Showing papers by "Ronald Klein published in 2015"

The Prevalence of Glaucoma in a Population-Based Study of Hispanic Subjects

Abstract: Objective: To determine the prevalence of glaucoma in a population-based sample of Hispanic adults older than 40 years. Methods: Using 1990 census data for Arizona, groups of persons living in sections of the city in Nogales and Tucson were randomly selected with a probability proportional to the Hispanic population older than 40 years. We tried to recruit all eligible adults in homes with 1 selfdescribed Hispanic adult. Detailed ocular examinations at a local clinic included visual acuity testing, applanation tonometry, gonioscopy, an optic disc evaluation, and a threshold visual field test. Open-angle glaucoma (OAG) was defined using a proposed international system for prevalence surveys, including threshold visual field defect and optic disc damage. Angle-closure glaucoma was defined as bilateral appositional angle closure, combined with optic nerve damage (judged by field and disc as for OAG). Results: Examinations were conducted in 72% (4774/ 6658) of eligible persons, with a 1.97% prevalence (95% confidence interval, 1.58%-2.36%) of OAG (94 persons). The age-specific OAG prevalence increased nonlinearly from 0.50% in those aged 41 to 49 years to 12.63% in those 80 years and older. Angle-closure glaucoma was detected in 5 persons (0.10%). Sex, blood pressure, and cigarette smoking were not significant OAG risk factors. Only 36 (38%) of the 94 persons with OAG were aware of their OAG before the study. Screening results with an intraocular pressure higher than 22 mm Hg (in the eye with a higher pressure) would miss 80% of the OAG cases. Conclusions: The prevalence of OAG in Hispanic persons was intermediate between reported values for white and black persons. The prevalence increased more quickly with increasing age than in other ethnic groups. Glaucoma was the leading cause of bilateral blindness.

The Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration

Abstract: OBJECTIVE To develop a fundus photographic severity scale for age-related macular degeneration (AMD). METHODS In the Age-Related Eye Disease Study, stereoscopic color fundus photographs were taken at baseline, at the 2-year follow-up visit, and annually thereafter. Photographs were graded for drusen characteristics (size, type, area), pigmentary abnormalities (increased pigment, depigmentation, geographic atrophy), and presence of abnormalities characteristic of neovascular AMD (retinal pigment epithelial detachment, serous or hemorrhagic sensory retinal detachment, subretinal or sub-retinal pigment epithelial hemorrhage, subretinal fibrous tissue). Advanced AMD was defined as presence of 1 or more neovascular AMD abnormalities, photocoagulation for AMD, or geographic atrophy involving the center of the macula. We explored associations among right eyes of 3212 participants between severity of drusen characteristics and pigmentary abnormalities at baseline and development of advanced AMD within 5 years of follow-up. RESULTS A 9-step severity scale that combines a 6-step drusen area scale with a 5-step pigmentary abnormality scale was developed, on which the 5-year risk of advanced AMD increased progressively from less than 1% in step 1 to about 50% in step 9. Among the 334 eyes that had at least a 3-step progression on the scale between the baseline and 5-year visits, almost half showed stepwise progression through intervening severity levels at intervening visits. Replicate gradings showed agreement within 1 step on the scale in 87% of eyes. CONCLUSIONS The scale provides convenient risk categories and has acceptable reproducibility. Progression along it may prove to be useful as a surrogate for progression to advanced AMD.

Cardiovascular Disease, Mortality, and Retinal Microvascular Characteristics in Type 1 Diabetes

Abstract: Results: The 20-year age-adjusted cumulative incidences were 18.1% for angina, 14.8% for myocardial infarction, and 5.9% for stroke. Severity of diabetic retinopathy was associated with angina and stroke. Arteriovenous ratio was associated with myocardial infarction. Of 273 deaths, 176 involved heart disease. The severity of retinopathy and arteriovenous ratio was associated with heart disease mortality. Nephropathy was more informative about the cardiovascular end points than were the blood vessel characteristics.

Smoking, central adiposity, and poor glycemic control increase risk of hearing impairment.

Abstract: Objectives To determine associations between smoking, adiposity, diabetes mellitus, and other risk factors for cardiovascular disease (CVD) and the 15-year incidence of hearing impairment (HI). Design A longitudinal population-based cohort study (1993–95 to 2009–10), the Epidemiology of Hearing Loss Study (EHLS). Setting Beaver Dam, Wisconsin. Participants Participants in the Beaver Dam Eye Study (1988–90; residents of Beaver Dam, WI, aged 43–84 in 1987–88) were eligible for the EHLS. There were 1,925 participants with normal hearing at baseline. Measurements Fifteen-year cumulative incidence of HI (pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz greater than 25 decibels hearing level in either ear). Cigarette smoking, exercise, and other factors were ascertained according to questionnaire. Blood pressure, waist circumference, body mass index, and glycosylated hemoglobin were measured. Results Follow-up examinations (≥1) were obtained from 87.2% (n = 1,678; mean baseline age 61). The 15-year cumulative incidence of HI was 56.8%. Adjusting for age and sex, current smoking (hazard ratio (HR) = 1.31, P = .048), education (<16 years; HR = 1.35, P = .01), waist circumference (HR = 1.08 per 10 cm, P = .02), and poorly controlled diabetes mellitus (HR = 2.03, P = .048) were associated with greater risk of HI. Former smokers and people with better-controlled diabetes mellitus were not at greater risk. Conclusion Smoking, central adiposity, and poorly controlled diabetes mellitus predicted incident HI. These well-known risk factors for CVD suggest that vascular changes may contribute to HI in aging. Interventions targeting reductions in smoking and adiposity and better glycemic control in people with diabetes mellitus may help prevent or delay the onset of HI.

Hearing-aid use and long-term health outcomes: hearing handicap, mental health, social engagement, cognitive function, physical health, and mortality

Abstract: Objective: To clarify the impact of hearing aids on mental health, social engagement, cognitive function, and physical health outcomes in older adults with hearing impairment. Design: We assessed hearing handicap (hearing handicap inventory for the elderly; HHIE-S), cognition (mini mental state exam, trail making, auditory verbal learning, digit-symbol substitution, verbal fluency, incidence of cognitive impairment), physical health (SF-12 physical component, basic and instrumental activities of daily living, mortality), social engagement (hours per week spent in solitary activities), and mental health (SF-12 mental component) at baseline, five years prior to baseline, and five and 11 years after baseline. Study sample: Community-dwelling older adults with hearing impairment (N = 666) from the epidemiology of hearing loss study cohort. Results: There were no significant differences between hearing-aid users and non-users in cognitive, social engagement, or mental health outcomes at any time point....

Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes

Abstract: Circulating microRNAs (miRNAs) have emerged as novel biomarkers of diabetes. The current study focuses on the role of circulating miRNAs in patients with type 1 diabetes and their association with diabetic retinopathy. A total of 29 miRNAs were quantified in serum samples (n = 300) using a nested case-control study design in two prospective cohorts of the DIabetic REtinopathy Candesartan Trial (DIRECT): PROTECT-1 and PREVENT-1. The PREVENT-1 trial included patients without retinopathy at baseline; the PROTECT-1 trial included patients with nonproliferative retinopathy at baseline. Two miRNAs previously implicated in angiogenesis, miR-27b and miR-320a, were associated with incidence and with progression of retinopathy: the odds ratio per SD higher miR-27b was 0.57 (95% CI 0.40, 0.82; P = 0.002) in PREVENT-1, 0.78 (0.57, 1.07; P = 0.124) in PROTECT-1, and 0.67 (0.50, 0.92; P = 0.012) combined. The respective odds ratios for higher miR-320a were 1.57 (1.07, 2.31; P = 0.020), 1.43 (1.05, 1.94; P = 0.021), and 1.48 (1.17, 1.88; P = 0.001). Proteomics analyses in endothelial cells returned the antiangiogenic protein thrombospondin-1 as a common target of both miRNAs. Our study identifies two angiogenic miRNAs, miR-320a and miR-27b, as potential biomarkers for diabetic retinopathy.

Self-Reported Hearing Difficulties Among Adults With Normal Audiograms: The Beaver Dam Offspring Study.

Abstract: OBJECTIVE Clinicians encounter patients who report experiencing hearing difficulty (HD) even when audiometric thresholds fall within normal limits. When there is no evidence of audiometric hearing loss, it generates debate over possible biomedical and psychosocial etiologies. It is possible that self-reported HDs relate to variables within and/or outside the scope of audiology. The purpose of this study is to identify how often, on a population basis, people with normal audiometric thresholds self-report HD and to identify factors associated with such HDs. DESIGN This was a cross-sectional investigation of participants in the Beaver Dam Offspring Study. HD was defined as a self-reported HD on a four-item scale despite having pure-tone audiometric thresholds within normal limits (<20 dB HL0.5, 1, 2, 3, 4, 6, 8 kHz bilaterally, at each frequency). Distortion product otoacoustic emissions and word-recognition performance in quiet and with competing messages were also analyzed. In addition to hearing assessments, relevant factors such as sociodemographic and lifestyle factors, environmental exposures, medical history, health-related quality of life, and symptoms of neurological disorders were also examined as possible risk factors. The Center for Epidemiological Studies-Depression was used to probe symptoms associated with depression, and the Medical Outcomes Study Short-Form 36 mental score was used to quantify psychological stress and social and role disability due to emotional problems. The Visual Function Questionnaire-25 and contrast sensitivity test were used to query vision difficulties. RESULTS Of the 2783 participants, 686 participants had normal audiometric thresholds. An additional grouping variable was created based on the available scores of HD (four self-report questions), which reduced the total dataset to n = 682 (age range, 21-67 years). The percentage of individuals with normal audiometric thresholds who self-reported HD was 12.0% (82 of 682). The prevalence in the entire cohort was therefore 2.9% (82 of 2783). Performance on audiological tests (distortion product otoacoustic emissions and word-recognition tests) did not differ between the group self-reporting HD and the group reporting no HD. A multivariable model controlling for age and sex identified the following risk factors for HD: lower incomes (odds ratio [OR] $50,000+ = 0.55, 95% confidence interval [CI] = 0.30-1.00), noise exposure through loud hobbies (OR = 1.48, 95% CI = 1.15-1.90), or firearms (OR = 2.07, 95% CI = 1.04-4.16). People reporting HD were more likely to have seen a doctor for hearing loss (OR = 12.93, 95% CI = 3.86-43.33) and report symptoms associated with depression (Center for Epidemiological Studies-Depression [OR = 2.39, 95% CI = 1.03-5.54]), vision difficulties (Visual Function Questionnaire-25 [OR = 0.93, 95% CI = 0.89-0.97]), and neuropathy (e.g., numbness, tingling, and loss of sensation [OR = 1.98, 95% CI = 1.14-3.44]). CONCLUSIONS The authors used a population approach to identify the prevalence and risk factors associated with self-reported HD among people who perform within normal limits on common clinical tests of auditory function. The percentage of individuals with normal audiometric thresholds who self-reported HD was 12.0%, resulting in an overall prevalence of 2.9%. Auditory and nonauditory risk factors were identified, therefore suggesting that future directions aimed at assessing, preventing, and managing these types of HDs might benefit from information outside the traditional scope of audiology.

The clinical implications of recent studies on the structure and function of the retinal microvasculature in diabetes

Abstract: The retinal blood vessels provide the opportunity to study early structural and functional changes in the microvasculature prior to clinically significant microvascular and macrovascular complications of diabetes. Advances in digital retinal photography and computerised assessment of the retinal vasculature have provided more objective and precise measurements of retinal vascular changes. Clinic- and population-based studies have reported that these quantitatively measured retinal vascular changes (e.g. retinal arteriolar narrowing and venular widening) are associated with preclinical structural changes in other microvascular systems (e.g. infarct in the cerebral microcirculation), as well as diabetes and diabetic complications, suggesting that they are markers of early microvascular dysfunction. In addition, there are new retinal imaging techniques to further assess alterations in retinal vascular function (e.g. flicker-induced vasodilatory response, blood flow and oxygen saturation) in diabetes and complications that result from the effects of chronic hyperglycaemia, inflammation and endothelial dysfunction. In this review, we summarise the latest findings on the relationships between quantitatively measured structural and functional retinal vascular changes with diabetes and diabetic complications. We also discuss clinical implications and future research to evaluate whether detection of retinal vascular changes has additional value beyond that achieved with methods currently used to stratify the risk of diabetes and its complications.

Intensive diabetes therapy and ocular surgery in type 1 diabetes.

Abstract: BACKGROUND The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. METHODS Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. RESULTS Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P = 0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P = 0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P = 0.01). The costs of surgery were 32% lower in the intensive-therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. CONCLUSIONS Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.)

Serum Lipids and Proliferative Diabetic Retinopathy and Macular Edema in Persons With Long-term Type 1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy.

Abstract: Importance Total serum and high-density lipoprotein cholesterol have been considered risk factors for severe vascular outcomes in persons with type 1 diabetes mellitus. Objective To examine the long-term relationships between these 2 serum lipids and the incidence and prevalence of proliferative diabetic retinopathy and macular edema. Design, Setting, and Participants Nine-hundred three persons with younger-onset type 1 diabetes mellitus who participated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Exposures Serum total and high-density cholesterol and history of statin use during the course of 5 visits spanning approximately 30 years (April 10, 1984, to February 13, 2014). Main Outcomes and Measures Prevalence and incidence of proliferative diabetic retinopathy and macular edema. Results A modest association was found for higher levels of high-density lipoprotein cholesterol and decreased prevalence of proliferative diabetic retinopathy (odds ratio per 10 mg/dL, 0.87; 95% CI, 0.82-0.93), adjusting for duration of diabetes mellitus, glycosylated hemoglobin A 1c , statin use, and end-stage renal disease. While adjusting for covariates, no associations of serum total or high-density lipoprotein cholesterol and incident proliferative diabetic retinopathy or macular edema, nor of statin use with decreased incidence of proliferative diabetic retinopathy or macular edema, were identified. Conclusions and Relevance In the course of long-duration diabetes mellitus during a time of changing medical care, there appeared to be little effect of serum lipids or statins on the incidence of proliferative diabetic retinopathy and macular edema.

Sustained supplementation and monitored response with differing carotenoid formulations in early age-related macular degeneration.

Abstract: To compare the impact of sustained supplementation using different macular carotenoid formulations on macular pigment (MP) and visual function in early age-related macular degeneration (AMD). Sixty-seven subjects with early AMD were randomly assigned to: Group 1 (20 mg per day lutein (L), 0.86 mg per day zeaxanthin (Z); Ultra Lutein), Group 2 (10 mg per day meso-zeaxanthin (MZ), 10 mg per day L, 2 mg per day Z; Macushield; Macuhealth), Group 3 (17 mg per day MZ, 3 mg per day L, 2 mg per day Z). MP was measured using customised heterochromatic flicker photometry and visual function was assessed by measuring contrast sensitivity (CS) and best-corrected visual acuity (BCVA). AMD was graded using the Wisconsin Age-Related Maculopathy Grading System (AREDS 11-step severity scale). At 3 years, a significant increase in MP from baseline was observed in all groups at each eccentricity (P 0.05 for all). At 36 months, compared with baseline, the following significant improvements (P<0.05) in CS were observed: Group 2—1.2, 6, and 9.6 cycles per degree (c.p.d.); Group 1—15.15 c.p.d.; and Group 3—6, 9.6, and 15.15 c.p.d. No significant changes in BCVA, or progression to advanced AMD, were observed. In early AMD, MP can be augmented with a variety of supplements, although the inclusion of MZ may confer benefits in terms of panprofile augmentation and in terms of CS enhancement.

The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy.

Abstract: We investigated the association of signals from previous GWAS and candidate gene meta-analyses for diabetic retinopathy (DR) or nephropathy (DN), as well as an EPO variant in meta-analyses of severe (SDR) and mild diabetic retinopathy (MDR). Meta-analyses of SDR (≥severe non-proliferative diabetic retinopathy (NPDR) or history of panretinal photocoagulation) and MDR (≥mild NPDR), defined based on seven-field stereoscopic fundus photographs, were performed in two well-characterized type 1 diabetes (T1D) cohorts: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC, n = 1,304) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, n = 603). Among 34 previous signals for DR, after controlling for multiple testing, no association was replicated in our meta-analyses. rs1571942 and rs12219125 at PLXDC2 locus showed nominally significant ( 0.05). Lack of replication of previous DR hits and EPO despite reasonable statistical power implies that many of these may be false positives. Consistent with pleiotropy, we provide suggestive collective evidence for association between DR and variants previously associated with DN without reaching statistical significance at any single locus.

Exome array analysis identifies CAV1/CAV2 as a susceptibility locus for intraocular pressure.

Abstract: Purpose. Intraocular pressure (IOP) is an important clinical parameter in the evaluation of ocular health. Elevated IOP is a major risk factor for primary open-angle glaucoma (POAG). The goal of this study was to identify rare and less common variants that influence IOP.

Retinal microvascular calibre and risk of diabetes mellitus: a systematic review and participant-level meta-analysis

Abstract: Aims/hypothesis The calibre of the retinal vessels has been linked to diabetes mellitus but studies have not shown consistent results. We conducted a participant-level meta-analysis to evaluate the association between retinal arteriolar and venular calibre and diabetes.

AAV9 supports wide-scale transduction of the CNS and TDP-43 disease modeling in adult rats.

Abstract: AAV9 has emerged as an efficient adeno-associated virus (AAV) serotype for gene transfer to the central nervous system. We have used this technique to study aspects of amyotrophic lateral sclerosis (ALS) by administering AAV encoding the ALS-related gene transactive response DNA binding protein of 43 kDa (TDP-43) to neonatal rats. However, inducing the expression in adult subjects would be preferable to mimic the adult onset of symptoms in ALS. We expressed either green fluorescent protein (GFP) or TDP-43 in adult rats after an intravenous (i.v.) route of administration to attempt wide-scale transduction of the spinal cord for disease modeling. In order to optimize the gene transfer, we made comparisons of efficiency by age, gender, and across several AAV serotypes (AAV1, AAV8, AAV9, and AAV10). The data indicate more efficient neuronal transduction in neonates, with little evidence of glial transduction at either age, no gender-related differences in transduction, and that AAV9 was efficient in adults relative to the other serotypes tested. Based on these data, AAV9 TDP-43 was expressed at three vector doses in adult female rats yielding highly consistent, dose-dependent motor deficits. AAV9 can be delivered i.v. to adult rats to achieve consistent pathophysiological changes and a relevant adult-onset system for disease modeling.

The associations between 6-n-propylthiouracil (PROP) intensity and taste intensities differ by TAS2R38 haplotype.

Abstract: Background/Aims: The influence of TAS2R38 haplotype on the relationship between the perceived intensity of propylthiouracil (PROP) and the basic tastes of salt, sweet, sour, and bitter (quinine) was evaluated in the Beaver Dam Offspring Study. Methods: Genotyping was performed on 1,670 participants aged ≥45 years (mean age = 54.4; range = 45-84), and suprathreshold taste intensity was measured using filter paper disks and a general labeled magnitude scale (0-100). Results: Among those with taste intensity data and the PAV or AVI haplotype (n = 1,258), the mean perceived intensity of PROP was 37.3 (SD = 30.0), but it varied significantly (p TAS2R38 diplotype was observed. There was a stronger association between PROP and each of the basic tastes in the PAV/PAV diplotype group than in the other groups. Conclusions: Directly measuring the perceived intensity of the 4 tastes, rather than using PROP intensity as an indicator of taste responsiveness, is recommended for studies of taste perception.

The Prevalence of Hearing Impairment and Associated Risk Factors

Abstract: Design: Data were collected as part of the Beaver Dam Offspring Study, an epidemiological cohort study of aging. Hearing impairment was defined as a pure-tone average (0.5, 1.0, 2.0, and 4.0 kHz) greater than 25 db hearing level in either ear. Word recognition in competing message (WRCM) was measured using the Northwestern University No. 6 word list. Questionnaire information about behaviors, environmental factors, and medical history was also collected. Participants: The participants (N =3 285) were offspring of participants of the population-based Epidemiology of Hearing Loss Study and ranged in age from 21 to 84 years (mean age, 49 years). Results: The prevalence of HI was 14.1%, and the mean (SD) WRCM score was 64% (15%). In a multivariate model, after age, sex, education, and occupational noise were controlled for, a history of ear surgery (odds ratio [OR], 4.11; 95% confidence interval [CI], 2.37-7.15), a larger central retinal venular equivalent (OR, 1.77; 95% CI, 1.20-2.60 [fourth quartile vs first quartile]), and a higher hematocrit percentage (OR, 0.77; 95% CI, 0.630.95 [per 5%]) were independently associated with HI. Factors associated with lower WRCM scores were similar but also included mean intima-media thickness (mean difference, �0.63%; 95% CI, �1.06% to �0.19%; P=.005 [per 0.1 mm]) and statin use (mean difference, �2.09%; 95% CI, �3.58% to �0.60%; P=.005).

Severity of age-related macular degeneration in 1 eye and the incidence and progression of age-related macular degeneration in the fellow eye: the Beaver Dam Eye Study.

Abstract: Importance Previous studies regarding the severity of age-related macular degeneration (AMD) in 1 eye and its prognostic implications for the fellow eye have focused on the incidence of neovascular AMD in the fellow eye of participants with neovascular AMD in the other eye. It is unclear to what extent the severity of AMD in 1 eye affects the incidence, progression, and regression of AMD in its fellow eye across the entire range of AMD severity. Objective To investigate the effect of the severity of AMD in 1 eye on the incidence, progression, and regression of AMD in the fellow eye. Design, Setting and Participants The Beaver Dam Eye Study is a longitudinal population-based study of age-related eye diseases conducted in the city and township of Beaver Dam, Wisconsin. Examinations were performed every 5 years over a 20-year period (from the baseline examination in 1988-1990 to 2008-2010). Study participants (n = 4379) were 43 to 86 years of age at the baseline examination. At baseline and in up to 4 subsequent examinations, retinal photographs were taken. Main Outcomes and Measures Incidence, progression, and regression of AMD (assessed by use of the Wisconsin Age-Related Maculopathy Grading System on retinal photographs and adjusted for age, sex, and the Y402H polymorphism in the complement factor H gene on chromosome 1q) and mortality. Results More severe AMD in 1 eye was associated with increased incidence of AMD and accelerated progression in its fellow eye (levels 1-2: hazard ratio [HR], 4.90 [95% CI, 4.26-5.63]; levels 2-3: HR, 2.09 [95% CI, 1.42-3.06]; levels 3-4: HR, 2.38 [95% CI, 1.74-3.25]; levels 4-5: HR, 2.46 [95% CI, 1.65-3.66]). Less severe AMD in 1 eye was associated with less progression of AMD in its fellow eye (levels 2-3: HR, 0.42 [95% CI, 0.33-0.55]; levels 3-4: HR, 0.50 [95% CI, 0.34-0.83]). We estimate that 51% of participants who develop any AMD always maintain AMD severity states within 1 step of each other between eyes; 90% of participants stay within 2 steps. Conclusions and Relevance Using multistate models, we show that AMD severity in 1 eye tracks AMD severity in its fellow eye.

Carotid Intima Media Thickness, Atherosclerosis, and 5-Year Decline in Odor Identification: The Beaver Dam Offspring Study

Abstract: Although olfactory impairment is common in older adults, many are unaware of their dysfunction suggesting some decline in olfactory function occurs slowly over time (1,2). Gradual declines in olfactory function with age may have different etiologies than sudden impairments that are associated with specific events (trauma or infection). A slow progression of subclinical decline in olfactory function would be similar to the long trajectory recognized in the development of cardiovascular disease (CVD), which begins as vascular changes and atherosclerosis early in adulthood and manifests as clinical disease years later. In CVD, the risk factor profile in midlife is believed to an important predictor of healthy aging and longevity (3); this may be true for olfactory impairment as well. Olfactory impairment and CVD have some risk factors in common such as smoking, diabetes mellitus, and exercise. Smoking, an important risk factor for atherosclerosis (4,5), has been associated with olfactory dysfunction in some studies (1,2,6,7), but not all (8). People with diabetes mellitus have an increased risk of developing atherosclerosis (9) and CVD (10), and some studies have found people with diabetes have more olfactory dysfunction, though again, findings have not been consistent (1,2,8,11). Weinstock and coauthors (11) found within a diabetes cohort that those with macrovascular disease (coronary artery or peripheral vascular) had impaired olfaction compared with those without macrovascular disease. In population studies, older adults in the Epidemiology of Hearing Loss Study who were current smokers or had a history of stroke were more likely to have olfactory impairment in cross-sectional analyses (1). Longitudinal analyses found the use of lipid-lowering medication and regular exercise were associated with a reduced risk of developing olfactory impairment at 5 years (12) and exercise was also associated with a reduced risk at 10 years (13). In a younger cohort, the Beaver Dam Offspring Study (BOSS), thicker carotid artery intima media thickness (IMT), a subclinical marker of generalized atherosclerosis, was associated with prevalent olfactory impairment (2). Together, these findings suggest that atherosclerosis may be associated with olfactory dysfunction that occurs with aging. However, to establish temporal sequence, longitudinal data are needed from a younger cohort that has not yet entered the period of greatest risk for olfactory impairment. The purpose of this study was to determine if subclinical markers of atherosclerosis are associated with a decline in olfactory function at 5 years in a primarily midlife cohort of adults participating in the longitudinal BOSS.

Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus

Abstract: Background Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Methods Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/√2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Results Baseline mean age was 24.6 years, mean duration of T1D 11.2 years, median AER 6.4 µg/min and mean iohexol GFR 129 mL/min/1.73 m(2). No associations were found between hepcidin/Cr and morphometric variables. Higher MCP-1/Cr was associated with higher interstitial fractional volume at baseline and after 5 years in women (baseline partial r = 0.244, P = 0.024; 5-year partial r = 0.299, P = 0.005), but not in men (baseline partial r = -0.049, P = 0.678; 5-year partial r = 0.026, P = 0.830). MCP-1 was not associated with glomerular lesions in either sex. Conclusions Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN.

Adiponectin, Insulin Sensitivity and Diabetic Retinopathy in Latinos With Type 2 Diabetes.

Abstract: Context and Objective: Insulin resistance and chronic inflammation are key elements in the pathogenesis of type 2 diabetes. We hypothesized that similar mechanisms could have a role in the development of diabetic retinopathy (DR), an important microvascular complication in Latinos with type 2 diabetes. Design and Setting: A cross-sectional, family-based, observational cohort study. Patients: Latino subjects with type 2 diabetes (n = 507), ascertained in families via a proband with known diabetes duration of 10 years or more and/or with DR, were included. Main Outcome Measures: Serum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). DR was assessed by seven-field digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale (range of severity levels, 10–85). Results: Fasting adiponectin concentrations were elevated in patients with DR compared to those w...

Visual Impairment in White, Chinese, Black, and Hispanic Participants from the Multi-Ethnic Study of Atherosclerosis Cohort

Abstract: Purpose: To describe the prevalence of visual impairment and examine its association with demographic, socioeconomic, and health characteristics in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.Methods: Visual acuity data were obtained from 6134 participants, aged 46–87 years at time of examination between 2002 and 2004 (mean age 64 years, 47.6% male), from six communities in the United States. Visual impairment was defined as presenting visual acuity 20/50 or worse in the better-seeing eye. Risk factors were included in multivariable logistic regression models to determine their impact on visual impairment for men and women in each racial/ethnic group.Results: Among all participants, 6.6% (n = 421) had visual impairment, including 5.6% of men (n = 178) and 7.5% of women (n = 243). Prevalence of impairment ranged from 4.2% (n = 52) and 6.0% (n = 77) in white men and women, respectively, to 7.6% (n = 37) and 11.6% (n = 44) in Chinese men and women, respectively. Older age was significantl...

Inflammatory and vascular markers and olfactory impairment in older adults

Abstract: Background: the incidence of olfactory impairment increases sharply in the eighth and ninth decades of life but the aetiology of age-related olfactory decline is not well understood. Inflammation and atherosclerosis are associated with many age-related conditions and atherosclerosis has been associated with olfactory decline in middle-aged adults. Objective: to determine if inflammatory markers and atherosclerosis are associated with the development of olfactory impairment in older adults. Design: longitudinal, population-based study. Setting/participants: a total of 1,611 participants, aged 53–97 years in the Epidemiology of Hearing Loss Study without olfactory impairment at the 1998–2000 examination and with follow-up at a subsequent examination 5 and/or 10 years later. Methods: the San Diego Odor Identification Test was used to measure olfaction. High sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α were measured in serum and carotid ultrasound images were obtained for the measurement of carotid intima media thickness (IMT) and plaque assessment. Medical history, behavioural and lifestyle information were obtained by interview. Results: inflammatory markers, IMT and plaque were not associated with the 10-year cumulative incidence of olfactory impairment in adjusted Cox proportional hazard models. Among those <60 years, the mean IMT [hazard ratio (HR) = 4.35, 95% confidence interval (CI) = 1.69–11.21, tertile 3 versus tertile 1] and the number of sites with plaque (HR = 1.56, 95% CI = 1.17–2.08, per site) were associated with an increased risk of developing an olfactory impairment at follow-up. Conclusion: subclinical atherosclerosis at a younger age may be a risk factor for the development of olfactory impairment.

Microvascular and Macrovascular Abnormalities and Cognitive and Physical Function in Older Adults: Cardiovascular Health Study

Abstract: Objectives To evaluate and compare the associations between microvascular and macrovascular abnormalities and cognitive and physical function Design Cross-sectional analysis of the Cardiovascular Health Study (1998–1999). Setting Community. Participants Individuals with available data on three or more of five microvascular abnormalities (brain, retina, kidney) and three or more of six macrovascular abnormalities (brain, carotid artery, heart, peripheral artery) (N = 2,452; mean age 79.5). Measurements Standardized composite scores derived from three cognitive tests (Modified Mini-Mental State Examination, Digit-Symbol Substitution Test, Trail-Making Test (TMT)) and three physical tests (gait speed, grip strength, 5-time sit to stand) Results Participants with high microvascular and macrovascular burden had worse cognitive (mean score difference = −0.30, 95% confidence interval (CI) = −0.37 to −0.24) and physical (mean score difference = −0.32, 95% CI = −0.38 to −0.26) function than those with low microvascular and macrovascular burden. Individuals with high microvascular burden alone had similarly lower scores than those with high macrovascular burden alone (cognitive function: −0.16, 95% CI = −0.24 to −0.08 vs −0.13, 95% CI = −0.20 to −0.06; physical function: −0.15, 95% CI = −0.22 to −0.08 vs −0.12, 95% CI = −0.18 to −0.06). Psychomotor speed and working memory, assessed using the TMT, were only impaired in the presence of high microvascular burden. Of the 11 vascular abnormalities considered, white matter hyperintensity, cystatin C–based glomerular filtration rate, large brain infarct, and ankle–arm index were independently associated with cognitive and physical function. Conclusion Microvascular and macrovascular abnormalities assessed using noninvasive tests of the brain, kidney, and peripheral artery were independently associated with poor cognitive and physical function in older adults. Future research should evaluate the usefulness of these tests in prognostication.

Small Drusen and Age-Related Macular Degeneration: The Beaver Dam Eye Study.

Abstract: We tested the hypothesis that large areas of small hard drusen (diameter 9086 µm²)) of only small hard drusen, and intermediate drusen, was used The five-year incidence of AMD was 3% in eyes at the start of the interval with no, minimal, small, and moderate areas of only small drusen and 5% and 25% for eyes with large area of only small drusen and intermediate drusen, respectively Compared to eyes with a moderate area of small drusen, the odds ratio (OR) of developing AMD in eyes with a large area of only small drusen was 18 (p < 0001) Compared to eyes with large area of only small drusen, eyes with intermediate drusen had an OR of 55 (p < 0001) of developing AMD Our results are consistent with our hypothesis that large areas of only small drusen are associated with the incidence of AMD