impact of Off-Axis Scan Acquisition on the Reproducibility of Total Retinal Thickness Measurements in SDOCT Volumes.

PURPOSE: Off-axis acquisition of spectral domain optical coherence tomography (SDOCT) images has been shown to increase total retinal thickness (TRT) measurements. We analyzed the reproducibility of TRT measurements obtained using either the retinal pigment epithelium (RPE) or Bruch's membrane as reference surfaces in off-axis scans intentionally acquired through multiple pupil positions. METHODS: Five volumetric SDOCT scans of the macula were obtained from one eye of 25 normal subjects. One scan was acquired through a central pupil position, while subsequent scans were acquired through four peripheral pupil positions. The internal limiting membrane, the RPE, and Bruch's membrane were segmented using automated approaches. These volumes were registered to each other and the TRT was evaluated in 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) regions. The reproducibility of the TRT obtained using the RPE was computed using the mean difference, coefficient of variation (CV), and the intraclass correlation coefficient (ICC), and compared to those obtained using Bruch's membrane as the reference surface. A secondary set of 1545 SDOCT scans was also analyzed in order to gauge the incidence of off-axis scans in a typical acquisition environment. RESULTS: The photoreceptor tips were dimmer in off-axis images, which affected the RPE segmentation. The overall mean TRT difference and CV obtained using the RPE were 7.04 ± 4.31 µm and 1.46%, respectively, whereas Bruch's membrane was 1.16 ± 1.00 µm and 0.32%, respectively. The ICCs at the subfoveal TRT were 0.982 and 0.999, respectively. Forty-one percent of the scans in the secondary set showed large tilts (> 6%). CONCLUSIONS: RPE segmentation is confounded by its proximity to the interdigitation zone, a structure strongly affected by the optical Stiles-Crawford effect. Bruch's membrane, however, is unaffected leading to a more robust segmentation that is less dependent upon pupil position. TRANSLATIONAL RELEVANCE: The way in which OCT images are acquired can independently affect the accuracy of automated retinal thickness measurements. Assessment of scan angle in a clinical dataset demonstrates that off-axis scans are common, which emphasizes the need for caution when relying on automated thickness parameters when this component of scan acquisition is not controlled for.

Validity of Automated Choroidal Segmentation in SS-OCT and SD-OCT.

PURPOSE: To evaluate the validity of a novel fully automated three-dimensional (3D) method capable of segmenting the choroid from two different optical coherence tomography scanners: swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT). METHODS: One hundred eight subjects were imaged using SS-OCT and SD-OCT. A 3D method was used to segment the choroid and quantify the choroidal thickness along each A-scan. The segmented choroidal posterior boundary was evaluated by comparing to manual segmentation. Differences were assessed to test the agreement between segmentation results of the same subject. Choroidal thickness was defined as the Euclidian distance between Bruch's membrane and the choroidal posterior boundary, and reproducibility was analyzed using automatically and manually determined choroidal thicknesses. RESULTS: For SS-OCT, the average choroidal thickness of the entire 6- by 6-mm2 macular region was 219.5 µm (95% confidence interval [CI], 204.9-234.2 µm), and for SD-OCT it was 209.5 µm (95% CI, 197.9-221.0 µm). The agreement between automated and manual segmentations was high: Average relative difference was less than 5 µm, and average absolute difference was less than 15 µm. Reproducibility of choroidal thickness between repeated SS-OCT scans was high (coefficient of variation [CV] of 3.3%, intraclass correlation coefficient [ICC] of 0.98), and differences between SS-OCT and SD-OCT results were small (CV of 11.0%, ICC of 0.73). CONCLUSIONS: We have developed a fully automated 3D method for segmenting the choroid and quantifying choroidal thickness along each A-scan. The method yielded high validity. Our method can be used reliably to study local choroidal changes and may improve the diagnosis and management of patients with ocular diseases in which the choroid is affected.