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Nutritional Interventions against Age-Related Macular Degeneration

         (Bernstein 2009) Download

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed world. This disease of the elderly robs them of central vision in one or both eyes leading to a devastating loss of the ability to drive, read, and recognize faces. In recent years, a number of novel treatments for the neovascular form of AMD (also known as "wet" or exudative AMD) have been introduced, and for the first time, the relentless downhill course of vision loss experienced by the majority of patients with this particularly malignant variant of AMD has been transformed to the stabilization and even improvement of vision in at least two-thirds of patients. Likewise, the slower, more insidious form of AMD known as dry AMD which leads to geographic atrophy of the macula has become the focus of pharmaceutical firms' efforts for intervention. Unfortunately, all of these novel treatments have limitations, and they tend to be very expensive. Thus, prevention of AMD is of paramount importance to reduce the healthcare burden of this blinding disorder. Accumulating evidence suggests that encouragement of increased consumption of fruits and vegetables rich in the xanthophyll carotenoids lutein and zeaxanthin is a simple, cost effective public health intervention that might help to decrease the incidence of AMD. In this review article, the scientific underpinnings for these nutritional recommendations will be surveyed.

Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD)

            (Bhutto, Baba et al. 2010) Download

Nitric oxide (NO) production by vascular endothelium is important in regulation of blood flow. Reduced production of NO can adversely affect blood flow and other vascular functions. We investigated the expression of three nitric oxide synthase (NOS) isoforms in retina and choroid of aged human eyes and eyes with AMD. Alkaline phosphatase immunohistochemistry was performed using antibodies against inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NOSs on cryopreserved sections from aged control donor eyes (n = 13) and eyes with AMD (n = 22). CD34 antibody was used as an endothelial cell (EC) marker. Three independent masked observers scored the intensity of the immunohistochemical reaction product. Mean scores from the aged control and AMD eyes were statistically compared. In aged control retinas, nNOS was in ganglion cells (RGCs) and neurons of both nuclear layers. In choroid, perivascular nerve fibers and retinal pigment epithelial (RPE) cells were nNOS+. eNOS and iNOS were confined to the retinal and choroidal vascular ECs. Some cells presumably melanocytes or dendritic cells in choroid were also eNOS+. In AMD eyes, nNOS was significantly lower in RGCs, neurons, retinal vessels and RPE (p < or = 0.05) compared to the aged control eyes. iNOS and eNOS showed no significant differences between aged control and AMD eyes except that there was significantly less eNOS in choroidal arteries (p = 0.006) and choroidal cells (p = 0.03) of AMD eyes. Although NO was not measured directly, these findings suggest that there is less NO produced in AMD eyes. The decrease in retinal nNOS in AMD eyes is probably related to neuronal degeneration. The decrease in nNOS and eNOS in AMD choroid could be associated with vasoconstriction and hemodynamic changes.

Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis

            (Chong, Wong et al. 2007) Download

OBJECTIVE: To evaluate the effectiveness of dietary antioxidants in the primary prevention of age related macular degeneration (AMD). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Search of seven databases without limits on year or language of publication, and retrieval of references in pertinent reviews and articles. METHODS: Two reviewers independently searched the databases and selected the studies, using standardised criteria. Randomised clinical trials and prospective cohort studies were included. Of the 4192 abstracts initially identified, 12 studies (nine prospective cohort studies and three randomised clinical trials) met the selection criteria and were included. Data extraction and study quality evaluation were independently reviewed, using standardised criteria. Results were pooled quantitatively using meta-analytic methods. RESULTS: The nine prospective cohort studies included 149 203 people, with 1878 incident cases of early AMD. The antioxidants investigated differed across studies, and not all studies contributed to the meta-analysis of each antioxidant. Pooled results from prospective cohort studies indicated that vitamin A, vitamin C, vitamin E, zinc, lutein, zeaxanthin, alpha carotene, beta carotene, beta cryptoxanthin, and lycopene have little or no effect in the primary prevention of early AMD. The three randomised clinical trials did not show that antioxidant supplements prevented early AMD. CONCLUSIONS: There is insufficient evidence to support the role of dietary antioxidants, including the use of dietary antioxidant supplements, for the primary prevention of early AMD.


Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis

            (Chong, Kreis et al. 2008) Download

OBJECTIVE: To systematically review the evidence on dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration (AMD). METHODS: Seven databases were systematically searched with no limits on publication year or language using standardized criteria. Randomized controlled trials and prospective cohort, case-control, and cross-sectional studies were included. Of 2754 abstracts identified, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies met the criteria. Measures of associations were pooled quantitatively using meta-analytic methods. RESULTS: Nine studies provided data on a total sample of 88 974 people, including 3203 AMD cases. A high dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk of late AMD (pooled odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.82). Fish intake at least twice a week was associated with a reduced risk of both early AMD (pooled OR, 0.76; 95% CI, 0.64-0.90) and late AMD (pooled OR, 0.67; 95% CI, 0.53-0.85). CONCLUSIONS: Although this meta-analysis suggests that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk of AMD, there is insufficient evidence from the current literature, with few prospective studies and no randomized clinical trials, to support their routine consumption for AMD prevention.

Red meat and chicken consumption and its association with age-related macular degeneration

            (Chong, Simpson et al. 2009) Download

Age-related macular degeneration (AMD) is the leading cause of blindness among older people, and diet has been postulated to alter risk of AMD. To evaluate associations between red meat and chicken intake and AMD, the authors conducted a cohort study of 6,734 persons aged 58-69 years in 1990-1994 in Melbourne, Australia. Meat intake was estimated from a food frequency questionnaire at baseline. At follow-up (2003-2006), bilateral digital macular photographs were taken and evaluated for AMD (1,680 cases of early AMD, 77 cases of late AMD). Logistic regression was used to estimate odds ratios, adjusted for age, smoking, and other potential confounders. Higher red meat intake was positively associated with early AMD; the odds ratio for consumption of red meat > or =10 times/week versus <5 times/week was 1.47 (95% confidence interval: 1.21, 1.79; P-trend < 0.001). Similar trends toward increasing prevalence of early AMD were seen with higher intakes of fresh and processed red meat. Conversely, consumption of chicken > or =3.5 times/week versus <1.5 times/week was inversely associated with late AMD (odds ratio = 0.43, 95% confidence interval: 0.20, 0.91; P-trend = 0.007). These results suggest that different meats may differently affect AMD risk and may be a target for lifestyle modification.

Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model

            (Ding, Lin et al. 2008) Download

Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD) including extracellular deposits containing amyloid-beta (Abeta) peptides. Immunotherapy targeting the Abeta protein has been investigated as a potential treatment for AD. Here, we present the rationale for extending this approach to treat AMD. We tested an anti-Abeta antibody administered systemically in a mouse model of AMD. Histological and functional measurements in treated animals compared to controls showed that following immunotherapy, the amounts of Abeta in the retina and brain were decreased and the ERG deficits in the retina were attenuated. These data support the hypothesis that Abeta is a therapeutic target for AMD.

Molecular pathology of age-related macular degeneration

            (Ding, Patel et al. 2009) Download

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the world. Although the etiology and pathogenesis of AMD remain largely unclear, a complex interaction of genetic and environmental factors is thought to exist. AMD pathology is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium, and Bruch's membrane, as well as, in some cases, alterations in choroidal capillaries. Recent research on the genetic and molecular underpinnings of AMD brings to light several basic molecular pathways and pathophysiological processes that might mediate AMD risk, progression, and/or response to therapy. This review summarizes, in detail, the molecular pathological findings in both humans and animal models, including genetic variations in CFH, CX3CR1, and ARMS2/HtrA1, as well as the role of numerous molecules implicated in inflammation, apoptosis, cholesterol trafficking, angiogenesis, and oxidative stress.


Inverse association of female hormone replacement therapy with age-related macular degeneration and interactions with ARMS2 polymorphisms

            (Edwards, Gallins et al. 2010) Download

Purpose. To investigate whether female reproductive history and hormone replacement therapy (HRT) or birth control pills (BCPs) influence risk for age-related macular degeneration (AMD) and whether genetic factors interact with HRT to modulate AMD risk. Methods. Related and unrelated female participants (n = 799) were examined and data were analyzed with generalized estimating equations with adjustment for age and smoking. Individuals with AMD grades 1 to 2 were considered to be unaffected (n = 239) and those with grades 3 to 5 were considered affected (n = 560). Results. When comparing all cases with controls, significant inverse associations were observed for HRT (odds ratio [OR] = 0.65, 95% CI 0.48-0.90, P = 0.008) and BCPs (OR = 0.60, 95% CI 0.36-0.10, P = 0.048). When analyses were stratified by AMD severity (early versus geographic atrophy versus neovascular), the inverse association remained significant (HRT OR = 0.45, 95% CI 0.30-0.66, P < 0.0001; BCP OR = 0.55, 95% CI 0.32-0.96, P = 0.036) only when comparing neovascular AMD with the control. All pair-wise HRT-genotype and BCP-genotype interactions were examined, to determine whether HRT or BCP modifies the effect of established genetic risk factors. The strongest interactions were observed for HRT x ARMS2 coding SNP (R73H) rs10490923 (P = 0.007) and HRT x ARMS2 intronic SNP rs17623531 (P = 0.019). Conclusions. These findings provide the first evidence suggesting that ARMS2 interacts with HRT to modulate AMD risk and are consistent with previous reports demonstrating a protective relationship between exogenous estrogen use and neovascular AMD. These results highlight the genetic and environmental complexity of the etiologic architecture of AMD; however, further replication is necessary to validate them.

Menopausal and reproductive factors and risk of age-related macular degeneration

            (Feskanich, Cho et al. 2008) Download

OBJECTIVE: To investigate whether estrogen exposures are associated with lower risks of age-related macular degeneration (AMD). METHODS: Postmenopausal hormone (PMH) use, past use of oral contraceptives (OCs), ages at menarche and menopause, and parity were assessed among 74,996 postmenopausal women. Over 22 years, cases of early (n = 554) and neovascular (n = 334) AMD with a visual acuity of 20/30 or worse were identified. Cox models were used to calculate the relative risk for each exposure, adjusted for smoking and other factors. RESULTS: Current PMH users had a notable 48% lower risk of neovascular AMD compared with those who had never used PMH, although risk did not decline linearly with longer durations of use. Risk was lowest for PMH users who had used OCs in the past (P value for interaction, .03). In contrast, risk of early AMD was a notable 34% higher among current PMH users and OC use was unassociated with risk. The only remarkable finding for the endogenous estrogenic factors was a 26% lower risk of early AMD for parous women. CONCLUSIONS: Although PMH and OC use were associated with a lower risk of neovascular AMD, no benefit was observed for early AMD. Factors influencing lifetime exposure to estrogens were not consistently associated with the disease.

Age-related macular degeneration: the molecular link between oxidative damage, tissue-specific inflammation and outer retinal disease: the Proctor lecture

            (Hollyfield 2010) Download

The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration

            (Johnson, Leitner et al. 2002) Download

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and/or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Similar observations in Alzheimer's disease (AD) have lead to the hypothesis that chronic localized inflammation is an important element of AD pathogenesis, with significant neurodegenerative consequences. Accordingly, the amyloid beta (A beta) peptide, a major constituent of neuritic plaques in AD, has been implicated as a primary activator of complement in AD. Here we show that A beta is associated with a substructural vesicular component within drusen. A beta colocalizes with activated complement components in these "amyloid vesicles," thereby identifying them as potential primary sites of complement activation. Thus, A beta deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD.


CKD increases the risk of age-related macular degeneration

         (Liew, Mitchell et al. 2008) Download

Age-related macular degeneration is the leading cause of irreversible blindness in the United States and often coexists with chronic kidney disease. Both conditions share common genetic and environmental risk factors. A total of 1183 participants aged 54+ were examined in the population-based, prospective cohort Blue Mountains Eye Study (Australia) to determine if chronic kidney disease increases the risk of age-related macular degeneration. Moderate chronic kidney disease (estimated glomerular filtration rate < 60 ml/min per 1.73 m(2) based on the Cockcroft-Gault equation) was present in 24% of the population (286 of 1183). The 5-yr incidence of early age-related macular degeneration was 3.9% in participants with no/mild chronic kidney disease (35 of 897) and 17.5% in those with moderate chronic kidney disease (50 of 286). After adjusting for age, sex, cigarette smoking, hypertension, complement factor H polymorphism, and other risk factors, persons with moderate chronic kidney disease were 3 times more likely to develop early age-related macular degeneration than persons with no/mild chronic kidney disease (odds ratio = 3.2; 95% confidence interval, 1.8 to 5.7, P < 0.0001). Each SD (14.8 ml/min per 1.73 m(2)) decrease in Cockcroft-Gault estimated glomerular filtration rate was associated with a doubling of the adjusted risk for early age-related macular degeneration (odds ratio = 2.0; 95% confidence interval, 1.5 to 2.8, P < 0.0001). In conclusion, persons with chronic kidney disease have a higher risk of early age-related macular degeneration, suggesting the possibility of shared pathophysiologic mechanisms between the two conditions.

Plasma protein pentosidine and carboxymethyllysine, biomarkers for age-related macular degeneration

            (Ni, Yuan et al. 2009) Download

Age-related macular degeneration (AMD) causes severe vision loss in the elderly; early identification of AMD risk could help slow or prevent disease progression. Toward the discovery of AMD biomarkers, we quantified plasma protein N(epsilon)-carboxymethyllysine (CML) and pentosidine from 58 AMD and 32 control donors. CML and pentosidine are advanced glycation end products that are abundant in Bruch membrane, the extracellular matrix separating the retinal pigment epithelium from the blood-bearing choriocapillaris. We measured CML and pentosidine by LC-MS/MS and LC-fluorometry, respectively, and found higher mean levels of CML (approximately 54%) and pentosidine (approximately 64%) in AMD (p < 0.0001) relative to normal controls. Plasma protein fructosyl-lysine, a marker of early glycation, was found by amino acid analysis to be in equal amounts in control and non-diabetic AMD donors, supporting an association between AMD and increased levels of CML and pentosidine independent of other diseases like diabetes. Carboxyethylpyrrole (CEP), an oxidative modification from docosahexaenoate-containing lipids and also abundant in AMD Bruch membrane, was elevated approximately 86% in the AMD cohort, but autoantibody titers to CEP, CML, and pentosidine were not significantly increased. Compellingly higher mean levels of CML and pentosidine were present in AMD plasma protein over a broad age range. Receiver operating curves indicate that CML, CEP adducts, and pentosidine alone discriminated between AMD and control subjects with 78, 79, and 88% accuracy, respectively, whereas CML in combination with pentosidine provided approximately 89% accuracy, and CEP plus pentosidine provided approximately 92% accuracy. Pentosidine levels appeared slightly altered in AMD patients with hypertension and cardiovascular disease, indicating further studies are warranted. Overall this study supports the potential utility of plasma protein CML and pentosidine as biomarkers for assessing AMD risk and susceptibility, particularly in combination with CEP adducts and with concurrent analyses of fructosyl-lysine to detect confounding factors.

Circulating anti-retinal antibodies as immune markers in age-related macular degeneration

            (Patel, Ohbayashi et al. 2005) Download

Age-related macular maculopathy (ARM) and age-related macular degeneration (AMD) are the leading causes of blindness in the Western world. Despite the magnitude of this clinical problem, very little is known about the pathogenesis of the disease. In this study, we analysed the sera (using indirect immunohistochemistry and Western blot analysis) from a very large cohort of such patients and normal age-matched controls to detect circulating anti-retinal antibodies. Patients with bilateral drusen (n = 64) and with chorioretinal neovascularization (CNV) (n = 51) were recruited in addition to age-matched control subjects (n = 39). The sera were analysed for anti-retinal immunoglobulins on retinal sections. The data were then correlated with the clinical features graded according to the International Classification and Grading System of ARM and AMD. The sera of patients with drusen (93.75%) and CNV (82.27%) were found to have a significantly (P = 0.02) higher titre of autoantibodies to the retina in comparison with controls (8.69%), indicating significant evidence of involvement of the immune process in early stages of AMD. Subsequent statistical analysis of the drusen group showed significant progressive staining (P = 0.0009) in the nuclei layers from early to late stages of ARM. Western blotting confirmed the presence of anti-retinal immunoglobulins to retinal antigens. As anti-retinal immunoglobulins are present in patients with bilateral drusen and exudative AMD, these antibodies could play a significant role in the pathogenesis of AMD. Whilst we do not have evidence that these antibodies precede disease onset, the possibility that their presence might contribute to disease progression needs to be investigated. Finally, the eventual identification of the target antigens detected by these antibodies may permit the future development of new diagnostic methods for ARM and AMD.

Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients

            (Rosen, Hu et al. 2009) Download

PURPOSE: Melatonin is a potent antioxidant and free radical scavenger. It has been reported that serum melatonin level is relevant to certain aging diseases. The purpose of this study was to investigate melatonin levels in age-related macular degeneration (AMD) patients by measurement of 6-sulfatoxymelatonin levels (aMT6s), the major metabolite of melatonin in urine, and compare it with a group of age- and gender-matched controls. METHODS: The first urine of the morning was collected from 43 AMD patients and 12 controls who did not have AMD. The level of aMT6s in specimens was measured by a commercial 6-sulfatoxymelatonin ELISA kit. The assay was performed by researchers, who were masked to the clinical information. To adjust for variation in the diluteness of urine, urinary creatinine level was measured and aMT6s levels were expressed as aMT6s/creatinine. RESULTS: The level of urinary aMT6s/creatinine (mean+/-SD) in AMD (6.24+/-3.45 ng aMT6s/mg creatinine) was significantly lower than that of the controls (10.40+/-4.51, p=0.0128). After adjustment for various factors (age, smoking, cancer, and coronary heart disease) that may influence the aMT6s level, the odds-ratio of urinary aMT6s comparing AMD patients to controls was 0.65 (95% confidence interval=0.48-0.88, p=0.0036), indicating that urinary aMT6s level in AMD patients was lower than in controls even after multivariate adjustment. CONCLUSIONS: Urinary aMT6s level in AMD patients was 40% lower than in age- and gender-matched controls. This difference between AMD patients and controls is present after adjustment for the factors of age, smoking, and histories of cancer and coronary heart disease. The significance of this result and the role of melatonin in the occurrence of AMD require further investigation.

Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization

            (Salminen, Kauppinen et al. 2010) Download

Age-related macular degeneration (AMD) can be classified into two main categories: the atrophic, dry form and the exudative, wet form. The crucial difference between dry and wet AMD is the development of choroidal neovascularization in wet AMD. One fundamental cause of the neovascularization is the increased expression of VEGF (vascular endothelial growth factor) in retinal pigment epithelial cells. Progression of AMD is linked to augmentation of cellular stress, for example, oxidative stress, proteotoxic stress, inflammation and hypoxia. All these conditions can trigger stress in endoplasmic reticulum (ER), which maintains protein quality control in cells. ER stress induces the unfolded protein response (UPR) via IRE1 (inositol-requiring protein-1), PERK (protein kinase RNA-like ER kinase) and ATF6 (activating transcription factor-6) transducers. UPR signaling is a double-edged sword, that is, it can restore cellular homeostasis as far as possible, but ultimately may lead to chronic, overwhelming stress that can cause apoptotic cell death. Interestingly, ER stress is a well-known inducer of angiogenesis in cancer. Moreover, stress conditions associated with the progress of AMD can induce the expression of VEGF. We discuss the role of ER stress in the regulation of neovascularization and the conversion of dry AMD to its wet, detrimental counterpart.

A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration

            (Tuo, Ross et al. 2009) Download

Age-related macular degeneration (AMD) is one of the leading cause of blindness among the elderly; however, current therapy options are limited. Epidemiological studies have shown that a diet that is high in omega-3 polyunsaturated (n-3) fatty acids can slow disease progression in patients with advanced AMD. In this study, we evaluated the effect of such a diet on the retinas of Ccl2(-/-)/Cx3cr1(-/-) mice, a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and A2E accumulation. Ccl2(-/-)/Cx3cr1(-/-) mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice that were given high levels of n-3 fatty acids had lesion reversion. We found a shunted arachidonic acid metabolism that resulted in decreased pro-inflammatory derivatives (prostaglandin E(2) and leukotriene B(4)) and an increased anti-inflammatory derivative (prostaglandin D(2)). We also measured lower ocular TNF-alpha and IL-6 transcript levels in the mice fed a diet of high n-3 fatty acids. Our findings in these mice are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. This murine model provides a useful tool to evaluate therapies that might delay the development of AMD.

The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment

            (Wang, Wang et al. 2011) Download

Although age-related macular degeneration (AMD) is not a classic inflammatory disease like uveitis, inflammation has been found to have an important role in disease pathogenesis and progression. Innate immunity and autoimmune components, such as complement factors, chemokines, cytokines, macrophages, and ocular microglia, are believed to be heavily involved in AMD development. Targeting these specific inflammatory molecules has recently been explored in an attempt to better understand and treat AMD. Although antivascular endothelial growth factor therapy is the first line of defence against neovascular AMD, anti-inflammatory agents such as corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents (eg, methotrexate and rapamycin), and biologics (eg, infliximab, daclizumab, and complement inhibitors) may provide an adjunct or alternative mechanism to suppress the inflammatory processes driving AMD progression. Further investigation is required to evaluate the long-term safety and efficacy of these drugs for both neovascular and non-neovascular AMD.


References

Bernstein, P. S. (2009). "Nutritional Interventions against Age-Related Macular Degeneration." Acta Hortic 841: 103-112.

Bhutto, I. A., T. Baba, et al. (2010). "Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD)." Exp Eye Res 90(1): 155-67.

Chong, E. W., A. J. Kreis, et al. (2008). "Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis." Arch Ophthalmol 126(6): 826-33.

Chong, E. W., J. A. Simpson, et al. (2009). "Red meat and chicken consumption and its association with age-related macular degeneration." Am J Epidemiol 169(7): 867-76.

Chong, E. W., T. Y. Wong, et al. (2007). "Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis." Bmj.

Ding, J. D., J. Lin, et al. (2008). "Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model." Vision Res 48(3): 339-45.

Ding, X., M. Patel, et al. (2009). "Molecular pathology of age-related macular degeneration." Prog Retin Eye Res 28(1): 1-18.

Edwards, D. R., P. Gallins, et al. (2010). "Inverse association of female hormone replacement therapy with age-related macular degeneration and interactions with ARMS2 polymorphisms." Invest Ophthalmol Vis Sci 51(4): 1873-9.

Feskanich, D., E. Cho, et al. (2008). "Menopausal and reproductive factors and risk of age-related macular degeneration." Arch Ophthalmol 126(4): 519-24.

Hollyfield, J. G. (2010). "Age-related macular degeneration: the molecular link between oxidative damage, tissue-specific inflammation and outer retinal disease: the Proctor lecture." Invest Ophthalmol Vis Sci 51(3): 1275-81.

Johnson, L. V., W. P. Leitner, et al. (2002). "The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration." Proc Natl Acad Sci U S A 99(18): 11830-5.

Liew, G., P. Mitchell, et al. (2008). "CKD increases the risk of age-related macular degeneration." J Am Soc Nephrol 19(4): 806-11.

Ni, J., X. Yuan, et al. (2009). "Plasma protein pentosidine and carboxymethyllysine, biomarkers for age-related macular degeneration." Mol Cell Proteomics 8(8): 1921-33.

Patel, N., M. Ohbayashi, et al. (2005). "Circulating anti-retinal antibodies as immune markers in age-related macular degeneration." Immunology 115(3): 422-30.

Rosen, R., D. N. Hu, et al. (2009). "Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients." Mol Vis 15: 1673-9.

Salminen, A., A. Kauppinen, et al. (2010). "Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization." Mol Med 16(11-12): 535-42.

Tuo, J., R. J. Ross, et al. (2009). "A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration." Am J Pathol 175(2): 799-807.

Wang, Y., V. M. Wang, et al. (2011). "The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment." Eye (Lond) 25(2): 127-39.