Doctor Research

Research Overview

Developed by Ophthalmologists from Eye Associates Medical Group in Sebastopol

Are-related Macular Degeneration (AMD) is a progressive degenerative disorder that potentially leads to blindness. The primary lesion in AMD resides in the Retinal Pigment Epithelium (RPE), and is thought to result from its high rate of molecular degradation.

RPE cells gradually accumulate sacs of molecular debris. These residual bodies (lipofuscin) are remnants of the incomplete degradation of abnormal molecules that have been damaged within the RPE cells or have derived from phagocytized rod and cone membranes.

Progressive engorgement of RPE cells with this functionless residue is associated with the extrusion of aberrant materials, which then accumulate in Bruch's membrane and aggregate in the form of Drusen and basal laminar deposits. These excretions contribute to the further deterioration of the retinal pigment epithelium (RPE). Loss of vision results from death of visual cells due to degeneration of RPE cells or to the effect of leakage of neovascular membranes, which invade the region of abnormal extracellular deposits.

Molecular renewal results from an exceedingly complex and varied network of synthetic and degradative pathways which are subject to genetic variability. Because of this variability, the antisenescent process in some individuals may be less efficient than in others.

Additional factors affecting the rate of senescence may be environmental in origin. These external factors are of particular importance because they are accessible to our intervention. For example, smoking tobacco has been identified as a risk factor for AMD.

REVIEW OF LITERATURE PRIOR TO AREDS

Although the exact cause of AMD remains unclear and the pathophysiology poorly understood, it has been hypothesized that oxidative damage is responsible for the degenerative changes. The retina is thought to be highly susceptible to oxidative stress because of its environment of a high concentration of light and oxygen and its being rich in polyunsaturated fatty acids¹. It has been theorized that light may lead to the generation of activated forms of oxygen in the outer retina and/or choroid². Reactive oxygen species such as superoxide and hydroxide free radicals may, in turn, cause lipid peroxidation of the photoreceptor outer segment membranes³. This theory has led to the hypothesis that oxygen free radicals liberated by light exposure could be inhibited from causing AMD by manipulating the levels of antioxidants in the outer retina³. The theory proposes that oral ingestion of megadoses of micronutrients and minerals would deliver increased tissue levels of substances with antioxidant capabilities at the level of the outer retina, and that by altering local levels of antioxidants, photoreceptor membrane lipid peroxidation would be prevented³. It is on this basis that dietary antioxidants have been hypothesized to play a protective role against Macular Degeneration. Epidemiological evidence exists that increasing intake of either Vitamin C, Vitamin E, or carotenoids is associated with greater plasma concentrations of antioxidant vitamins.⁴.

One group of investigators recently tested the hypothesis of increased oxidative damage in AMD by examining surgical specimens of macular choroidal neovascular membranes from donor and post-mortem eyes with Age-Related Macular Degeneration by quantitative electron microscopic immunocytochemistry⁵. They found that macular RPE cells of eyes with neovascular AMD have high levels of certain antioxidant enzymes, suggesting that oxidative stress causes pathologic upregulation of these enzymes. The much higher heme oxygenase-1 and heme oxygenase-2 antigen levels in older than younger individuals suggest that protective mechanisms against oxidation, and hence to the development of AMD, decrease with age.

Animal studies have supported the antioxidant theory of preventing Macular Degeneration. Primate studies have shown that altered levels of dietary Vitamin A or Vitamin E can lead to retinal degeneration⁶. Rats that receive dietary supplementation of Vitamin C are less vulnerable to experimentally induced retinal phototoxicity, such as loss of rhodopsin and photoreceptor nuclei compared with rats that do not receive Vitamin C supplementation⁷. Other animal models have also suggested that retinal damage can be modulated by the presence of zinc, a micronutrient which can facilitate antioxidant enzymes⁸.

The data provided through epidemiological studies also support the association between antioxidant vitamins or micronutrients with AMD.

In the National Health and Nutrition Examination Survey (NHANES), the intake of fruits and vegetables rich in Vitamin A was found to be lower in those subjects with AMD⁹.

The Baltimore Longitudinal Study on Aging, a population-based study performed at a geriatrics center in Baltimore, explored the potential connection between antioxidants and AMD in a cross-sectional study¹⁰. Participants with the highest plasma levels of various antioxidant substances such as Vitamins E and C and beta-carotene, were less likely to have any evidence of AMD when compared with participants with the lowest blood levels of the same substances. Individuals with the highest blood levels were one half as likely to have AMD when compared with those with the lowest levels. The results for Vitamin E and an antioxidant index (made up of all 3 nutrients) achieved statistical significance¹⁰.

The Eye Disease Case Control Study also evaluated the relation between antioxidants and AMD; however, this study concentrated only on patients with the neovascular form of the disease. Antioxidant status was assessed by biochemical analysis of serum levels of various antioxidants and detailed histories of dietary consumption by food frequency questionnaire. In this study, each measure of antioxidant substances had an inverse relationship between antioxidant substances and the presence of neovascular AMD. Individuals with higher serum levels of various carotenoids or with greater dietary consumption of carotenoid-containing food sources were significantly less likely to have advanced AMD. High Vitamin C consumption also was associated with a marginal reduction in disease risk. However, serum levels of Vitamins A and C and dietary intake of Vitamin E were not associated with the presence or absence of AMD¹¹.

In the Beaver Dam Eye Study, a population-based study conducted in Beaver Dam, Wisconsin, researchers evaluated the relationship between serum levels of tocopherols and carotenoids and AMD¹². They found the average levels of Vitamin E (α-tocopherol) were lower in people with exudative AMD (p=0.03), though the difference was no longer statistically significant after adjusting for serum cholesterol. Persons with levels of lycopene, the most abundant carotenoid in the serum, in the lowest quintile were twice as likely to have AMD¹². A study using the same cohort was also conducted looking at associations between antioxidant and zinc intake (assessed by food frequency questionnaire) and the 5 year incidence of early AMD in Beaver Dam. This study showed no significant inverse associations between antioxidant or zinc intake and the incidence of overall early AMD¹. Because there were too few incident late ARM cases in the cohort, no conclusions were able to be drawn whether antioxidant intake is associated with the progression of early AMD to late stage. However, another study using the same cohort showed there was a weak protective effect of zinc on the development of some forms of early AMD¹³.

French investigators in the Pathologies Oculaires Liées à L'Age (POLA) Study found that lipid-standardized plasma α-tocopherol levels showed a significant negative association with late AMD¹⁴. In fact, they found the risk of late AMD was reduced by 82% in the highest quintile of α-tocopherol-lipid compared with the lowest. [OR-0.5, p=0.07 for highest quintile α-tocopherol to lowest.] They defined late AMD as the presence of neovascular AMD or geographic atrophy within a grid representing 3000um from the foveola on fundus photographs.

LITERATURE REFERENCES PRIOR TO AREDS

VandenLangenberg GM., Mares-Perlman JA., Klein R., Klein BE., et at.: Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epi 1998; 148:204-214.
Young RW.: Solar radiation and age-related macular degeneration. Surv Ophthalmol 1988; 32:252-69.
Bressler NM., Bressler SB.: Preventative ophthalmology. Ophthalmology 1995; 102:1206-11.
Jacques PF., Halpner AD., Blumberg JB.: Influence of combined antioxidant nutrient intakes on their plasma concentrations in an elderly population. Am J Clin Nutr 1995; 62:1228-33.
Frank RN., Amin RH., Puklin JE.: Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. Am J. Ophth 1999; 127:694-709.
Hayes KC.: Retinal degeneration in monkeys induced by deficiencies of Vitamin E or A. Inv Ophthalmol 1974; 13:499-510.
Organisciak Dt., Wang H., Li Z-Y, Tso M.: The protective effect of ascorbate in retinal light damage of rats. Invest Ophthalmol Vis Sci 1985; 26:1580-88.
Leure-du Pree AE., McCain CJ.: Effects of severe zinc deficiency on the morphology of the rat pigment epithelium. Invest Ophth Vis Sci 1982; 23:425-34.
Goldberg J., Flowerdew G., Smith E.: Factors associated with age-related macular degeneration: an analysis of data from the first National Health and Nutrition Examination Survey. Am J Epidemiol 1988; 128:700-10.
West S., Vitale S., Hallfrisch J., Munoz B., Muller D., Bressler S., Bressler N.: Are antioxidants or supplements protective for Age-Related Macular Degeneration?Arch Ophthalmol 1994; 112:222-227.
Seddon JM., Ajani UA., Sperduto RD.: Dietary carotenoids, Vitamins A, C, and E, and advanced Age-Related Macular Degeneration. JAMA 1994; 272:1413-1420.
Mares-Perlman JA., Brady WE., Klein R., Klein BE., et at.: Serum antioxidant and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol 1995; 113:1518-23.
Mares-Perlman JA., Klein R., Klein BE. et al.: Association of zinc and antioxidant nutrients with age-related maculopathy. Arch Ophthalmol 1996; 114:991-997.
Delcourt C., Cristol JP., Tessier .F, et al.: Age-Related Macular Degeneration and antioxidant status in the POLA Study. Arch Ophthalmol 1999; 117:1384-90.
Bird AC., Bressler NM., Bressler SB.: An international classification and grading system for age-related maculopathy and Age-Related Macular Degeneration. Survey of Ophthalmology 1995; 39:367-374.
Bressler NM., Bressler SB., West SK., Fine SL., Taylor HR.: The grading and prevalence of macular degeneration in Chesapeake Bay Watermen. Arch Ophthalmol 1989; 107:847-852.
Christen WG., Ajani UA., Glynn RJ., et al.: Prospective cohort study of antioxidant vitamin supplement use and the risk of age-related maculopathy. Am J Epi 1999; 149;476-484.
Christen WG.: Antioxidant vitamins and age-related eye disease. Proc Assoc Amer Phys 1999; 111:16-21.
Goodman DS.: Vitamin A and retinoids in health and disease. N Engl J Med 1984; 310:1023-31.
Jacques PF.: The potential preventive effects of Vitamins for cataract and Age-Related Macular Degeration. Int J Vitam Nutr Res 1999; 69(3):198-205.