reduction in incident neovascular AMD with increased consumption of lutein and zeaxanthin. These participants were also less likely to smoke and consumed more omega-3 fatty acids [35]. In 2006, the Carotenoids in Age-Related Macular Degeneration Study (CAREDS) concluded that luteinand zeaxanthin-rich diets may protect against intermediate AMD in female patients less than 75 years of age [36]. A large populationbased study, the Pathologies Oculaires Liees – a l’Age (POLA) study – was also strongly suggestive of a protective role of the xanthophylls, particularly zeaxanthin, among patients with the highest dietary intake for protection against AMD and cataract [37]. The Eye Disease Case Control Study also showed a 43% lower risk for AMD among patients with the highest quintile of carotenoid intake compared with those in the lowest quintile [38].

The Food and Drug Administration conducted a review of the literature in 2006 regarding lutein/ zeaxanthin supplementation, which concluded that the current data is not yet strong enough to support treatment recommendations with lutein

and zeaxanthin [39]. This view was also espoused by the most recent Cochrane Review on supplementation for slowing the progression of macular degeneration [4].

Given the large body of data suggesting a possible protective effect of lutein and zeaxanthin on macular degeneration and the need for further clarification regarding a potential therapeutic role for these xanthophylls in the treatment of AMD, the Age Related Eye Disease Study 2 (AREDS2) includes two randomization arms with lutein and zeaxanthin supplementation. One arm of the randomization includes lutein 10 mg and zeaxanthin 2 mg only, while the second arm also includes the omega-3 fatty acids (docosohexanoeic acid [350 mg] and eicosapentanoic acid [650 mg]) (Fig. 5.1, Table 5.1) [25].

Fatty Acids

The long-chain polyunsaturated fatty acids (LCPUFAs) and docosahexaenoic acid (DHA) are present in high concentrations in the outer

segments of photoreceptors. DHA, synthesized from the dietary precursors, alpha-linoleic acid (ALA), and eicosapentaenoic acid (EPA), is an important structural component of retinal membranes and is constantly shed throughout the visual cycle [40]. Dietary LCPUFAs are primarily derived from oily fish (tuna, sardines, salmon, mackerel, herring, and trout) [40] and ALA is primarily derived from plant-based foods (flaxseed, flaxseed oil, walnuts, walnut oil, soybeans, soybean oil, pumpkin seeds, rapeseed (canola) oil, and olive oil).

Evidence is growing regarding the potential mechanisms by which LCPUFAs may be involved in the pathogenesis of AMD, as several LCPUFA– derived mediators are implicated in immunomodulation and inflammatory responses [41–46]. Ocular inflammation results in the cleavage of membrane-bound LCPUFAs and the production of multiple paracrine and autocrine mediators of retinal inflammation, neovascularization, and cell survival [42, 43, 47, 48], all of which play a role in the pathogenesis of AMD.

A number of studies have shown an inverse relationship between rates of AMD and intake of omega-3 LCPUFAs. The dietary ancillary study of the Eye Disease Case Control Study (EDCCS) showed a reduced risk of neovascular AMD with increased dietary intake of omega-3 LCPUFAs and fish (OR 0.6 for both when comparing highest with lowest quintiles) [38]. A cross-sectional population-based study in a European population showed a 53% reduced risk of neovascular macular degeneration in participants who ate fish more than once per week [49]. The results of a metaanalysis showed that fish intake of twice or more per week compared with intake less that once per month was associated with a 37% reduction in

risk of early AMD. A protective effect was also demonstrated against late AMD [50]. A secondary analysis of the United States twin study also showed that fish consumption and omega-3 fatty acid intake reduce the risk of AMD [51]. Supplementation has been demonstrated to increase serum concentration of EPA, though the clinical significance of this is not yet known [52].

Higher intakes of DHA and EPA were associated with a lower risk of progression to advanced AMD in the AREDS population, independent of AREDS supplementation [53]. Participants with the highest intake of omega-3 long-chain polyunsaturated fatty acids were approximately half as likely to have neovascular AMD at baseline (for DHA + EPA, OR: 0.65, 95% CI 0.50–0.85) [54]. They were also less likely to progress over a six-year period from bilateral drusen to central geographic atrophy than participants with the lowest intake of these LCPUFAs (OR: 0.65, 95% CI 0.45–0.92) [54, 55]. In a nested cohort study of AREDS, patients with moderate to high risk of advanced AMD and the highest consumption of omega-3 fatty acids demonstrated a 30% reduction in incident advanced AMD [48].

In the Blue Mountain Eye Study, a reduction in 10-year incident early AMD was shown with dietary intake of one serving of fish per week or greater [34]. Another large Australian cohort study also showed that higher omega-3 fatty acid intake was inversely associated with early AMD when the highest and lowest quartiles were compared [56]. Conversely, the third National Health and Nutrition Examination Survey did not show a statistically significant association between fish intake and prevalence of AMD [57]. In their metaanalysis of omega-3 fatty acid consumption

and risk of AMD, Chong et al. concluded that consumption of omega-3 fatty acids may be associated with a lower risk of AMD but overall, evidence was insufficient to recommend supplementation for primary prevention in the general population [50].

There is a growing body of clinical and scientific evidence that supports a role for omega-3 fatty acids in the pathogenesis and progression of AMD. As this evidence accumulates, the need for a large multi-center randomized controlled trial is apparent. The AREDS2 will address the effect of DHA + EPA supplementation (1 g/day) on the secondary prevention of AMD [25].

Vitamin E

Vitamin E is present in the retina in the form of alpha-tocopherol [58]. It is a potent antioxidant and free-radical scavenger that has been investigated as a potential disease modifying agent in AMD. Dietary sources of Vitamin E include whole grains, fortified cereals, and nuts [59].

Vitamin E intervention in the Vitamin E Cataract and Age-Related Maculopathy (VECAT) Study showed no effect of Vitamin E supplementation on the incidence of early or late AMD, although a slight reduction in hypopigmentation was shown in patients with early AMD [60]. Other data regarding intake of Vitamin E and risk of AMD have been mixed. High dietary intake of Vitamin E was shown to reduce risk of incident AMD in Physician’s Health Study, though this finding was not statistically significant. (RR 0.87) [61]. In contrast, participants in the highest tertiles of Vitamin E intake in the Blue Mountain Eye Study had a higher risk of late AMD than those in the lowest tertile of consumption, though this trend was also not significant [18]. Vitamin E was not shown to have any effect on the incidence of AMD in the Eye Disease Case Control Study [38]. The AREDS formulation contained 400 IU of Vitamin E and when used in combination with Vitamins C, zinc, and beta-carotene, was shown to reduce the risk of advanced AMD in participants at intermediate risk of progression [13]. In the Rotterdam Study, a reduced risk of incident

AMD was shown with increased dietary intake of Vitamin E [19].

A large meta-analysis of trials examining the impact of Vitamin E on mortality showed a minimally increased risk of mortality with Vitamin E supplementation both when used alone or in combination with beta-carotene and Vitamin A (RR 1.04) [62]. AREDS mortality analyses did not show any increased risk of death with AREDS supplementation [11].

Vitamin C

Vitamin C is a water-soluble glucose-derived molecule, which plays an important role in collagen, catecholamine, and neurohormone synthesis. Additionally, it serves as an antioxidant by scavenging free radicals and detoxifying them in the retina and other neural tissue [63]. Vitamin C plays an important role in immune function, iron absorption, and vitamin E regeneration [64]. Dietary consumption is required since it is not produced endogenously. It is found primarily in citrus fruits, tomatoes, potatoes, red and green peppers, broccoli, kiwi, and strawberries [19, 64].

Vitamin C is found in rod outer segments and Muller cells and protects Vitamin E (alphatocopherol), which is an important retinal membrane component, from UV irradiation-induced oxidation [65]. Vitamin C also allows Vitamin E regeneration, thus improving its anti-oxidant effects on the retina [66].

One prominent study did not demonstrate a significant association between above and belowmedian intake of Vitamin C and incident AMD [18]. However, another study has shown that an above-median intake of vitamin C, when combined with vitamin E, beta-carotene, and zinc, was associated with a 35% reduced risk of incident AMD when compared with below-median intake of at least one of these nutrients [19]. Overall, data regarding a potential therapeutic role for Vitamin C

oxidative status.

Pearl

Rotterdam [34]

•Population-based prospective cohort study

•Designed to assess frequency and determinants of common diseases

•A validated food frequency questionnaire (FFQ) was used to assess the intake of a number of common nutrients

•Results:

A lower risk of incident AMD was shown among patients with energyadjusted above-median dietary consumption of vitamin A, C, E, zinc, and beta-carotene when compared with patients with below-median consumption [34].

Zinc

Zinc is primarily stored in muscle, bone, skin, hair, and liver of adults [67], and is primarily found in oysters, red meat, poultry, beans, nuts, whole grains, crab, lobster, and dairy products. Grain and plant bioavailability is less than that from animal sources [68]. Zinc and other metals (such as copper) play an important role in the visual cycle and photoreceptor survival [69] and is found primarily in pigment-rich ocular structures (retina, choroid, retinal pigment epithelium (RPE)). As a cofactor and major constituent of several important enzymes (carbonic anhydrase, alcohol dehydrogenase, Cu, Zn-superoxide dismutase), zinc plays an active role in rhodopsin synthesis (through interactions with Vitamin A), protein stabilization, modification of photoreceptor plasma membranes, modulation of synaptic transmission, and protection against cellular stresssignaling pathways [67, 69, 70]. In the RPE, zinc helps to induce metallothionein synthesis, which may help in the removal of hydroxyl radicals [67]. Animal studies have demonstrated a connection between zinc deficiency and anencephaly, anophthalmia, microphthalmia, and impaired immune

function [70–72]. In humans, zinc deficiency has been linked to night-blindness, AMD, impaired dark adaption, and other pigmentary retinopathies [67, 70, 73–75]. Furthermore, zinc levels in the neural retina and choroid have been shown to vary with age [69]. In male patients, zinc has been shown to decline with age in the neural retina and increases with age in the choroid. No agerelated change has been demonstrated in the RPE [69, 75]. Primates with early onset macular degeneration were found to have decreased levels of zinc [76]; however, studies regarding the role of zinc in AMD in humans have been conflicting.

A positive treatment effect from oral zinc supplementation has been speculated for some time [77]. A study by Newsome et al. in 2008 showed that oral supplementation with zinc-monocysteine (25 mg twice daily) improved macular function (visual acuity, contrast sensitivity) in patients with dry AMD over placebo [78]. The AREDS study showed an odds reduction for the development of advanced AMD as well as for the progression of intermediate AMD to advanced AMD [13]. Confirmed by the Blue Mountains Eye Study, patients with >15.8 mg/day of zinc supplementation (the highest tertile of intake) were 46% less likely to develop early AMD and 44% less likely to develop any AMD [18]. The Beaver Dam Eye Study showed an inverse association between zinc intake and the incidence of pigmentary abnormalities, but demonstrated no significant inverse associations between zinc intake and incidence of early AMD [79]. In patients with the exudative form of AMD in one eye, oral zinc substitution was found to have no short-term (24 months) effect on the course of AMD [80]. Serum zinc levels were assessed in the AREDS where an increase of 17% was found in patients taking zinc-containing formulations. This effect was seen at both 1 and 5 years [81]. Patients taking zinc were more likely to have been hospitalized for genitourinary complaints than those who were not on zinc formulations (7.5 vs. 4.9% for both men and women and 8.6% vs. 4.4% for men alone) [13]. Recent data has suggested that patients homozygous for the risk-conferring phenotype of complement factor H (Y402H/Y402H) have a reduced treatment response to zinc [82].