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.

Skin Intrinsic Fluorescence and Selected Measures of Visual Function and aging in Older Adults.

Purpose: Functional, structural and metabolic decline in many systems and in combination contribute to biologic aging and may be manifest as increased risk of morbid events such as neuropathy, albuminuria, and coronary artery disease or mortality. A biologic marker of aging may be a useful tool in identifying persons at increased risk of morbidity or mortality. We have measured skin intrinsic fluorescence (SIF) in a group of older adults to determine whether this easily determined measure could serve as such a biomarker. Methods: Survivors of a population based study of older adults in a moderate sized Midwestern town. Of the 1181 persons participating, 939 had measures of skin intrinsic fluorescence (SIF) and at least one functional or diagnostic characteristic at the most recent examination. Characteristics such as blood pressure, forced expiratory volume, vision, time to walk a standard course and medical history and their associations with SIF measures were examined. Mortality after the last examination with respect to SIF was also investigated. There were 118 deaths among those who participated in this phase of the study. All analyses pertinent to these findings were adjusted for age. Results: SIF measures were significantly associated with low contrast sensitivity, more errors on frequency doubling technology testing (loss of peripheral vision), self-reported poor vision, slow gait, poor forced expiratory volume, and self-reported poor health. SIF was also associated with increased risk of death. All of these analyses were adjusted for age. Conclusions: Skin intrinsic fluorescence provides easily obtained markers of age-related functional outcomes, suggesting SIF measurements may be useful to identify persons who may benefit from more frequent medical scrutiny to decrease morbidity and mortality.

Retinal vessel diameters confound the relationship of pregnancy to retinopathy and infant outcomes in T1D.

OBJECTIVES: To determine whether: 1) retinal vessel diameters in pregnant and non-pregnant women with type 1 diabetes (T1D) alter the relationship of pregnancy to severity of diabetic retinopathy (DR); and 2) retinal vessel diameters in early pregnancy alter the relationship of severity of DR in the mother to severe adverse outcome in the infant. METHODS: Two cohorts of women with T1D, one composed of pregnant women and the other of non-pregnant women of child-bearing age, were recruited in Wisconsin. Baseline examinations (including retinal photography and collection of diabetes-related characteristics) were conducted, with follow-up approximately one year later. Retinal images were graded according to the modified Airlie House classification protocol, and retinal vessel diameters were measured from digitized images. The latter were included in analyses as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). RESULTS: In multivariate models: 1) Pregnancy was significantly associated with both incidence (OR = 4.43, CI = 1.42-13.79) and progression (OR = 2.62, CI = 1.52-4.51) of DR. Neither CRAE nor CRVE were significant, but their addition modestly altered the associations of pregnancy to worsening DR; 2) Baseline retinopathy (OR = 1.28, CI = 1.05-1.57) was associated with severe adverse outcome in the infant. This association was unchanged by adjustment for retinal vessel diameters. CONCLUSIONS: Pregnancy is associated with worsening DR in women with T1D. DR severity in early pregnancy is associated with severe adverse outcome in the infant. The retinal vessel diameters CRAE and CRVE were not associated with these outcomes but were modest confounders of the association of pregnancy to worsening DR.

Supplements and age-related eye conditions the beaver dam eye study.

OBJECTIVE: To investigate the association of use of vitamin, mineral, and nonvitamin nonmineral supplements with common age-related eye diseases. DESIGN: Population-based prospective study with incidence data. PARTICIPANTS: Subjects were participants in the Beaver Dam Eye Study who contributed data in 1988 to 1990 (n = 4926), 1993 to 1995 (n = 3722), 1998 to 2000 (n = 2962), and 2003 to 2005 (n = 2375). METHODS: Use of all medications and supplements were collected from study participants at each of 4 examinations. Intraocular pressure (IOP) measurement and fundus and lens photography were done at each visit. Visual field data are available only from baseline. Photographs of the lenses, retina, and discs were graded using standard protocols by trained graders. MAIN OUTCOME MEASURES: Incidence of age-related cataracts, macular degeneration (AMD), and high IOP for one set of analyses and incidence of supplement use for the second set of analyses. RESULTS: There was little evidence of any significant associations between supplement use and incident ocular outcomes except for a small protective effect for cortical cataracts by vitamins A and D, zinc, and multivitamins and increased odds of late AMD. Late AMD was associated with incident use of vitamins A, C, and E and zinc. CONCLUSIONS: Age-related macular degeneration seems to precede use of vitamins A, C, and E and zinc. This may reflect advice by family, friends, and health care providers about the benefits of Age-Related Eye Disease Study-like supplements.

A longitudinal study of nonvitamin, nonmineral supplement use: prevalence, associations, and survival in an aging population.

PURPOSE: We sought to describe population and survival characteristics in nonvitamin, nonmineral (NVNM) supplement users in a population-based cohort study. METHODS: People from 43 to 86 years of age living in Beaver Dam, Wisconsin, participated in a baseline examination from 1988 to 1990 (n = 4,926) and three follow-up examinations at 5-year intervals (n = 3,722, 2,962, 2,375 at each successive examination). Medication and supplement use, medical and lifestyle factors were collected during the examination and survival was monitored through 2002. RESULTS: NVNM supplement use increased from 5% at baseline, to 6% at the second, to 21% at the third to 30% at the fourth examination. In general, younger age, vitamin or mineral use, and taking more medications was directly related to NVNM supplement use, while current smoking and history of other systemic diseases (e.g., cardiovascular disease, cancer) was inversely related to NVNM supplement use. After adjusting for age, sex, and other medical and lifestyle factors, users of NVNM supplements had lower mortality (hazard ratio, 0.74; 95% confidence interval, 0.57-0.95, p = 0.02) than nonusers. CONCLUSIONS: NVNM supplement users had a healthier lifestyle and fewer co-morbid medical conditions and were more likely to survive after adjusting for these factors than non-users.

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

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.

Relation of statin use to the 5-year incidence and progression of age-related maculopathy.

OBJECTIVE: To examine the association of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) with the 5-year incidence of age-related maculopathy (ARM). DESIGN: Population-based cohort study. Participants included persons 48 to 91 years old examined March 1, 1993, through June 14, 1995, living in Beaver Dam, Wis (N = 3684), of whom 2780 participated in a follow-up 5 years later. METHODS: Standardized procedures were used for physical examinations, blood sample collection, and questionnaire administration. Age-related maculopathy was determined by grading images of the posterior pole using a standard protocol. Standard univariate and multivariate analyses were performed. MAIN OUTCOME MEASURES: Incidence and progression of ARM was measured over the 5-year interval. RESULTS: While controlling for age and sex, statin use was not found to be associated with the 5-year incidence of early ARM (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.47-2.67), progression of ARM (OR, 1.22; 95% CI, 0.54-2.76), or incidence of late ARM (OR, 0.41; 95% CI, 0.12-1.45). CONCLUSIONS: These findings do not suggest an association between statin use and incident ARM over a 5-year period. Further investigation of these relationships in larger studies over a longer period is needed.

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 (ß = 0.75; P = .04), specifically calcium channel blockers (ß = -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 (ß = -2.04; P = .09); ß-blockers (ß = -1.02; P = .10) and oral corticosteroids (ß = 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.

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.

Variability of measurement of retinal vessel diameters.

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.

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.

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 m(2) 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 m(2) 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 m(2) 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.