Risk factors and biomarkers of age-related macular degeneration

Lambert, Nathan G.; Elshelmani, Hanan; Singh, Mukesh; Mansergh, Fiona C.; Wride, Michael A.; Padilla, Maximilian; Keegan, David; Hogg, Ruth; Ambati, Balamurali K.

doi:10.1016/j.preteyeres.2016.04.003

Cited by 276 publications

(251 citation statements)

References 411 publications

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“…The strong correlation between dietary carbohydrate and lipids within the context of AMDf emphasizes their metabolic connection. C40:6 PC, C22:6 LPE, and C22:6 CE are of particular interest, because soft drusen, an established clinical indication of AMD in humans, contain many such lipids, and variants in cholesterol-related genes are risk factors for AMD (3,52). Our data also point to downstream lipid peroxidation-related products, specifically CEP and 4-HNE, in the etiology of AMDf (37,38).…”

Section: Discussionmentioning

confidence: 67%

“…Additionally, such metabolomic investigation would lead to biomarkers. Having biomarkers and models in which AMDf development and progression can be monitored would facilitate diagnosis and prognosis as well as further understanding of diet-AMD pathomechanistic etiologies (3).…”

Section: Significancementioning

confidence: 99%

“…The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.…”

mentioning

confidence: 99%

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Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

181

174

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Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

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Section: Discussionmentioning

confidence: 67%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

181

174

View full text Add to dashboard Cite

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“…Some of these epidemiological risk factors for AMD can be modified, and include body-mass index (BMI), smoking tobacco, diet, and blood lipid and cholesterol levels [35]. However, other factors cannot be modified at present, including genotype at a given risk locus, sex, ethnicity, and age.…”

Section: Introductionmentioning

confidence: 99%

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

2016

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Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults over 50 years old. Genetic, epidemiological, and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease, which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and progression. Many of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age, including cardiovascular disease (CVD). In this review, we present epidemiological findings associating AMD with a variety of lipid pathway genes, cardiovascular phenotypes, and relevant environmental exposures. Despite a number of studies showing significant associations between AMD and these lipid/cardiovascular factors, results have been mixed and as such the relationships among these factors and AMD remain controversial. It is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

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“…Five-year risks of progressing to late AMD are estimated to increase approximately 100-fold depending on the actual stage of AMD, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest-intermediate AMD risk group. 2,11,12 Fluorescence lifetime imaging ophthalmoscopy (FLIO) can identify early retinal changes in degenerative retinal diseases and has been shown to provide not only information about the integrity of the RPE but of the photoreceptors as well. [13][14][15][16][17][18][19][20][21][22] FLIO measures the lifetime time span of naturally occurring retinal fluorophores on excitation with a blue laser light impulse.…”

mentioning

confidence: 99%

Fluorescence lifetimes of drusen in age‐related macular degeneration

Dysli

Fink

Wolf

et al. 2017

Acta Ophthalmologica

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PURPOSE. The purpose of this study was to characterize fundus autofluorescence lifetimes of retinal drusen in patients with AMD. METHODS.Patients with AMD and retinal drusen and healthy controls of similar age were examined. A fluorescence lifetime imaging ophthalmoscope was used. Retinal autofluorescence was excited using a 473-nm pulsed laser, and fundus autofluorescence lifetimes of the central retina (308) were measured in two distinct spectral channels (short: 498 to 560 nm [SSC]; long: 560 to 720 nm [LSC]). Mean retinal autofluorescence lifetimes, corresponding fundus autofluorescence intensity images, spectral domain optical coherence tomography, color fundus images, and clinical data were investigated. Patients were analyzed in two distinct groups (soft drusen and reticular pseudodrusen) and compared with control subjects.RESULTS. Sixty-four eyes of 64 patients with AMD and retinal drusen (age: mean 6 SD, 78 6 8.5 years; range, 59 to 94 years) were investigated and compared with a control group of 20 age-matched healthy subjects. Mean retinal autofluorescence lifetimes in patients with AMD was significantly prolonged compared with the healthy control eyes (mean 6 SEM: SSC, 486 6 18 vs. 332 6 11 ps, P < 0.0001; LSC: 493 6 9 vs. 382 6 17 ps, P < 0.0001). Areas of drusen featured a wide range of fluorescence lifetime values. Long lifetimes were identified in areas of atrophy and in areas of intraretinal hyperreflective deposits. Short lifetimes corresponded to deposits within the photoreceptor outer segment band.CONCLUSIONS. Mean retinal autofluorescence lifetimes in AMD patients are significantly prolonged. Intraretinal deposits cause prolonged lifetimes, whereas deposits in the area of the outer photoreceptor segments lead to short fluorescence lifetimes.Keywords: fluorescence lifetimes, fundus autofluorescence, retinal imaging, FLIO, age-related macular degeneration, AMD, deposits, drusen A MD is caused by age-related metabolic disorders in the retina, which leads to thickening of the Bruch membrane with calcifications, basal laminar deposits, and appearance of drusen. The predominant symptom is progressive central vision loss. The prevalence of advanced AMD is estimated to increase from 2.2% in 65-year-old patients to more than 21% in patients older than 90 years.1 Various risk factors have been identified, including age, sex, arterial hypertension, arteriosclerosis, elevated serum lipids, smoking, alcohol abuse, exposure to UV light, and various genetic factors. 2-6The hallmark of early AMD is the presence of retinal drusen, which can be classified into soft drusen of various sizes (small, medium, large), hard drusen, cuticular drusen, crystalline drusen, and reticular pseudodrusen. 4,7 In the biomicroscopic fundus examination, drusen are seen as discrete, yellow-white punctuate elevations. Retinal drusen are focal deposits of extracellular debris located between the basal lamina of the RPE and the inner collagenous layer of the Bruch membrane and are mainly concentrated within the posterior pole. The ...

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Risk factors and biomarkers of age-related macular degeneration

Cited by 276 publications

References 411 publications

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

Fluorescence lifetimes of drusen in age‐related macular degeneration

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