Lorraine G. Danforth

Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction and the 20-Year Cumulative Incidence of Early Age-Related Macular Degeneration: The Beaver Dam Eye Study

IMPORTANCE Modifying levels of factors associated with age-related macular degeneration (AMD) may decrease the risk for visual impairment in older persons. OBJECTIVE To examine the relationships of markers of inflammation, oxidative stress, and endothelial dysfunction to the 20-year cumulative incidence of early AMD. DESIGN, SETTING, AND PARTICIPANTS This longitudinal population-based cohort study involved a random sample of 975 persons in the Beaver Dam Eye Study without signs of AMD who participated in the baseline examination in 1988-1990 and up to 4 follow-up examinations in 1993-1995, 1998-2000, 2003-2005, and 2008-2010. EXPOSURES Serum markers of inflammation (high-sensitivity C-reactive protein, tumor necrosis factor-α receptor 2, interleukin-6, and white blood cell count), oxidative stress (8-isoprostane and total carbonyl content), and endothelial dysfunction (soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1) were measured. Interactions with complement factor H (rs1061170), age-related maculopathy susceptibility 2 (rs10490924), complement component 3 (rs2230199), and complement component 2/complement factor B (rs4151667) were examined using multiplicative models. Age-related macular degeneration was assessed from fundus photographs. MAIN OUTCOMES AND MEASURES Early AMD defined by the presence of any size drusen and the presence of pigmentary abnormalities or by the presence of large-sized drusen (≥125-μm diameter) in the absence of late AMD. RESULTS The 20-year cumulative incidence of early AMD was 23.0%. Adjusting for age, sex, and other risk factors, high-sensitivity C-reactive protein (odds ratio comparing fourth with first quartile, 2.18; P = .005), tumor necrosis factor-α receptor 2 (odds ratio, 1.78; P = .04), and interleukin-6 (odds ratio, 1.78; P = .03) were associated with the incidence of early AMD. Increased incidence of early AMD was associated with soluble vascular cell adhesion molecule-1 (odds ratio per SD on the logarithmic scale, 1.21; P = .04). CONCLUSIONS AND RELEVANCE We found modest evidence of relationships of serum high-sensitivity C-reactive protein, tumor necrosis factor-α receptor 2, interleukin-6, and soluble vascular cell adhesion molecule-1 to the 20-year cumulative incidence of early AMD independent of age, smoking status, and other factors. It is not known whether these associations represent a cause and effect relationship or whether other unknown confounders accounted for the findings. Even if inflammatory processes are a cause of early AMD, it is not known whether interventions that reduce systemic inflammatory processes will reduce the incidence of early AMD.

Drug use and five-year incidence of age-related cataracts: The Beaver Dam Eye Study☆

OBJECTIVE To evaluate incident cataract after a 5-year interval with respect to medication use. DESIGN Population-based incidence study. MAIN OUTCOME Incident cataract judged from standard photographs. SETTING Study subjects were adults 43 to 86 years of age in 1988 to 1990 and again in 1993 to 1995. All participants were examined and interviewed, and photographs were taken. All procedures and grading were done by protocols at both examinations. All medications in current use, prescribed as well as over-the-counter, were brought to the examination site, and the names were recorded at that time. RESULTS There were 678 drug preparations (active ingredients) being used at the baseline examination. Significantly lower incidences of nuclear cataracts 5 years later occurred in those who took thiazide diuretics (odds ratio [OR] = 0.79, 95% confidence interval [CI] 0.63, 1.00) and aspirin (OR = 0.76, 95% CI 0.61, 0.95) at the baseline examination. There were significantly more incident cortical cataracts in those taking oral steroids (OR = 2.59, 95% CI 1.45, 4.62), amitriptyline (OR = 2.03, 95% CI 1.09, 3.79), oral hypoglycemic agents (OR 2.06, 95% CI 1.23, 3.44), and insulin (OR = 3.38, 95% CI 1.61, 7.08). There were significantly more incident posterior subcapsular cataracts in those taking potassium-sparing diuretics (OR = 2.13, 95% CI 1.42, 3.18) and oral hypoglycemic agents (OR = 2.89, 95% CI 1.57, 5.33). Considering past use with never and current use did not alter the patterns of associations. We were not able to separate the effects of antihypertensive or diuretic agents from that of hypertension. However, hypoglycemic agents were no longer associated with any cataract type after stratifying by diabetes status. CONCLUSIONS Although many different medications were being used at the baseline examination in the Beaver Dam Eye Study cohort, few were associated with incident cataract. However, with the high frequency of use of medications and the possibility that effects of current exposure may occur in the future, it is reasonable to follow this and other older cohorts for the development of cataract.

Associations of selected medications and visual function: the Beaver Dam Eye Study

Aim: To investigate association of drug use and visual function. Methods: A cross sectional population based study was carried out on participants in the 1993–5 examination phase of the Beaver Dam Eye Study. All drugs in current use by study participants were recorded. Performance based and self assessed visual functions were obtained at the time of the study evaluation. The main outcome measure was the relation of levels of visual functions by use of specific drugs. Results: Many classes of drugs were associated with decreases in at least two performance based visual functions. For example, high blood pressure drugs were significantly associated with poorer best corrected visual acuity, poorer near vision, and poorer contrast sensitivity (p<0.001 for all). Patterns of association for self assessed visual functions were not as strong. However, use of glaucoma drops and benzodiazepines were associated with poorer self assessed visual functions in most circumstances cited. Conclusions: Many commonly used medications are inversely associated with visual functions in a middle and older aged population. This may influence the ability to perform complex tasks and quality of life.

Estimating glomerular filtration rate in a population-based study

Background: Glomerular filtration rate (GFR)-estimating equations are used to determine the prevalence of chronic kidney disease (CKD) in population-based studies. However, it has been suggested that since the commonly used GFR equations were originally developed from samples of patients with CKD, they underestimate GFR in healthy populations. Few studies have made side-by-side comparisons of the effect of various estimating equations on the prevalence estimates of CKD in a general population sample. Patients and methods: We examined a population-based sample comprising adults from Wisconsin (age, 43–86 years; 56% women). We compared the prevalence of CKD, defined as a GFR of <60 mL/min per 1.73 m2 estimated from serum creatinine, by applying various commonly used equations including the modification of diet in renal disease (MDRD) equation, Cockcroft–Gault (CG) equation, and the Mayo equation. We compared the performance of these equations against the CKD definition of cystatin C >1.23 mg/L. Results: We found that the prevalence of CKD varied widely among different GFR equations. Although the prevalence of CKD was 17.2% with the MDRD equation and 16.5% with the CG equation, it was only 4.8% with the Mayo equation. Only 24% of those identified to have GFR in the range of 50–59 mL/min per 1.73 m2 by the MDRD equation had cystatin C levels >1.23 mg/L; their mean cystatin C level was only 1 mg/L (interquartile range, 0.9–1.2 mg/L). This finding was similar for the CG equation. For the Mayo equation, 62.8% of those patients with GFR in the range of 50–59 mL/min per 1.73 m2 had cystatin C levels >1.23 mg/L; their mean cystatin C level was 1.3 mg/L (interquartile range, 1.2–1.5 mg/L). The MDRD and CG equations showed a false-positive rate of >10%. Discussion: We found that the MDRD and CG equations, the current standard to estimate GFR, appeared to overestimate the prevalence of CKD in a general population sample.

Cross-sectional Associations of Medication and Supplement Use With Retinal Vascular Diameter in the Beaver Dam Eye Study

IMPORTANCE Retinal vessel diameters are being measured to examine their relationship with ocular and systemic disease and, in some studies, to calculate the risk of disease. Important factors that directly affect retinal vessel diameters, such as medication use, should be considered when estimating these associations. OBJECTIVE To quantify the association between selected medications and supplements and retinal vessel diameters. DESIGN, SETTING, AND PARTICIPANTS In a prospective cohort investigation, 4926 participants (aged 43-86 years at baseline) in the Beaver Dam Eye Study were evaluated every 5 years during 20 years of follow-up from 1988 to 2010. MAIN OUTCOMES AND MEASURES Central retinal arteriolar equivalent and central retinal venular equivalent measured from the Early Treatment Diabetic Retinopathy Study fundus photograph field 1. RESULTS After Bonferroni correction, the use of any blood pressure medication (β = 0.75; P = .04), specifically calcium channel blockers (β = -1.02; P < .001), was significantly associated with wider central retinal arteriolar equivalent adjusting for refraction, photograph focus, age, systolic blood pressure, height, examination phase, educational level, smoking and drinking histories, and presence of diabetes mellitus and emphysema. Use of prostaglandin analogues was marginally associated with narrower central retinal arteriolar equivalent (β = -2.04; P = .09); β-blockers (β = -1.02; P = .10) and oral corticosteroids (β = 2.13; P = .07) were marginally associated with changes in the central retinal venular equivalent. CONCLUSIONS AND RELEVANCE Several medications are associated with central retinal arteriolar and venular equivalents. Prostaglandin analogues, calcium channel blockers, and oral corticosteroids have the largest relative effects. After Bonferroni correction was applied, the use of calcium channel blockers was most strongly associated with change in the central retinal arteriolar equivalent. The presence of factors that are associated with retinal vessel diameters should be considered when using retinal vessel diameter as an outcome or when using these measures to assess the risk of systemic or ocular disease.

Selected Sun-Sensitizing Medications and Incident Cataract

OBJECTIVE To examine the relationship between the use of sun-sensitizing medications and cumulative incidence of age-related cataract. METHODS Sun exposure was estimated from residential history of adults in the Midwestern community of Beaver Dam, Wisconsin, which permitted calculation of Wisconsin sun-years at the baseline examination. Medication history was reported at each examination. Cataract presence was determined by standardized lens photographs that were taken at each examination and graded according to standard protocols. RESULTS No significant effects were noted of Wisconsin sun-year exposure or use of sun-sensitizing medications on the cumulative incidence of any type of age-related cataract when controlling for age and sex. However, an interaction term combining Wisconsin sun-years and use of any sun-sensitizing medication was significant (P = .04) such that risk of cortical cataract is significantly higher for the joint risk group. Further controlling for the presence of diabetes mellitus, history of heavy drinking, and hat or sunglasses use did not alter the relationships. CONCLUSIONS Data suggest that the use of sun-sensitizing medications interacts with sun exposure to influence the risk of cortical cataract, a common age-related cataract. If confirmed, this finding may have important implications for medication use.

The Relationship of Serum Soluble Receptor for Advanced Glycation End Products (sRAGE) and Carboxymethyl Lysine (CML) to the Incidence of Diabetic Nephropathy in Persons With Type 1 Diabetes

We hypothesized that persons with type 1 diabetes with higher serum levels of carboxymethyl lysine (CML) and soluble receptor for advanced glycation end products (sRAGE) are at a higher risk of developing incident diabetic nephropathy (DN). We examined this hypothesis using data from up to four follow-up examinations over a 22-year period in persons with type 1 diabetes participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). We also examined the relationship of CML and sRAGE to mortality. Descriptions of the cohort, participation statistics, and reasons for nonparticipation have appeared elsewhere (1). Of 1,210 persons with type 1 diabetes receiving care in an 11-county area of south central Wisconsin in 1979–1980, 996 were examined in 1980–1982. The individuals were 3–79 years of age with type 1 diabetes duration of 1–59 years. These persons participated in up to six follow-up examinations in 1984–1986 ( n = 903), 1990–1992 ( n = 816), 1994–1996 ( n = 667), 2000–2001 ( n = 567), 2005–2007 ( n = 520), and 2012–2014 ( n = 414). The tenets of the Declaration of Helsinki were followed, and institutional review board approval was obtained from the University of Wisconsin–Madison. Written informed consent was obtained. Starting with the third examination in 1990–1992 and continuing with follow-up examinations, serum was collected, processed, and frozen at −80°C. Serum sRAGE and CML levels were measured …

Variability of Measurement of Retinal Vessel Diameters

Abstract Purpose: To examine the effects of various cardiovascular, ocular, and lifestyle factors on retinal vessel diameters over short periods of time. Methods: Subjects were invited to have photographs of their retina taken at each of three study visits. The same eye was photographed each time. The photographs were digitized and retinal vessel diameters were measured. Measurements from the retinal photographs taken consecutively (at visit 2 and visit 3), and 1, 3, and 4 weeks apart (between visits 1 and 2, 2 and 3, and 1 and 3, respectively) were compared. Results: There were 63 persons who participated in all study visits and had gradable vessel measurements from all five images used in the analysis. Correlations for pairs of study visits were high, and decreased slightly with increasing length of the time interval. For consecutive photographs taken, and 1 week, 3 weeks, and 4 weeks apart, correlations were 0.95, 0.90, 0.91, and 0.86, respectively, for central retinal arteriolar equivalent (CRAE) and 0.95, 0.90, 0.91, and 0.87, respectively, for central retinal venular equivalent (CRVE). We examined the associations of blood pressure levels, smoking habits, time since last eating, exercising, consuming caffeine, and taking anti-hypertensive medication, and image focus with CRAE and CRVE. We found no consistent pattern of association of any of these characteristics with short-term changes in CRAE and CRVE. Conclusion: Retinal vessel diameters are stable over short intervals of time and none of the factors studied were consistently associated with change in the diameters of either vessel type.

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.

Variability in Spectral-Domain Optical Coherence Tomography over 4 Weeks by Age

ABSTRACT Purpose: To quantify variation in spectral-domain optical coherence tomography (SD-OCT) measures of total retinal thickness (top of inner limiting membrane to top of retinal pigment epithelium, RPE) and RPE thickness measures over a 4-week period and by age. Methods: A total of 76 volunteers aged 40–85 years were seen at three visits over 4 weeks. Two Topcon SD-OCT scans were taken at each visit. Following grid re-centration, total retinal and RPE thickness were determined in nine subfields. Multilevel modeling was used to quantify variance between scans and by age. Results: In the central circle, mean total retinal thickness was 237.9 µm (standard deviation, SD, 23.5 µm) and RPE thickness was 46.0 µm (SD 5.3 µm). Intraclass correlation coefficient in the central circle was 0.988 for total retinal thickness and 0.714 for RPE thickness. Pairwise measures taken within 4 weeks were strongly correlated (p > 0.95). Within-subject variation of total retinal thickness increased significantly with age. Subjects in the oldest age group had significantly increased among- and within-subject variability in measures of RPE thickness. Conclusions: Correlation between retinal thickness measures was very high (>0.95) over a period of 4 weeks with small changes likely due to variation in measurement. Increasing variability in total retinal and RPE thickness measures with age suggest that the use of more and/or higher quality images to calculate mean thickness to reduce variability may benefit the study of these measures in older persons. This may also impact sample size calculations for future studies of SD-OCT measures in older adults.