Hyperpolarized 129Xe MR Spectroscopy in the Lung Shows 1-year Reduced Function in Idiopathic Pulmonary Fibrosis.

Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (129Xe) MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Materials and Methods In a prospective study, healthy volunteers and participants with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Participants with IPF were followed up with forced vital capacity percent predicted (FVC%p), diffusing capacity of the lungs for carbon monoxide percent predicted (DLco%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10%, reduction in DLco%p by at least 15%, or admission to hospice care. CT and MRI were spatially coregistered and a measure of pulmonary gas transfer (red blood cell [RBC]-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. Results Sixteen healthy volunteers (mean age, 57 years ± 14 [SD]; 10 women) and 22 participants with IPF (mean age, 71 years ± 9; 15 men) were evaluated, as follows: nine IPF progressors (mean age, 72 years ± 7; five women) and 13 nonprogressors (mean age, 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 vs 8.2% ± 5.9; P = .03) and RBC-to-barrier ratio (0.26 ± 0.06 vs 0.20 ± 0.06; P = .03) at baseline were associated with progression of IPF. Participants with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 vs 0.28 ± 0.05; P = .01) but not in fibrotic regions of the lung (0.15 ± 0.09 vs 0.14 ± 0.04; P = .62) relative to the nonprogressive group. Conclusion In this preliminary study, functional measures of gas transfer and ventilation measured with xenon 129 MRI and the extent of fibrotic structure at CT were associated with idiopathic pulmonary fibrosis disease progression. Differences in gas transfer were found in regions of nonfibrotic lung. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gleeson and Fraser in this issue.

Dynamic contrast enhanced MRI for the evaluation of lung perfusion in idiopathic pulmonary fibrosis.

BACKGROUND: The objective of this work was to apply quantitative and semiquantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF). METHODS: In this prospective trial 41 subjects, including healthy control and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year; progressive IPF (IPFprog) subjects were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted forced vital capacity (FVC % pred) or diffusing capacity of the lung for carbon monoxide (D LCO % pred) measured during follow-up visits. 35 out of 41 subjects were retained for final baseline analysis (control: n=15; IPFstable: n=14; IPFprog: n=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: control versus IPF groups and control versus IPFstable versus IPFprog groups, using linear regression analysis. Each measure was compared with FVC % pred, D LCO % pred and the lung clearance index (LCI % pred) using a Spearman rank correlation. RESULTS: DCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprog compared with both IPFstable (p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV and D LCO % pred (rs= -0.48, p=0.022) and LCI % pred (rs= +0.47, p=0.015). Significant group differences were detected in age (p<0.001), D LCO % pred (p<0.001), FVC % pred (p=0.001) and LCI % pred (p=0.007). CONCLUSIONS: Global analysis obscures regional changes in pulmonary haemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

Oxidized Low-density Lipoprotein and the Incidence of Age-related Macular Degeneration.

PURPOSE: To examine the relationship between serum oxidized low-density lipoprotein (ox-LDL) cholesterol and the incidence of age-related macular degeneration (AMD) over a 25-year period in a sample of persons from the population-based Beaver Dam Eye Study (BDES). DESIGN: Observational prospective cohort study. PARTICIPANTS: A total of 4972 people from the BDES (aged 43-84 years and living in Beaver Dam, Wisconsin in 1988) seen during at least 1 of 6 examination phases at approximately 5-year intervals between 1988 and 2016. METHODS: A 50% random sample of participants (N = 2468) was selected for ox-LDL measurements. Stored frozen specimens from every examination phase were processed using an enzyme-linked immunosorbent assay from a single batch. All available intervals were included for a person, resulting in 6586 person-visits. MAIN OUTCOME MEASURES: Age-related macular degeneration was assessed using the Wisconsin Age-related Maculopathy Grading System, and severity was defined using a 5-step severity scale. The severity of the worse eye at each examination was used for analyses. A multi-state Markov (MSM) model was fit to simultaneously assess the ox-LDL relationship to all AMD transitions, including incidence of any AMD, incidence of late AMD, and worsening and improvement of AMD over the 25 years of the study. RESULTS: The mean (standard deviation) level of ox-LDL was 75.3 (23.1) U/L at the baseline examination. When adjusting for age, sex, ARMS2 and CFH risk alleles, and examination phase, the ox-LDL at the beginning of a period was not statistically significantly associated with the incidence of any AMD (hazard ratio per 10 U/L ox-LDL was 1.03, 95% confidence interval 0.98,1.09). Furthermore, ox-LDL was not associated with worsening anywhere along the AMD severity scale, nor with incidence of late AMD. The lack of relationships of ox-LDL to the incidence of any AMD or worsening of AMD remained after adjustment for history of statin use, smoking status, body mass index, and history of cardiovascular disease (data not shown). CONCLUSIONS: Our findings do not provide evidence for statistically significant relationships between ox-LDL and AMD disease development or worsening of AMD.

Aldose Reductase Polymorphisms, Fasting Blood Glucose, and Age-Related Cortical Cataract.

Purpose: To determine whether there is an association between polymorphisms of the AKR1B1 gene and cortical cataract in the presence of hyperglycemia. Methods: In the second cross section of the Blue Mountains Eye Study (BMES), 3508 participants (2334 at 5-year follow-up and 1174 newly recruited participants) were examined during 1997 to 2000. Cataract was graded from lens photographs using the Wisconsin Cataract Grading System. Fasting blood glucose (FBG) was measured. Continuous imputed dosages of minor alleles of 17 AKR1B1 single nucleotide polymorphisms (SNPs) were assessed for associations with prevalent cortical cataract. Gene-environment interactions between SNPs and FBG were examined. Odds ratios (OR) and 95% confidence intervals (CI) for prevalent cortical cataract were estimated using logistic regression adjusting for age, sex, smoking, hypertension, education, and myopia. A P value of 0.005 was considered statistically significant after correction for 10 independent tests. Replication of significant associations found in the BMES sample was conducted in the Singapore Epidemiology of Eye Diseases (SEED) study (n = 10,033). Results: No polymorphism was associated with prevalent cortical cataract. A significant interaction was observed between rs9640883 and FBG (Pinteraction = 0.004), with increased cortical cataract prevalence associated with rs9640883 minor allele dosage in those with FBG >6.0 mM (strata-specific OR 1.72, 95% CI 1.09-2.72). No similar association was found in participants with normal FBG (OR 0.85, 95% CI 0.69-1.04). This interaction was not evident in the SEED study. Conclusions: The identified interaction between rs9640883 and FBG in relation to cortical cataract was not replicated but may warrant further investigation.

Neural dysfunction and retinopathy in persons with type 1 diabetes.

OBJECTIVE: To determine associations of microvascular and neuropathic complications of diabetes cross-sectionally and longitudinally in persons with long-term type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Persons receiving care for T1D in South Central Wisconsin were identified in 1979-1980 and examined approximately every 5 years. Associations between neuropathic and microvascular complications were examined at most prior visits, when information on several neuropathic complications was collected. Temporal relationships were examined by modeling incidence between examinations across the visits. RESULTS: Adjusting for duration of diabetes, glycated hemoglobin, and systolic blood pressure, the following were cross-sectionally associated with prevalent PDR (proliferative diabetic retinopathy): the presence of sensory neuropathy (SN) as reported at each Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) examination (odds ratio (OR) = 2.76, confidence interval (CI) = 1.71, 4.48) and the heartrate variability measures RMSD (square root of the mean of squared differences of successive RR intervals) (OR = 0.24, CI = 0.16, 0.37) and SDNN (standard deviation of successive RR intervals) (OR = 0.26, CI = 0.17, 0.39). Findings were similar for prevalent ME (macular edema) as assessed from spectral-domain optical coherence tomography (SD-OCT). The presence of PDR (OR = 2.13, CI = 1.63, 2.78) and ME (OR = 2.36, CI = 1.66, 3.34) were both significantly associated with incident WESDR SN. WESDR SN was associated with incident PDR (OR = 1.53, CI = 1.09, 2.15) but not incident ME (OR = 1.31, CI = 0.92, 1.87). CONCLUSIONS: Sensory neuropathy and heartrate variability were significantly associated with prevalent PDR and ME in people with long-term T1D. PDR and ME were significantly associated with incident sensory neuropathy, and sensory neuropathy was significantly associated with incident PDR. Studies using earliest detectable markers of microvascular and neurologic abnormalities are needed to determine which of the two systems 'fails' first. Such information might suggest a temporal sequence of diabetes complications.

The Relationship of Retinal Vessel Geometric Characteristics to the Incidence and Progression of Diabetic Retinopathy.

PURPOSE: To examine the relationships of retinal vessel geometric characteristics (RVGCs) to the incidence and progression of diabetic retinopathy (DR). DESIGN: Observational, prospective cohort study. PARTICIPANTS: Nine hundred ninety-six persons with type 1 diabetes mellitus (T1DM) and 1370 persons with type 2 diabetes mellitus (T2DM) seen at a baseline examination who were eligible for follow-up examinations at subsequent 5-year intervals. A total of 3846 person-interval data from these follow-up examinations are the basis for the analyses. METHODS: Diabetic retinopathy and macular edema were assessed by grading of 30° stereoscopic color fundus photographs. Retinal vessel geometric characteristics were assessed using the Singapore I Vessel Assessment program from a digitized copy of 1 of the field 1 fundus photographs obtained at baseline and follow-up. MAIN OUTCOME MEASURES: The 5-year incidence of any DR, progression of DR, and incidence of proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME) in right eyes. RESULTS: Incident DR occurred in 45%, progression in 32%, PDR in 10%, and CSME in 5%. While adjusting for glycated hemoglobin, duration of diabetes, and other factors, retinal arteriolar simple tortuosity was associated significantly with the incidence of any DR (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01-1.35). Retinal venular branching angle was associated significantly with progression of DR (OR, 1.18; 95% CI, 1.03-1.36), retinal venular curvature tortuosity was associated significantly with the incidence of PDR (OR, 1.15; 95% CI, 1.01-1.30), and retinal venular branching angle (OR, 1.41; 95% CI, 1.10-1.82) was associated significantly with the incidence of CSME. There were no significant associations of other RVGCs with any of the DR outcomes in the full multivariate model. Inclusion of all possible RVGCs did not improve the predictive value of the models that already included retinal vessel diameter and baseline DR severity level. CONCLUSIONS: Retinal vessel geometric characteristics of the retinal venules were associated with progression of DR; however, most of the RVGCs measured from digitized fundus photographs added little to the assessment of risk of incidence and progression of DR when other risk factors were considered in T1DM and T2DM.

Exome Array Analysis of Nuclear Lens Opacity.

PURPOSE: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. METHODS: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. RESULTS: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10-6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10-5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10-6) and among never smokers (N = 790, p = 2.67 × 10-6). CONCLUSIONS: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.

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.

Skin Intrinsic Fluorescence and Age-Related Macular Degeneration: The Beaver Dam Eye Study.

Purpose: To determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD. Methods: SIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45° stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person. Results: There were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00-2.74, P = 0.05) and SIF03 (1.81, 1.16-2.81, P = 0.008) were associated with geographic atrophy. Conclusions: There was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship.

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.

Nerve Fiber Layer Thickness and Characteristics Associated with Glaucoma in Community Living Older Adults: Prelude to a Screening Trial?

PURPOSE: To examine the associations of nerve fiber layer (NFL) thickness with other ocular characteristics in older adults. METHODS: Participants in the Beaver Dam Eye Study (2008-2010) underwent spectral domain optical coherence tomography (SD-OCT) scans of the optic nerve head, imaging of optic discs, frequency doubling technology (FDT) perimetry, measurement of intraocular pressure (IOP), and an interview concerning their history of glaucoma and use of drops to lower eye pressure. Self-reported histories of glaucoma and the use of drops to lower eye pressure were obtained at follow-up examinations (2014-2016). RESULTS: NFL thickness measured on OCTs varied by location around the optic nerve. Age was associated with mean NFL thickness. Mean NFL was thinnest in eyes with larger cup/disc (C/D) ratios. Horizontal hemifield defects or other optic nerve-field defects were associated with thinner NFL. NFL in persons who reported taking eye drops for high intraocular pressure was thinner compared to those not taking drops. After accounting for the presence of high intraocular pressure, large C/D ratios or hemifield defects, eyes with thinner NFL in the arcades were more likely (OR = 2.3 for 30 micron thinner NFL, p = 0.04) to have incident glaucoma at examination 5 years later. CONCLUSION: Retinal NFL thickness was associated with a new history of self-reported glaucoma 5 years later. A trial testing the usefulness of NFL as part of a screening battery for predicting glaucoma in those previously undiagnosed might lead to improved case finding and, ultimately, to diminishing the risk of visual field loss.

Oxidized Low-Density Lipoprotein and the Incidence of Proliferative Diabetic Retinopathy and Clinically Significant Macular Edema Determined From Fundus Photographs.

IMPORTANCE: Studies have shown oxidized low-density lipoprotein to be associated with the incidence of proliferative retinopathy and other complications of type 1 diabetes mellitus. Because low-risk interventions are available to modify oxidized low-density lipoprotein, it is important to examine the relationships between this factor and the incidence of proliferative retinopathy and of macular edema, 2 important causes of visual impairment in people with type 1 diabetes. OBJECTIVE: To determine the association of oxidized low-density lipoprotein with the worsening of diabetic retinopathy and the incidence of proliferative retinopathy and of macular edema. DESIGN, SETTING, AND PARTICIPANTS: Of 996 participants with type 1 diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 730 were examined up to 4 times (1990-1992, 1994-1996, 2005-2007, and 2012-2014) over 24 years and had assays of oxidized low-density lipoprotein and fundus photographs gradable for diabetic retinopathy and macular edema. Analyses started July 2014 and ended February 2015. MAIN OUTCOMES AND MEASURES: Worsening of diabetic retinopathy, incidence of proliferative diabetic retinopathy, and incidence of macular edema as assessed via grading of color stereo film fundus photographs. The levels of oxidized low-density lipoprotein collected from serum samples at the time of each examination were measured in 2013 and 2014 from frozen serum. RESULTS: The cohort at baseline had a mean (SD) level of oxidized low-density lipoprotein of 30.0 (8.5) U/L. While adjusting for duration of diabetes, glycated hemoglobin A1c level, and other factors, we found that neither the level of oxidized low-density lipoprotein at the beginning of a period nor the change in it over a certain period was associated with the incidence of proliferative diabetic retinopathy (hazard ratio [HR], 1.11 [95% CI, 0.91-1.35], P = .30; odds ratio [OR], 1.77 [95% CI, 0.99-3.17], P = .06), the incidence of macular edema (HR, 1.04 [95% CI, 0.83-1.29], P = .74; OR, 1.08 [95% CI, 0.44-2.61], P = .87), or the worsening of diabetic retinopathy (HR, 0.94 [95% CI, 0.83-1.07], P = .34; OR, 1.32 [95% CI, 0.83-2.09], P = .24). CONCLUSIONS AND RELEVANCE: Our findings do not provide evidence for a relationship between increasing levels of serum oxidized low-density lipoprotein and the incidence of macular edema or the worsening of diabetic retinopathy in persons with type 1 diabetes. The potential increase in the HR for incident proliferative retinopathy, with an increase in oxidized low-density lipoprotein level over the preceding period, warrants further investigation of this relationship.

Relation of smoking, drinking, and physical activity to changes in vision over a 20-year period: the Beaver Dam Eye Study.

OBJECTIVE: To describe the relationships of lifestyle characteristics to changes in vision and incidence of visual impairment (VI) over a 20-year period in the Beaver Dam Eye Study (BDES). DESIGN: Longitudinal, population-based cohort study. PARTICIPANTS: A cohort of 4926 persons aged 43 to 86 years participated in the baseline examinations in 1988-1990, and 3721, 2962, 2375, and 1913 persons participated in follow-up examinations in 1993-1995, 1998-2000, 2003-2005, and 2008-2010, respectively. METHODS: Best-corrected visual acuity (BCVA) measured by a modified Early Treatment Diabetic Retinopathy Study protocol. MAIN OUTCOME MEASURES: Change in number of letters read correctly and incidence of VI based on BCVA in the better eye assessed at each examination over a 20-year period. RESULTS: The 20-year cumulative incidence of VI was 5.4%. There was a mean loss of 1.6 letters between examinations, with a 20-year loss of 6.6 letters. While adjusting for age, income, and age-related macular degeneration (AMD) severity, being a current or past smoker was related to a greater change in the numbers of letters lost. Persons who had not consumed alcoholic beverages over the past year and sedentary persons had higher odds of incident VI than persons who drank occasionally or who were physically active. For example, in women with early AMD and annual household income less than $10,000, the estimated 20-year cumulative incidence of VI in those who drank occasionally and were physically active was 5.9% compared with 25.8% in women who had not consumed alcoholic beverages over the past year and were sedentary. CONCLUSIONS: Three modifiable behaviors-smoking, drinking alcohol, and physical activity-were associated with changes in vision. Further evidence that changes in these behaviors will result in less loss of vision is needed because of the expected increase in the burden of VI due to the aging of the population.

Place-based exposure and cataract risk in the Beaver Dam cohort.

According to the Centers for Disease Control and Prevention, with an aging U.S. population an estimated 30 million people will be diagnosed with cataract by 2020. Several modifiable risk factors have been identified for nuclear cataract, cortical cataract, and posterior subcapsular cataract (PSC), including smoking, diabetes, and steroid medications. In the study described here, the authors evaluated residential location as a potential proxy of risk factors for cataracts in the Beaver Dam Eye Study cohort established in 1987. Cataract risk was calculated using general estimating equation modeling to account for correlation between eyes. Fifteen-year cumulative incidence rates were calculated for each type of cataract by eye. Of the 4926 study participants, 3253 seen at the baseline examination were included in the analyses. Compared to urban residents, the odds ratio (95% confidence interval) for rural participants' risk of cortical, nuclear, and PSC was 0.92 (0.73, 1.16), 0.85 (0.69, 1.06), and 0.71 (0.48, 1.05), respectively, adjusting for age, sex, educational status, and smoking status. The lowest cumulative incidences were for those living in rural areas, compared to edge or urban areas for all three types of cataracts.

Measures of body shape and adiposity as related to incidence of age-related eye diseases: observations from the Beaver Dam Eye Study.

PURPOSE: To examine the effect of obesity on the incidence of age-related eye disease. METHODS: Participants of the Beaver Dam Eye Study were examined every 5 years over a 20-year period (1988-1990 through 2008-2010). Lens and fundus photographs were used to evaluate presence and severity of cataract and macular degeneration. Height and weight were measured at all examinations. Waist and hip circumference were measured at all examinations beginning at the first follow-up (1993-1995). Models of ocular outcomes over 15 years were stratified by sex and smoking status. RESULTS: Overall, 2641 participants contributed 5567 person-visits to 15-year incidence analysis. Female nonsmokers had increased risk of late AMD associated with higher body mass index (BMI; hazard ratio [HR] per 2.5 kg/m(2) 1.31, 95% confidence interval [CI] 1.15-1.50, P < 0.001), waist to hip ratio (HR per 0.1 cm/cm 1.95, 95% CI 1.33-2.86, P < 0.001), waist circumference (HR per 5 cm 1.21, 95% CI 1.10-1.34, P < 0.001), and waist to height ratio (HR per 0.1 cm/cm 1.74, 95% CI 1.31-2.31, P < 0.001). Increased BMI was also associated with early AMD in female nonsmokers (HR 1.10, 95% CI 1.02-1.19, P = 0.02). CONCLUSIONS: Female nonsmokers had risk of late AMD associated with increasing measures of greater obesity and increased risk of early AMD associated with greater BMI.

Genetic susceptibility, dietary antioxidants, and long-term incidence of age-related macular degeneration in two populations.

OBJECTIVE: To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk. DESIGN: Pooled data analysis of population-based cohorts. PARTICIPANTS: Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS). METHODS: Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], ß-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (≥ 2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses. MAIN OUTCOME MEASURES: All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale. RESULTS: In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P=0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P=0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between ß-carotene or vitamin C and genetic risk status. CONCLUSIONS: Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions.

Changing incidence of lens extraction over 20 years: the Beaver Dam eye study.

OBJECTIVE: To investigate trends in the incidence of lens extraction over the past 20 years. DESIGN: Longitudinal population-based cohort study. PARTICIPANTS: Persons who participated in the Beaver Dam Eye Study. METHODS: Eligible persons 43 to 84 years of age living in the city or township of Beaver Dam, Wisconsin, were recruited from 1987 through 1988. Participants were followed up every 5 years from 1993 through 1995, from 1998 through 2000, from 2003 through 2005, and from 2008 through 2010 after the baseline examination from 1988 through 1990. Examinations consisted of ocular examination with lens photography and grading; medical history; and measurements of blood pressure, height, and weight. Adjustments were made for age and gender. Values of risk variables were updated, and the incidence of lens extraction surgery was calculated in each 5-year interval. MAIN OUTCOME MEASURES: Incidence of lens extraction with regard to presence of clinically significant lens opacity and visual function. RESULTS: Age- and gender-adjusted incidence of lens extraction increased over the 4 intervals from 1.8% (95% confidence interval [CI], 1.3%-2.5%) in the interval between the first and second study examinations to 11.7% (95% CI, 9.9%-13.8%) in the most recent study interval. The increase in incidence of surgery was significantly higher at successive intervals in persons without clinically significant lens opacity at each preceding examination (interval 1, 0.8% [95% CI, 0.6%-1.1%]; interval 4, 9.4% [95% CI, 7.8%-11.2%]) compared with persons with at least 1 detectable type of opacity (interval 1, 9.2% [95% CI, 6.4%-13.2%]; interval 4, 16.5% [95% CI, 13.4%-20.0%]). Recency of examination was not attenuated by adjusting for additional risk factors. There was no evidence that the increased incidence in surgery was preceded by poorer visual acuity, near vision, or contrast sensitivity at the beginning of each interval. CONCLUSIONS: The incidence of lens extraction has increased over the past 20 years in persons older than 65 years. The relative increase of surgery is higher in those without any clinically significant lens opacity and in persons with visual acuity better than 20/40 at an examination as measured 5 years before observed incidence of lens extraction.

Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium.

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.