Progression of Age-Related Macular Degeneration

Seddon, Johanna M.; Côté, Jean-Charles; Davis, Nancy J; Rosner, Bernard

doi:10.1001/archopht.121.6.785

Cited by 338 publications

(96 citation statements)

References 52 publications

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“…This statistic highlights the role of additional factors, besides hyperglycemia, that continue to promote tissue dysfunction and damage during diabetes. In nondiabetic patients, hypertension can lead to retinopathy (41)(42)(43), while obesity increases the risk for the development and progression of age-related macular (retinal) degeneration (44,45). Since RBP4 is a proinflammatory adipokine that is often elevated in patients with obesity, cardiovascular disease, and type 2 diabetes, we sought to determine whether the elevation of RBP4 levels could promote retinal dysfunction and/or degeneration.…”

Section: S Erum Retinol-binding Protein 4 (Rbp4) Is the Sole Specificmentioning

confidence: 99%

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients. S erum retinol-binding protein 4 (RBP4) is the sole specific transport protein for vitamin A (retinol) in the blood (1-4).The eye is the organ most dependent on the RBP4-mediated delivery of retinol to maintain optimal function, as RBP4 loss of function in either mice or humans impairs retinal function, leading to visual impairment, while other organ systems remain intact (5-7). However, in the past decade numerous clinical studies have linked increased serum levels of RBP4 to disease, including obesity (8, 9), insulin resistance (8-13), type 2 diabetes (9, 13), and cardiovascular disease (hypertension, atherosclerosis, stroke) (14-18). This appears to be more than a spurious correlation, since recent studies have demonstrated that RBP4 is an adipokine (adipose-derived cytokine) with retinoid-independent, proinflammatory activity that contributes to the development of insulin resistance (13,(19)(20)(21). Moreover, a human single nucleotide polymorphism that increases RBP4 promoter activity confers a 2-fold increase for the risk of type 2 diabetes (22, 23).Several studies have provided mechanistic insights into RBP4-induced insulin resistance. Mice with genetic or pharmacologic elevation of RBP4 levels develop insulin resistance (13), whereas lowering of RBP4 levels improves insulin sensitivity in mice (13,24). RBP4 inhibits insulin signaling in adipocytes indirectly by activating proinflammatory cytokine production in macrophages through retinol-independent and Toll-like receptor 4 (TLR4)-and c-Jun N-terminal kinase (JNK)-dependent ...

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Section: S Erum Retinol-binding Protein 4 (Rbp4) Is the Sole Specificmentioning

confidence: 99%

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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“…One modifiable factor is dietary total fat intake. The results of Seddon et al (2003) show that higher total fat intake increased the risk of progression to the advanced forms of AMD, with a relative risk (RR) of 2.90 (95% confidence interval, 1.15-7.32) for the highest fat-intake quartile relative to the lowest fatintake quartile, after controlling for other factors (P trend = 0.01).…”

Section: Examplementioning

confidence: 99%

“…According to Seddon et al (2003), eyes with extensive small drusen (≥ 15 drusen; with size of drusen < 63 μm), nonextensive intermediate drusen (< 20 drusen; with size of drusen ≥ 63μm but < 125μm), or pigment abnormalities associated with AMD were assigned a grade of 2. Eyes with extensive intermediate or large drusen (size of drusen ≥ 125μm) were assigned a grade of 3.…”

Section: Examplementioning

confidence: 99%

“…Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness in the United States and other developed countries throughout the world (Seddon et al, 2003). Evidence is accumulating regarding modifiable factors that may decrease the risk of progression to the advanced forms of AMD.…”

Section: Introductionmentioning

confidence: 99%

“…A total of 261 individuals were included in the analyses. Details about the study are provided in Seddon et al (2003). The average age of the subjects was 72.3 years (sd = 6.1, range = [60,87]).…”

Section: Introductionmentioning

confidence: 99%

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Assessing Discrimination of Risk Prediction Rules in a Clustered Data Setting

Rosner¹,

Qiu²,

Lee³

2013

Risk Assessment and Evaluation of Predictions

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The AUC (area under ROC curve) is a commonly used metric to assess discrimination of risk prediction rules; however, standard errors of AUC are usually based on the Mann-Whitney U test that assumes independence of sampling units. For ophthalmologic applications, it is desirable to assess risk prediction rules based on eye-specific outcome variables which are generally highly, but not perfectly correlated in fellow eyes (eg. progression of individual eyes to age-related macular degeneration (AMD)). In this article, we use the extended Mann-Whitney U test (Rosner et al, 2009) for the case where subunits within a cluster may have different progression status and assess discrimination of different prediction rules in this setting. Both data analyses based on progression of AMD and simulation studies show reasonable accuracy of this extended MannWhitney U test to assess discrimination of eye-specific risk prediction rules.

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Progression of Age-Related Macular Degeneration

Seddon¹

2003

Arch Ophthalmol

Self Cite

341

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Background: Individuals with early or intermediate stages of age-related macular degeneration (AMD) make up a large, growing segment of the elderly population. Evidence is sparse regarding modifiable factors that may decrease the risk of progression to the advanced forms of AMD.Objective: To advise patients with a high risk for advanced forms of AMD about preventive measures through our evaluation of the relationship between dietary fat intake and the progression of early or intermediate AMD to the advanced stages of the disease associated with visual loss.Design: A prospective cohort study with an average follow-up time of 4.6 years.Setting: A hospital-based clinical retinal practice specializing in macular degeneration. Patients:The 261 participants were aged 60 years and older and had some sign of nonexudative AMD and visual acuity of 20/200 or better in at least 1 eye.Main Outcome Measure: Progression to advanced AMD, which was defined as having geographic atrophy or neovascular disease.Results: Higher total fat intake increased the risk of progression to the advanced forms of AMD, with a relative risk (RR) of 2.90 (95% confidence interval, 1.15-7.32) for the highest fat-intake quartile relative to the lowest fat-intake quartile, after controlling for other factors (P trend=.01). Animal fat intake was associated with a 2-fold increased risk of progression (RR, 2.29 for the highest quartile compared with the lowest quartile; 95% confidence interval, 0.91-5.72), although the trend for increasing risk with higher animal fat intake was not significant (P=.09). Higher vegetable fat intake had a stronger relationship with increased risk of AMD progression with an RR of 3.82 (95% confidence interval, 1.58-9.28) for the highest quartile compared with the lowest quartile (P trend=.003). Saturated, monounsaturated, polyunsaturated, and transunsaturated fats increased the likelihood of progression (RR, 2.09 and P trend=.08; RR, 2.21 and P trend=.04; RR, 2.28 and P trend=.04; RR, 2.39 and P trend = .008, respectively). Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake. Processed baked goods, which are higher in some of these fats, increased the rate of AMD progression approximately 2-fold, and nuts were protective.Conclusions: Among individuals with the early or intermediate stages of AMD, total and specific types of fat intake, as well as some fat-containing food groups, modified the risk of progression to advanced AMD. Fish intake and nuts reduced risk. Since advanced AMD is associated with visual loss and reduced quality of life, these preventive measures deserve additional research and greater emphasis.

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Progression of Age-Related Macular Degeneration

Cited by 338 publications

References 52 publications

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Assessing Discrimination of Risk Prediction Rules in a Clustered Data Setting

Progression of Age-Related Macular Degeneration

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