Macular Degeneration: Klein R

Klein R, Klein BE. · No affiliation provided · Am J Ophthalmol. · Pubmed #15059716 No free full text.

This publication has no abstract.

Klein R. · Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA. · Ophthalmic Epidemiol. · Pubmed #17896295 No free full text.

Abstract: PURPOSE: To provide an over-view of progress in the epidemiology of age-related macular degeneration. METHODS: Review of epidemiological and clinical trial findings regarding AMD since initial National Eye Institute sponsored epidemiology meeting in 1982. RESULTS: A growing number new epidemiological studies have provided data on the prevalence and long-term incidence of AMD. Despite a similar prevalence of early AMD in whites, blacks, and hispanics, whites have higher prevalence of late AMD. An age-period cohort effect has been shown in the Beaver Dam Eye Study suggesting that AMD incidence may be declining among younger birth cohorts. Genetic factors such as complement factor H have been shown to be strongly associated with AMD. Smoking is strongly related to risk of AMD. Randomized controlled clinical trials have shown the benefits of zinc-antioxidant supplementation in preventing visual loss in persons with signs of early AMD and anti-vascular endothelial growth factor agents in restoring vision in eyes with neovascular AMD. CONCLUSIONS: Despite remarkable progress in understanding AMD, many questions remain that can only be addressed by continuation of longitudinal population-based studies.

Wong TY, Wong T, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, Probst C, Sledge I. · Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia. · Ophthalmology. · Pubmed #17675159 No free full text.

Abstract: PURPOSE: To describe the natural history and progression of visual loss in eyes with untreated neovascular age-related macular degeneration (AMD). DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Four thousand three hundred sixty-two untreated neovascular AMD patients from published interventional studies. METHODS: A systematic review of the literature from 1980 to August 2005 was performed. Studies reporting disease progression outcomes for untreated patients with neovascular AMD were included. Outcome measures were summarized using simple counts and means. Random effects meta-analyses were conducted and tests of heterogeneity were performed where appropriate. MAIN OUTCOME MEASURES: Changes in visual acuity (VA) loss, development of comorbidities, and fellow eye involvement. RESULTS: Fifty-three primary studies were included. Nearly half of the studies (28) were randomized clinical trials. The quality of the studies was high, with over 80% providing level I or II evidence. Mean baseline VA among study patients was 0.64 logarithm of the minimum angle of resolution (logMAR) (approximately 20/87 Snellen). The mean VA change in logMAR progressed from 0.1 (1 line lost) at 3 months to 0.3 (2.7 lines lost) after 12 months and 0.4 (4 lines lost) after 24 months. The proportion of patients who developed severe vision loss (>6 lines) from baseline increased from 21.3% at 6 months to 41.9% by 3 years. The proportion of patients with VA worse than logMAR 1.0 (20/200 Snellen) increased from 19.7% at baseline to 75.7% by 3 years. Neovascular AMD developed in the fellow eye in 12.2% of patients by 12 months and in 26.8% by 4 years. Meta-analyses of vision outcome by subtype of neovascular AMD were not possible. CONCLUSIONS: A doubling of the visual angle of presenting VA may be expected to occur in the year after initial presentation in eyes with untreated neovascular AMD. No conclusions can be drawn as to the differences in rates of disease progression by neovascular AMD subtype. The diversity of reporting formats, paucity of long-term natural history data, and heterogeneity among the reported clinical studies impose limits to the clear understanding of long-term prognosis for visual function in neovascular AMD.

Holz FG, Pauleikhoff D, Klein R, Bird AC. · Department of Ophthalmology (F.G.H.), University of Heidelberg, Heidelberg, Germany. · Am J Ophthalmol. · Pubmed #15013875 No free full text.

Abstract: PURPOSE: To review the evidence that exists concerning the pathogenesis of lesions in late age-related macular disease (AMD). DESIGN: Review of the literature. METHODS: A review of both experimental evidence and clinical observations that address these problems. RESULTS: There is good evidence that choroidal neovascularization (CNV) is due to a change in the balance of growth factors derived from the retinal pigment epithelial basolateral plasma membrane domain (retinal pigment epithelium). Retinal angiomatous proliferation may also have a similar pathogenesis involving the apical domain. Detachment of the retinal pigment epithelium is likely to be a consequence of increased resistance of the Bruch membrane to water flow due to deposition of lipids. Geographic atrophy is preceded by accumulation of autofluorescent material in the retinal pigment epithelium and possible causal relationships between the two have been demonstrated. CONCLUSION: There is increasing understanding concerning the sequence of events that lead to those lesions causing loss of central vision in AMD. Therapeutic approaches that address the underlying mechanisms are more likely to succeed than current treatment options. Such an approach has already been initiated in the management of choroidal neovascularization.

Klein R, Peto T, Bird A, Vannewkirk MR. · Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin 53726, USA. · Am J Ophthalmol. · Pubmed #15013873 No free full text.

Abstract: PURPOSE: To review the epidemiology of age-related macular degeneration (AMD). DESIGN: Evidence from epidemiologic data regarding the natural history of AMD and its risk factors are presented. RESULTS: Large, soft drusen associated with pigmentary abnormalities increase the risk of progression to advanced AMD. Large soft drusen may fade over time. Advanced AMD is more likely to be present in whites than blacks, despite the similar prevalence of soft drusen in both groups. Neovascular AMD is more frequent than geographic atrophy in most population-based studies in whites in America, Australia, and the Netherlands than in similar population-based studies in Iceland and Norway. After age and family history, there are few consistent relationships of risk factors to AMD. Of these, the relationship of smoking, hypertension, and cataract surgery to advanced AMD have been most consistent. CONCLUSIONS: Long-term epidemiologic studies have provided information on the distribution and the natural history of AMD and its associated risk factors. It is not known what effect reduction of blood pressure and the cessation of smoking might have on the incidence and progression of AMD.

Hawkins BS, Bird A, Klein R, West SK. · The Wilmer Ophthalmological Institute, Baltimore, MD 21205-2010, USA. · Mol Vis. · Pubmed #10562650 links to  free full text

Abstract: For more than two decades, researchers have sought to identify "risk factors" for age-related macular degeneration (AMD), a major cause of irreversible vision loss in the Western world, particularly in the elderly. Two issues have complicated this search: failure to differentiate between different stages of AMD and misinterpretation of measures of association (odds ratios) and risk (risk ratios) derivable from different research designs. Fortunately, in more recent epidemiologic studies, more attention has been given to these issues. Three groups of potential "risk factors" that have been studied were reviewed: those known to be risk factors for cardiovascular disease, environmental factors, and racial and ethnic factors. Of these, only tobacco smoking, a known risk factor for cardiovascular disease, has been demonstrated to be associated with AMD consistently across many studies of different design, carried out within different populations. The available evidence supports at least a doubling of risk of late AMD associated with long-term smoking, a factor that is under the control of the individual. The preponderance of evidence has not supported other factors to the same degree. Presently, racial and ethnic factors are high priorities for further research.

Klein R, Klein BE, Cruickshanks KJ. · Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 53705-2397, USA. · Prog Retin Eye Res. · Pubmed #10192518 No free full text.

Abstract: The prevalence of age-related maculopathy (ARM) varies considerably in different locations and racial/ethnic groups around the world. At present there are insufficient data to determine whether it is likely that these differences in prevalence, especially for the early forms of ARM are due to variations in genetic and environmental factors or due to variations in age of the cohorts and methods used to ascertain and define ARM. In three population-based studies of whites living in Beaver Dam, Wisconsin, Blue Mountains, Australia, and Rotterdam, The Netherlands, in which similar methods of ascertainment and classification were used to detect and define ARM, late ARM was present in 1.2%, 1.4%, and 1.2% of the population less than 86 years of age, respectively. While data from clinical studies suggest that late ARM associated with choroidal neovascularization is rare in blacks compared with whites, some epidemiological studies suggest that late ARM may be similar in blacks and whites. There are still too few data from various ethnic/racial groups around the world and too few population-based data in older Hispanic and Asian populations to make meaningful comparisons. There is a need for further research into the distribution of ARM and its possible causes using similar methodologies to ascertain and define the disease. Further insights will be gained when genotypes associated with ARM are discovered.

SanGiovanni JP, Chew EY, Agrón E, Clemons TE, Ferris FL, Gensler G, Lindblad AS, Milton RC, Seddon JM, Klein R, Sperduto RD, Anonymous00450. · National Eye Institute, Bethesda, Maryland, USA. · Arch Ophthalmol. · Pubmed #18779490 No free full text.

Abstract: OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL, Anonymous00135. · The EMMES Corporation, Rockville, Maryland 20850-1707, USA. · Ophthalmology. · Pubmed #15808240 links to  free full text

Abstract: PURPOSE: To describe the association of demographic, behavioral, medical, and nonretinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA) in the Age-Related Eye Disease Study (AREDS), a randomized trial of antioxidants and zinc supplementation prophylaxis for development of advanced AMD. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Of individuals with early or intermediate AMD at baseline with a median follow-up of 6.3 years, 788 were at risk of developing advanced AMD in one eye (the fellow eye had advanced AMD), and 2506 were at risk in both eyes. METHODS: The incidence of neovascular AMD and CGA was assessed from stereoscopic color fundus photographs taken at baseline and at annual visits beginning at year 2. MAIN OUTCOME MEASURES: Neovascular AMD was defined as photocoagulation for choroidal neovascularization, or photographic documentation at the reading center of any of the following: nondrusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and subretinal fibrosis. Central geographic atrophy was defined as geographic atrophy involving the center of the macula. RESULTS: In multivariable models, in persons at risk of advanced AMD in both eyes, while controlling for age, gender, and AREDS treatment group, the following variables were statistically significantly associated with the incidence of neovascular AMD: race (odds ratio [OR], white vs. black, 6.77; 95% confidence interval [CI], 1.24-36.9) and larger amount smoked (OR, >10 vs. < or =10 pack-years [a pack-year is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09). The following were statistically significantly associated with the incidence of CGA: less education (OR, high school graduate or less vs. college graduate, 1.75; 95% CI, 1.10-2.78), greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65), larger amount smoked (OR, >10 pack-years vs. < or =10 pack-years, 1.82; 95% CI, 1.25-2.65), and antacid use (OR, 0.29; 95% CI, 0.09-0.91). In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31), and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59). CONCLUSIONS: Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD, and suggest other associations (e.g., use of antacids and antiinflammatory medications) that warrant further study. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. .

Liao D, Mo J, Duan Y, Klein R, Scott IU, Huang KA, Zhou H. · Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA. · Open Ophthalmol J. · Pubmed #19516892 links to  free full text

Abstract: OBJECTIVE: To investigate whether age-related macular degeneration (AMD) is associated with the development of ischemic and hemorrhagic stroke among elderly Americans. DESIGN: Population-based cohort study. PARTICIPANTS: The five percent random sample of 2000-2003 Medicare enrollees was obtained. The cohort (n=1,519,086) consisted of enrollees who were aged 65 or older at the first two-year (January 1, 2000 to December 31, 2001). METHODS: Baseline demographic variables and chronic conditions (AMD and type, history of myocardial infarction (MI), stroke, hypertension, and diabetes) were defined based on the occurrence of relevant ICD-9 codes in relevant diagnosis fields of the baseline Medicare Data. We excluded 215,900 persons who had a diagnosis of MI or stroke during baseline period to form a cohort of 1,303,186 individuals who were free of major cardio-cerebral vascular disease (CVD) at baseline. MAIN OUTCOME MEASURES: In two years of follow-up (January 1, 2002 to December 31, 2003), a total of 89,501 incident stroke cases were identified, including 80,018 ischemic, 7048 hemorrhagic, and 2,435 stroke cases of both types. RESULTS: Baseline mean age was 75 years (Standard Divination=7.7), with 60% women and 88% whites. The prevalence of AMD was 10.6%, with 19.7% being neovascular AMD and 80.3% being non-neovascular AMD. Baseline age, gender, race, hypertension, and diabetes adjusted 2-year incident odds ratios and 95% confidence internal of stroke associated with AMD were 1.31 (1.26, 1.36) for neovascular AMD, 1.18 (1.15, 1.21) for non-neovascular AMD, and 1.21 (1.18, 1.23) for either neovascular or non-neovascular AMD. CONCLUSION: The findings are suggestive of an association between AMD, especially neovascular AMD, and incident stroke, independent of demographic factors and co-morbidity. These findings, if confirmed by other studies that control for smoking and other lifestyle covariables not measured in this study, suggest the possibility of shared common antecedents between stroke and AMD.

Klein BE, Klein R. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 610 N Walnut St, Room 407 WARF, Madison, WI 53726, USA. · JAMA. · Pubmed #19475785 No free full text.

This publication has no abstract.

Baker ML, Wang JJ, Rogers S, Klein R, Kuller LH, Larsen EK, Wong TY. · Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia. · Arch Ophthalmol. · Pubmed #19433718 No free full text.

Abstract: OBJECTIVE: To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals. METHODS: This population-based study included 2,088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing. RESULTS: After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores, < or =30) were more likely to have early AMD (odds ratio, 1.38; 95% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD. CONCLUSIONS: In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.

Bravo HC, Lee KE, Klein BE, Klein R, Iyengar SK, Wahba G. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Proc Natl Acad Sci U S A. · Pubmed #19420224 links to  free full text

Abstract: We present a method for examining the relative influence of familial, genetic, and environmental covariate information in flexible nonparametric risk models. Our goal is investigating the relative importance of these three sources of information as they are associated with a particular outcome. To that end, we developed a method for incorporating arbitrary pedigree information in a smoothing spline ANOVA (SS-ANOVA) model. By expressing pedigree data as a positive semidefinite kernel matrix, the SS-ANOVA model is able to estimate a log-odds ratio as a multicomponent function of several variables: one or more functional components representing information from environmental covariates and/or genetic marker data and another representing pedigree relationships. We report a case study on models for retinal pigmentary abnormalities in the Beaver Dam Eye Study. Our model verifies known facts about the epidemiology of this eye lesion--found in eyes with early age-related macular degeneration--and shows significantly increased predictive ability in models that include all three of the genetic, environmental, and familial data sources. The case study also shows that models that contain only two of these data sources, that is, pedigree-environmental covariates, or pedigree-genetic markers, or environmental covariates-genetic markers, have comparable predictive ability, but less than the model with all three. This result is consistent with the notions that genetic marker data encode--at least in part--pedigree data, and that familial correlations encode shared environment data as well.

Chiu CJ, Milton RC, Klein R, Gensler G, Taylor A. · Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Department of Ophthalmology School of Medicine, Tufts University, 711 Washington Street, Boston, MA 02111, USA. · Ophthalmology. · Pubmed #19410952 No free full text.

Abstract: PURPOSE: Because foods provide many nutrients that may interact to modify risk for multifactorial diseases such as age-related macular degeneration (AMD), we sought to develop a composite scoring system to summarize the combined effect of multiple dietary nutrients on AMD risk. This has not been done previously. DESIGN: Cross-sectional study. PARTICIPANTS: From the 4003 participants in the Age-Related Eye Disease Study (AREDS), there were 7,934 eyes included in this study. METHODS: Considering dietary intakes of vitamins C and E, zinc, lutein/zeaxanthin, docosahexaenoic acid, eicosapentaenoic acid, and low-dietary glycemic index (dGI) from AREDS baseline information, we assigned each nutrient a percentile rank score then summed them into a compound score for each participant. Using eye as the unit of analysis, we evaluated the association between the compound score and risk of prevalent AMD. Validation, fitness, and performance of the model were evaluated using bootstrapping techniques, adjusted quasi-likelihood under the independence model criterion, and the c-index, respectively. MAIN OUTCOME MEASURES: Stereoscopic fundus photographs of the macula were taken and graded at baseline using the AREDS protocol and AMD Classification System. RESULTS: Our results showed that higher compound scores were associated with lower risk for early AMD, indicated by drusen, and advanced AMD. Validation analyses indicated that these relationships are robust (the average 50-time bootstrapping per quartile odds ratios = 0.727, 0.827, and 0.753, respectively, for drusen, and 0.616, 0.536, and 0.572, respectively, for advanced AMD). Model selection analyses suggested that the compound score should be included, but that measures of dietary beta-carotene should not be included. CONCLUSIONS: We found that consuming diets that provide low dGI and higher intakes of these nutrients were associated with the greatest reduction in risk for prevalent drusen and advanced AMD, whereas dietary beta-carotene did not affect these relationships. These findings warrant further prospective studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Klein R, Knudtson MD, Lee KE, Klein BE. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 610 N Walnut St, Room 417 WARF, Madison, WI 53726-2336, USA. · Arch Ophthalmol. · Pubmed #19204238 No free full text.

Abstract: OBJECTIVE: To examine the associations of the serum cystatin C level and chronic kidney disease with the incidence of age-related macular degeneration (AMD) over 15 years. METHODS: In this population-based cohort study of 4926 individuals aged 43 to 86 years at baseline, 3779 participated in 1 or more follow-up examinations. Age-related macular degeneration was determined by grading photographs of the macula. Individuals were defined as having mild or moderate to severe chronic kidney disease based on a value of more than 45 mL/min/1.73 m(2) to 60 mL/min/1.73 m(2) or less and 45 mL/min/1.73 m(2) or less, respectively, according to the Modification of Diet in Renal Disease Study equation. RESULTS: While controlling for age and other risk factors, the level of serum cystatin C at baseline was associated with the incidence of early AMD (odds ratio per log standard deviation [95% confidence interval], 1.16 [1.01-1.35]) and exudative AMD (1.42 [1.03-1.96]) but not geographic atrophy (0.89 [0.56-1.41]) or progression of AMD (1.02 [0.88-1.18]). Mild chronic kidney disease was associated with the 15-year cumulative incidence of early AMD (odds ratio per log standard deviation, 1.36 [95% confidence interval, 1.00-1.86]) but not the incidence of other AMD end points. CONCLUSION: There is a relationship between the level of serum cystatin C and chronic kidney disease with the incidence of AMD. The underlying biological processes remain to be determined.

Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726-2336, USA. · Ophthalmology. · Pubmed #19167079 No free full text.

Abstract: OBJECTIVE: To examine the 25-year cumulative incidence of macular edema (ME) and its relation to various risk factors. DESIGN: Population-based study. PARTICIPANTS: A total of 955 insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in baseline examinations (1980-1982) and at least 1 of 4 follow-up (4-, 10-, 14-, and 25-year) examinations (n=891) or died before the first follow-up examination (n=64). METHODS: Stereoscopic color fundus photographs were graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. Competing risk of death was included in statistical models. MAIN OUTCOME MEASURES: Incidence of ME and clinically significant ME (CSME). RESULTS: The 25-year cumulative incidence was 29% for ME and 17% for CSME. Annualized incidences of ME were 2.3%, 2.1%, 2.3%, and 0.9% in the first, second, third, and fourth follow-up periods of the study, respectively. In univariate analyses, the incidence of ME was associated with male sex, more severe diabetic retinopathy, higher glycosylated hemoglobin, proteinuria, higher systolic and diastolic blood pressure, and more pack-years of smoking. Multivariate analyses showed that the incidence of ME was related to higher baseline glycosylated hemoglobin (hazard ratio [HR] per 1% 1.17; 95% confidence interval [CI], 1.10-1.25; P<0.001) and higher systolic blood pressure (HR per 10 mmHg 1.15; 95% CI, 1.04-1.26; P=0.004) and marginally to proteinuria (HR 1.43; 95% CI, 0.99-2.08; P=0.06). CONCLUSIONS: These data show that relatively high 25-year cumulative rates of incidence of ME were related to glycemia and blood pressure. The lower risk of incident ME in the last period of the study may reflect recent improvement in care.

Chew EY, Sperduto RD, Milton RC, Clemons TE, Gensler GR, Bressler SB, Klein R, Klein BE, Ferris FL. · National Eye Institute, Bethesda, Maryland, USA. · Ophthalmology. · Pubmed #19091420 No free full text.

Abstract: PURPOSE: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). METHODS: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. MAIN OUTCOME MEASURES: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). RESULTS: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. CONCLUSIONS: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Wang JJ, Rochtchina E, Smith W, Klein R, Klein BE, Joshi T, Sivakumaran TA, Iyengar S, Mitchell P. · Vision Research, Department of Ophthalmology and the Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. · Am J Epidemiol. · Pubmed #19074778 No free full text.

Abstract: At baseline in 1992-1994, the authors assessed the combined effects of complement factor H (CFH) genotypes with smoking, fish consumption, and inflammatory markers on the risk of age-related macular degeneration (AMD) in 3,654 persons aged > or =49 years. They reexamined 75% of the survivors after 5 and 10 years, confirming incident AMD by side-by-side photographic grading. Of the 2,452 persons followed in the Blue Mountains Eye Study, 1,881 were genotyped (rs1061170), with CC, CT, and TT identified in 13.6%, 46.7%, and 39.7%, respectively. AMD risk increased with each additional C allele (early AMD: age- and sex-adjusted relative risk (RR) = 1.6, 95% confidence interval (CI): 1.2, 1.9; late AMD: RR = 2.3, 95% CI: 1.5, 3.6). Late AMD risk among current smokers with the CC/CT genotypes (RR = 10.7, 95% CI: 3.4, 33.9) was 5-fold that for genotypically similar nonsmokers (RR = 2.2, 95% CI: 0.9, 5.5) versus current nonsmokers with TT genotypes. Weekly compared with less than weekly consumption of fish was associated with reduced late AMD risk in participants with the CC genotype (RR = 0.15, 95% CI: 0.03, 0.8) but not the CT (RR = 0.7, 95% CI: 0.3, 2.0) or TT (RR = 1.3, 95% CI: 0.2, 7.2) genotypes. This study documents joint contributions from genetic and systemic factors in determining the progression of AMD.

Grassi MA, Mazzulla DA, Knudtson MD, Huang WW, Lee KE, Klein BE, Nicolae DL, Klein R. · Department of Surgery, University of Chicago, Illinois 60637, USA. · Am J Ophthalmol. · Pubmed #19054495 No free full text.

Abstract: PURPOSE: To determine whether patient self-report of prior laser treatment can be used as a reliable tool for assessing the presence of severe diabetic retinopathy. DESIGN: This was a retrospective study on two groups of diabetic subjects. METHODS: One hundred patients with diabetes were recruited from the general eye and retina clinics at the University of Chicago Hospitals. The patients were asked, "Have you ever received laser treatment for your diabetic eye disease (DED)?" A chart review was then conducted noting if the patient had received either focal laser treatment for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy. Data from the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) were also analyzed. Participant responses to the question "Have you had laser photocoagulation treatment for your eyes?" were analyzed with documentation of photocoagulation scars determined by grading seven-standard field color fundus photographs. RESULTS: In the University of Chicago group, 96 of 100 (96%) of patients were accurate in reporting whether they had received previous laser treatment for DED (sensitivity 95.8%, specificity 96.1%, and positive predictive value 88.5%). In the WESDR analysis, 2,329 of 2,348 (99%) of participants were accurate in reporting whether they had prior laser treatment for DED (sensitivity 96.0%, specificity 99.5%, and positive predictive value 95.6%). CONCLUSIONS: The high sensitivity and specificity of our results validate the use of patient self-report as a useful tool in assessing past laser treatment for severe diabetic retinopathy. Patient self-report may be a useful surrogate to clinical examination or medical record review to determine the presence of severe diabetic retinopathy.

Peeters A, Magliano DJ, Stevens J, Duncan BB, Klein R, Wong TY. · Department of Epidemiology and Preventive Medicine, Monash University, Victoria, Australia. · Arch Ophthalmol. · Pubmed #19001224 No free full text.

Abstract: OBJECTIVE: To examine the association between changes in waist-hip ratio (WHR), a measure of abdominal obesity, and age-related macular degeneration (AMD). METHODS: A total of 12 515 persons from a population-based cohort study, aged 45 to 64 years in 1987 to 1989, were followed up over 6 years. The percentage change in WHR during follow-up was ranked into sex-specific deciles; an increase in WHR was defined as the top 10% of change and a decrease in WHR as the bottom 10%. The association of increased or decreased WHR and presence of AMD at follow-up was determined using logistic regression adjusting for potential confounders. RESULTS: The average change in WHR was an increase of 2%, ranging from a decrease of 44% to an increase of 102%. A decrease in WHR of 3% or more was associated with 29% lower odds of any AMD (odds ratio = 0.71; 95% confidence interval, 0.52-0.97). This effect was most pronounced among obese participants at baseline, where a decrease in WHR was associated with 59% lower odds of AMD (odds ratio = 0.41; 95% confidence interval, 0.20-0.82). CONCLUSIONS: Middle-aged persons who had a 3% or greater reduction in WHR over time were less likely to have AMD, particularly among those who were initially obese.

Chang B, Mandal MN, Chavali VR, Hawes NL, Khan NW, Hurd RE, Smith RS, Davisson ML, Kopplin L, Klein BE, Klein R, Iyengar SK, Heckenlively JR, Ayyagari R. · The Jackson Laboratory, Bar Harbor, ME 04609, USA. · Hum Mol Genet. · Pubmed #18805803 No free full text.

Abstract: We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd2). These mice had normal fundi, electroretinograms (ERGs) and retinal histology at 6 months of age; vessel attenuation, RPE atrophy and pigmentary abnormalities at 14 months, which progressed to complete loss of photoreceptors and extinguished ERG by 22 months. Genetic analysis revealed that the retinal degeneration in arrd2 segregates in an autosomal recessive manner and the disease gene localizes to mouse chromosome 10. A positional candidate cloning approach detected a nonsense mutation in the mouse double minute-1 gene (Mdm1), which results in the truncation of the putative protein from 718 amino acids to 398. We have identified a novel transcript of the Mdm1 gene, which is the predominant transcript in the retina. The Mdm1 transcript is localized to the nuclear layers of neural retina. Expression of Mdm1 in the retina increases steadily from post-natal day 30 to 1 year, and a high level of Mdm1 are subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd2 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that the depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd2 mice. Analysis of a cohort of patients with age-related macular degeneration (AMD) wherein the susceptibility locus maps to chromosome 12q, a region bearing the human ortholog to MDM1, did not reveal association between human MDM1 and AMD.

Klein R, Knudtson MD, Lee KE, Gangnon RE, Klein BE. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726-2336, USA. · Ophthalmology. · Pubmed #18762073 No free full text.

Abstract: OBJECTIVE: To examine relationships of age, period, and birth cohort with the 5-year incidence of age-related macular degeneration (AMD). DESIGN: Population-based cohort study with 4 examination visits 5 years apart from 1988 through 1990, 1993 through 1995, 1998 through 2000, and 2003 through 2005. PARTICIPANTS: Two thousand nine hundred sixty-eight persons (6603 participant visits) and 3588 persons (8184 participant visits) 43 to 86 years of age at baseline contributing to the incidence of early and late AMD, respectively. METHODS: Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. MAIN OUTCOME MEASURES: Five-year incidence of early AMD. RESULTS: While controlling for age, there was a lower 5-year incidence of early AMD in later rather than in earlier birth cohorts (odds ratio per increasing category, 0.70; 95% confidence interval, 0.62-0.78; P<0.001). This remained while controlling for smoking, blood pressure, and other related factors. There was no evidence for a period or birth cohort effect with late AMD. CONCLUSIONS: Lower incidence of early AMD in more recent birth cohorts is likely the result of unmeasured risk factors for early AMD. Further study of possible unmeasured risk factors that may have caused this cohort effect may help to identify new modifiable risk factors for AMD. Diminishing incidence of early AMD in later birth cohorts would be expected to result in lower long-term estimates of future incidence of AMD than do current estimates that do not take this effect into account.

Klein R, Meuer SM, Knudtson MD, Klein BE. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726, USA. · Am J Ophthalmol. · Pubmed #18672224 No free full text.

Abstract: PURPOSE: To examine the change in size and location of pure geographic atrophy (GA). DESIGN: Population-based cohort study. METHODS: Ninety-five persons with GA either at baseline or at the one of the three five-year follow-up examinations, or both, were identified. Using computer-assisted software, the lesion area and greatest linear dimension (GLD) were calculated. Thirty-two persons (53 multiple eye-visit pairs) were seen at multiple visits five years apart with GA in the same eye to evaluate changes in total area and GLD. RESULTS: At the first occasion when pure GA was identified (n = 95), 45% had a single GA lesion, 18% had multifocal GA lesions, and 37% had a merged GA lesion. Of 53 eyes with multiple visits, the overall increase in atrophy was 6.4 mm(2) over a five-year period. The atrophy progressed to involve the foveal center in 47% of 19 eyes, and there was a mean decrease of 17 letters read correctly. Eyes with multifocal GA were most likely to have the area of atrophy increase (mean, 12 mm(2)), to have atrophy progress to the foveal center (83%), and to have a decrease in vision (mean, 22 letters), whereas eyes with a single GA lesion were least likely to have the area of atrophy increase (mean, 2 mm(2)), to have the lesion progress to the foveal center (22%), and to have a decrease in vision (mean, 10 letters). CONCLUSIONS: These are the first population-based data describing the five-year change in eyes with pure GA. Information on progression of GA will be useful for clinical trials of new interventions for GA.

Klein R, Knudtson MD, Klein BE. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726-2336, USA. · Arch Ophthalmol. · Pubmed #18541850 links to  free full text

Abstract: OBJECTIVE: To examine the association of pulmonary symptoms, disease, and function with the incidence of age-related macular degeneration (AMD). DESIGN: Population-based cohort study of persons aged 43 to 86 years at baseline (N = 4926), of whom 3779 participated in 1 or more follow-up examinations. METHODS: Stereoscopic photographs of the macula were graded to determine the presence of AMD. Existence of emphysema, asthma, and respiratory symptoms was determined from subjects' medical history questionnaires; the peak expiratory flow rate was measured using a Mini-Wright Peak Flow Meter (Clement Clarke International, Harlow, England). Discrete logistic hazard and logistic regression models were used. MAIN OUTCOME MEASURES: Incidence and progression of AMD. RESULTS: While controlling for age, sex, and other factors, a history of emphysema at baseline was found to be associated with the 15-year cumulative incidence of increased retinal pigment (odds ratio, 2.08; 95% confidence interval, 1.06-4.06), retinal pigment epithelium depigmentation (2.40; 1.23-4.67), and exudative AMD (3.65; 1.24-10.73). Mild pulmonary symptoms were associated with the 5-year incidence of exudative AMD (odds ratio, 3.83; 95% confidence interval, 1.39-10.58), and the fourth (ie, highest) quartile of pulmonary expiratory flow rate showed a protective effect for progression of AMD among women (0.36; 0.15-0.86). CONCLUSION: Independent of smoking, a history of emphysema and respiratory symptoms and function are modestly but inconsistently associated with the incidence and progression of AMD.

Klein R, Knudtson MD, Klein BE, Wong TY, Cotch MF, Liu K, Cheng CY, Burke GL, Saad MF, Jacobs DR, Sharrett AR. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726-2397, USA. · Ophthalmology. · Pubmed #18538409 No free full text.

Abstract: OBJECTIVE: To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T-->C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: We included 5887 persons aged 45 to 84 years with gradable AMD. METHODS: Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained. MAIN OUTCOME MEASURE: Prevalence of AMD. RESULTS: While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33-4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21-3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14-2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06-1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14-3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00-3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10-2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09-3.10), and large drusen area (OR, 1.66; 95% CI, 1.02-2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. CONCLUSIONS: This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.