Volume 80, Issue 10, Pages 592-598 (October 2009)

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Macular pigment and healthy vision

Article Outline

• Lutein and zeaxanthin increase MPOD

• Lutein, zeaxanthin, and AMD risk

• AMD risk and MPOD

• Conclusions

• References

A growing body of evidence has established a link between lutein and zeaxanthin, higher levels of MPOD, increased visual performance, and decreased risk for AMD and other age-related eye diseases. A number of findings suggest that MPOD measurement may be a reliable tool to identify individuals at risk for or experiencing early-stage AMD. Devices are commercially available to measure MPOD and new objective technologies are emerging.

Lutein and zeaxanthin are carotenoids that filter harmful, high-energy blue wavelengths of light and act as antioxidants in the eye, helping protect and maintain healthy ocular tissues. Of the 600+ carotenoids found in nature, only 2 are deposited in high quantities in the retina (macula) of the eye: lutein and zeaxanthin. These 2 carotenoids comprise the macular pigment, which is responsible for the characteristic yellow coloration of the macula.1 Lutein and zeaxanthin are distinguished biochemically from other carotenoids by the presence of a hydroxyl group at each end molecule. This characteristic allows lutein and zeaxanthin to be positioned in lipid membranes exposed to aqueous environments. It is likely that lutein and zeaxanthin interact with membranes in the eye to protect the macula from damaging blue light as the macular pigment maximally absorbs light at a wavelength of 460 nm.1, 2 Their ability to absorb or filter blue light can be measured as macular pigment optical density (MPOD). MPOD is directly related to the quantity of lutein and zeaxanthin in the macula.

In addition to the macula, lutein and zeaxanthin are found in the lens. Oxidation of the lens proteins is a major cause of cataracts.3 As antioxidant nutrients neutralize free radicals associated with oxidative stress and retinal damage, lutein and zeaxanthin may reduce the risk of cataract. In fact, a recent study found that higher dietary intake of lutein, zeaxanthin, and vitamin E was associated with a significantly decreased risk of cataract formation.4

Lutein and zeaxanthin increase MPOD

Studies have found that high levels of lutein and zeaxanthin in the serum and diet are associated with a reduced risk for advanced age-related macular degeneration (AMD).5, 6, 7 There is also evidence that individuals with low levels of lutein and zeaxanthin in the serum and diet have lower macular pigment density.8, 9, 10 Therefore, it can be inferred that low levels of macular pigment may be a potential risk factor for AMD. In autopsy eyes, there was approximately 30% less macular pigment in eyes with AMD compared with control eyes.11

One of the largest clinical trials evaluating the impact of lutein upon MPOD was the Lutein Antioxidant Supplementation Trial (LAST).12 This trial supplemented 90 men who had atrophic AMD with 10 mg of lutein, 10 mg lutein plus antioxidants, or a placebo over the course of 1 year. Those receiving 10 mg of lutein experienced a 36% increase in MPOD, and a 43% increase was observed in those subjects who received 10 mg of lutein plus antioxidants. Additionally, visual acuity, visual function, photo-stress recovery time, and contrast sensitivity were also significantly improved in both groups receiving lutein.

Another trial determined that in healthy subjects after supplementation with 10 mg of lutein and 2 mg zeaxanthin, MPOD increased significantly over the course of 6 months.13 This increase in MPOD positively correlated with the subjects' ability to tolerate glaring light and recover from photo stress. These data suggest that high lutein concentrations in the macula can improve visual function in both healthy subjects and those with age-related eye disease.

The majority of published clinical studies show a positive effect on MPOD from either lutein/zeaxanthin supplementation or consumption in the form of dark green, leafy vegetables (see Table 1). Variations in results could be attributed to differences in study populations as well as the methods used to measure MPOD, type of diet consumed by the study subjects, and how closely subjects adhered to the supplementation/dietary regimens used. Regardless, the body of evidence suggests increased lutein intake, through lutein-rich food or dietary supplements, is likely to result in increased deposition of lutein and zeaxanthin into the macular area of the eye.

Table 1.

Intervention studies examining the effect of lutein and zeaxanthin on MPOD


Study	Cohort	Protocol	Effect on MPOD
Aleman et al.14 2001	47 retinitis pigmentosa and 11 Usher syndrome patients	20 mg/d lutein for 6 months	Half the patients experienced an increase in MPOD
Berendschot et al.15 2000	8 healthy adult subjects	10 mg/d lutein for 8 weeks	Significant increase in mean MPOD
Bernstein et al.16 2002	46 elderly subjects	High carotenoid diet or lutein supplement for 12 weeks	No change in mean MPOD
Bone et al.17 2003	3 healthy adult subjects	2.4 to 30 mg/d lutein and 30 mg/d zeaxanthin for 20 weeks	Increase in mean MPOD
Bone et al.18 2007	10 healthy adult subjects	5.5 mg/d lutein, 14.9 mg/d meso-zeaxanthin, 1.4 mg/d zeaxanthin for 4 months	Significant increase in MPOD
Cardinault et al.19 2003	12 healthy young and 17 healthy elderly subjects	9 mg/d lutein for 5 weeks	No change in mean MPOD
Duncan et al.20 2002	7 choroideremia (form of retinal degeneration) patients	20 mg/d lutein for 6 months	Significant increase in mean MPOD
Francoise et al.21 2006	46 healthy adults	4-6 mg/d lutein for 12 weeks	No change in mean MPOD
Hammond et al.9 1997	13 healthy adult subjects	10 mg/d lutein for 15 weeks	Significant increase in mean MPOD
Johnson et al.10 2000	7 healthy adult subjects	10 mg/d lutein 15 for weeks	Significant increase in mean MPOD
Johnson et al.22 2008	49 healthy women	12 mg/d lutein for 4 months	Significant increase in MPOD
Koh et al.23 2004	7 early ARM and 6 controls	10 mg/d lutein for 20 weeks	Significant increase in MPOD in both groups
Kopsell et al.24 2006	20 healthy adults	3 mg/d or 4.3 mg/d lutein for 12 weeks	Significant increase in MPOD in high lutein group
Kvansakul et al.25 2006	22 healthy males	10 mg/d lutein and 10 mg/d zeaxanthin for 6 months	Significant increase in MPOD
Landrum et al.26 1997	2 healthy adult subjects	30 mg/d lutein for 20 weeks	Significant increase in mean MPOD
Landrum et al.27 2000	24 healthy adult subjects	2.4 mg/d lutein for 6 months	Significant increase in mean MPOD
Morganti et al.28 2004	50 healthy adults	6 mg/d lutein for 2 months	Significant increase in MPOD
Richer et al.12 2004	90 AMD patients	10 mg/d lutein for 12 months	Significant increase in mean MPOD
Richer et al.29 2007	59 AMD patients	10 mg/d lutein for 12 months	Significant increase in MPOD with no plateau after 12 months' supplementation
Rodriguez-Carmona et al.30 2006	92 healthy adults	10 mg/d lutein for 6 months	Significant increase in MPOD
Schalch et al.31 2007	92 healthy adults	10 mg/d lutein for 6 months followed by 20 mg/d lutein for additional 6 months	Signfiicant increase in MPOD
Schweitzer et al.32 2002	10 health adults	6 mg/d lutein for 40 days	Increase in MPOD
Stringham et al.13 2008	40 healthy young adults	10 mg/d lutein and 2 mg/d zeaxanthin for 6 months	Significant increase in MPOD
Trieschman et al.33 2007	136 healthy adults	12 mg/d lutein and 1 mg/d zeaxanthin	Significant increase in MPOD
Wenzel et al.34 2006	24 adult females	6 eggs/week for 3 months	Significant increase in MPOD
Wenzel et al.35 2007	3 healthy adults	30 mg/d lutein and 2.7 mg/d zeaxanthin for 4 months	Significant increase in MPOD
Yolton et al.36 2002	45 healthy young adults	6 mg/d lutein for 7 months	No change in mean MPOD
Zeimer et al.37 2009	108 adults with and without AMD	12 mg/d lutein and 1 mg/d zeaxanthin for 6 months	Significant increase in MPOD

Lutein, zeaxanthin, and AMD risk

A link between lutein and zeaxanthin intake and AMD risk was first uncovered in an epidemiologic study published in 1994.6 This study compared the risk of developing AMD with nutrient intake and showed a significant 57% risk reduction for AMD as lutein and zeaxanthin intake reached 6 mg per day. Subsequent epidemiologic research suggests a positive association between lutein intake, serum levels of lutein, and AMD risk in humans (see Table 2). These studies provide insight from an observational perspective suggesting that dietary sources of lutein are associated with a reduced risk for AMD. However, controlled long-term intervention studies in humans are needed to establish causality.

Table 2.

Observation studies showing an inverse association between lutein and AMD risk


Study	Measured Outcome(s)	Result(s)
Bernstein et al.41 2002	Lutein supplementation and MPOD in AMD patients	MPOD significantly higher in AMD patients using lutein supplementation versus subjects without supplementation
Cho et al.42 2004	Fruit and vegetable intake and age-related maculopathy risk	Fruit intake was inversely associated with the risk of neovascular age-related maculopathy
Delcourt et al.43 2006	Serum lutein and zeaxanthin levels and age-related maculopathy and cataract risk	Lutein and zeaxanthin were significantly inversely associated with the risk of age-related maculopathy
Eye Disease Case-Control Study5 1993	Serum lutein levels and AMD risk	Significant inverse relationship between serum lutein concentration and AMD risk
Gale et al.44 2003	Serum lutein and zeaxanthin levels and AMD risk	Inverse relationship between serum lutein and/or zeaxanthin concentration and AMD risk
Moeller et al.45 2006	Serum lutein and zeaxanthin levels and AMD risk	Inverse relationship between serum lutein and/or zeaxanthin concentration and AMD risk
Seddon et al.6 1994	Dietary intake of carotenoids and AMD risk	Significant inverse relationship between lutein intake and AMD risk
Snellen et al.7 2002	Lutein intake and AMD risk	The prevalence rate of AMD in patients with low antioxidant intake and low lutein intake was twice as high as that in patients with high intake
Tan et al.46 2008	Lutein and zeaxanthin intake and AMD risk	Significant inverse relationship between lutein and zeaxanthin intake and AMD risk
Vu et al.47 2006	Lutein and zeaxanthin intake and AMD risk	Significant inverse relationship between lutein and zeaxanthin intake and AMD risk

One such study, the Age-Related Eye Disease Study 2 (AREDS 2) conducted by the National Eye Institute, is currently under way. AREDS 2 will add the carotenoids lutein (10 mg/d) and zeaxanthin (2 mg/d), alone or in combination with the omega-3 fatty acids, docosahexaenoic acid (350 mg/d) and eicosapentaenoic acid (650 mg/d) to the original AREDS supplement formulation and assess the progression to AMD in individuals at high risk for the disease. An additional goal of the study is to assess whether forms of the AREDS supplement with reduced zinc and/or no beta-carotene work as well as the original supplement in reducing the risk of progression to advanced AMD.

In June 2008, 80 participating U.S. centers completed recruitment of 4,000 AMD patients for the study with each patient receiving treatment for 5 years. In addition to evaluating the rate of AMD progression, other outcomes will be simultaneously evaluated, including the effects of supplementation on the development of cataracts, cardiovascular disease, vision loss, visual function, and cognitive function, as well as genetic risk factors to AMD. One subset of participants in the AREDS 2 study will have their MPOD measured using autofluorescence spectroscopy (AF).

Since the original AREDS study was completed, additional evidence regarding nutrition and eye health has come to light. The decision to add lutein and zeaxanthin to the AREDS supplement formula was in part a result of analysis of the dietary intake of lutein and zeaxanthin in the AREDS participants that showed that those individuals with the highest intake had the lowest risk for AMD.38 In addition, a study comparing the amounts of lutein and zeaxanthin in donor eyes with and without AMD found that eyes with the highest quartile of lutein and zeaxanthin had an 82% lower risk for AMD compared with the lowest quartile.39 Another study currently in progress is the Carotenoids and Co-antioxidants in Age-Related Maculopathy (CARMA) study, which is investigating the potential benefits of supplementation with lutein and zeaxanthin and vitamin C, E, and zinc on the progression of age-related maculopathy.40

The body of evidence summarized in Table 2 must be evaluated collectively to determine the merits of supplementing the diet with a given nutrient. With this in mind, current research appears to support a beneficial role for lutein in eye health. Lutein intake may increase levels of this xanthophyll in the macula providing protection against damaging blue light and free radicals that contribute to AMD progression.

AMD risk and MPOD

Although a direct link between AMD and MPOD requires further investigation, research suggests a strong indirect relationship when the body of evidence is considered (see Table 3). High concentrations of macular pigment, lutein and zeaxanthin, protect the macula from photo-oxidative damage caused by blue light.1, 2 This raises the question as to whether higher levels of MPOD or specific MPOD distributions help protect the eye against AMD. Associations have been made between risk factors for AMD and factors that influence MPOD levels such as sex, age, iris color, smoking, dietary intake, body mass index, and the presence of existing diseases.48, 49, 50 As the optical density and spatial distribution of macular pigment have been shown to differ among individuals, determination of the relationship between MPOD spatial profiles in normal and diseased human subjects may predicate MPOD levels and possible relationships between MPOD and pathophysiology of the human eye.51, 52

Table 3.

Relationship between AMD risk and MPOD


Study	Study Type	Findings
Age-Related Eye Disease Study Research Group 200738	Epidemiologic	AREDS subjects reporting the highest dietary intake of lutein and zeaxanthin were statistically less likely to have advanced AMD (both neovascular AMD or geographic atrophy) or large or extensive intermediate drusen than those reporting lowest dietary lutein/zeaxanthin intake.
Beatty et al.57 2001	Clinical study of 46 healthy white subjects	An age-related decline in the amounts of lutein and zeaxanthin in the retina (MPOD) was observed. Additionally, MPOD was significantly less in 9 healthy subjects known to be at high risk for AMD compared to 9 matched eyes at no such risk.
Bernstein et al.41 2002	Clinical study	Average levels of lutein and zeaxanthin in eyes of subjects with AMD were 32% lower than levels in eyes of subjects without signs of AMD.
Bone et al.39 2001	Research study on donor eyes at autopsy with and without AMD	Retinas of persons with AMD had significantly lower lutein and zeaxanthin in the macula than retinas of persons without signs of AMD
Ciulla and Hammond60 2004	Clinical study with 390 subjects including subjects with cataracts (22) and AMD (59)	The amount of lutein and zeaxanthin in the macula (MPOD) did not change significantly with age even when elderly subjects with cataracts and AMD were considered. However, the low numbers of subjects with eye diseases might have limited the power of the study.
Eye Disease Case-Control Study 19935	Epidemiologic	Data from this study indicated that persons with higher levels of circulating micronutrients having antioxidant capabilities, particularly carotenoids, have a reduced risk of neovascular AMD.
Koh et al.23 2004	Clinical study with 13 subjects—7 with early ARM and 6 healthy eyes	Supplementation with lutein and zeaxanthin at 10 mg/day for 18 to 20 weeks resulted in increased MPOD in all subjects, even those with age-related maculopathy. The degree of MPOD increase in eyes with age-related maculopathy was statistically similar to those in healthy eyes. These data indicate that the potentially beneficial effects of lutein and zeaxanthin supplementation are not restricted to healthy eyes.
LaRowe et al.58 2008	Cross-sectional study	After excluding women likely to have unstable diets and those having conditions related to AMD risk, a potentially protective trend (although not statistically significant) was observed between the amounts of lutein and zeaxanthin in the retina and AMD. Also, it was reported that higher levels of lutein and zeaxanthin in the retina may slow advancement of AMD.
Nolan et al.61 2007	Epidemiologic	MPOD was significantly inversely associated with risk factors for age-related maculopathy including age, smoking, and family history of the disease.
Obana et al.59 2008	Clinical study in Japanese subjects	MPOD levels declined with age in healthy Japanese subjects and were significantly lower in age-related maculopathy patients than in healthy subjects younger than 60. MPOD was also significantly lower in subjects with late AMD (late age-related maculopathy) than in subjects with early age-related maculopathy.
Richer et al.12 2004	Clinical study with 90 AMD patients (half receiving lutein/zeaxanthin and half placebo)	Supplementation with 10 mg/day for 12 months resulted in a 36% increase in MPOD in these AMD patients as well as improvements in visual functionality (visual acuity, contrast sensitivity, and glare recovery)
Seddon et al.6 1994	Epidemiologic	Persons with a diet rich in lutein/zeaxanthin (6 mg/day) had significantly less (57%) risk to have AMD than persons with a diet low (1 mg/day) in these xanthophylls

There are a few devices commercially available to measure MPOD. These devices utilize one of the following methods: heterochromatic flicker photometry (HFP), resonance Raman spectroscopy, and autofluorescence imaging (AFI). HFP is a subjective test that involves color intensity matching of flickering blue and green light.53, 54 The subject varies the intensities of the 2 lights until the perception of flicker is minimized or eliminated. MPOD is calculated from the level of maximum radiance of blue light needed to match the reference light and cause a “null-flicker.” Resonance Raman spectroscopy utilizes a low-intensity argon laser to illuminate a subject's retina, which resonantly excites the macular carotenoids. The wavelength-shifted light is analyzed and used to calculate MPOD.55 AFI is a relatively new technology that utilizes the fluorescence of lipofuscin in the retinal pigment epithelium (RPE). To measure macular pigment with this technique, the fluorescence of lipofuscin is excited at a wavelength also blocked by macular pigment. Thus, the fluorescence of lipofuscin is attenuated in direct relationship to the amount of macular pigment present. AFI, now being utilized in AREDS 2, has advantages over other methods in that it can obtain an objective, rapid measurement that not only quantifies macular pigment levels but also is capable of mapping spatial variations in macular pigment distribution.56

Evaluating the relationship between AMD and MPOD is challenging because of the special equipment required to measure MPOD, difficulties in accurately measuring MPOD in elderly patients, particularly those with eye diseases, and the normal variability in MPOD among individuals. However, a number of findings suggest that MPOD measurement may be a reliable marker to identify individuals at risk or experiencing early-stage AMD.39, 41, 57, 58, 59 Low levels of MPOD may indicate a decrease in the light-filtering capacity of the macula, thereby increasing one's risk for AMD. Conversely, high levels of MPOD may be a protective factor against photo-oxidative damage by blue light and reduce an individual's risk for AMD as well as potentially other age-related eye diseases.

Conclusions

A proper diet, including a variety of fruits and vegetables, has been shown clinically to help protect against development or progression of AMD. Over the last 2 decades, an understanding of the macular pigment and its role in eye protection has prompted researchers to investigate the impact of lutein and zeaxanthin consumption on MPOD and age-related eye disease. A growing body of evidence has established a positive correlation among increased lutein consumption, higher levels of MPOD, and decreased risk for AMD. Therefore, the components of macular pigment, lutein and zeaxanthin, are likely able to protect against chronic and cumulative eye damage through their capacity to filter the most energetic and potentially damaging wavelengths of visible light and neutralize free radicals caused by oxidative stress. Although more research is needed to definitively identify low levels of MPOD as a causative factor of AMD, it is biologically plausible that MPOD may decrease the progression of age-related maculopathy and AMD, and adequate supplementation with lutein and zeaxanthin may help decrease the rate if not the progression of these ocular diseases.

References

1. 1Snodderly DM, Brown PK, Delori FC, et al. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. Invest Ophthalmol Vis Sci. 1984;25(6):660–673. MEDLINE

2. 2Snodderly DM, Auran JD, Delori FC. The macular pigment. II. Spatial distribution in primate retinas. Invest Ophthalmol Vis Sci. 1984;25(6):674–685. MEDLINE

3. 3Williams DL. Oxidation, antioxidants and cataract formation: a literature review. Vet Ophthalmol. 2006;9(5):292–298. MEDLINE | CrossRef

4. 4Christen WG, Liu S, Glynn RJ, et al. Dietary carotenoids, vitamins C and E, and risk of cataract in women: a prospective study. Arch Ophthalmol. 2008;126(1):102–109. CrossRef

5. 5Antioxidant status and neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol. 1993;111(1):104–109. MEDLINE

6. 6Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272(18):1413–1420. MEDLINE

7. 7Snellen EL, Verbeek AL, Van Den Hoogen GW, et al. Neovascular age-related macular degeneration and its relationship to antioxidant intake. Acta Ophthalmol Scand. 2002;80(4):368–371. MEDLINE | CrossRef

8. 8Beatty S, Nolan J, Kavanagh H, et al. Macular pigment optical density and its relationship with serum and dietary levels of lutein and zeaxanthin. Arch Biochem Biophys. 2004;430(1):70–76. MEDLINE | CrossRef

9. 9Hammond BR, Johnson EJ, Russell RM, et al. Dietary modification of human macular pigment density. Invest Ophthalmol Vis Sci. 1997;38(9):1795–1801. MEDLINE

10. 10Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density. Am J Clin Nutr. 2000;71(6):1555–1562. MEDLINE

11. 11Landrum JT, Bone RA, Kilburn MD. The macular pigment: a possible role in protection from age-related macular degeneration. Adv Pharmacol. 1997;38:537–556. MEDLINE | CrossRef

12. 12Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75(4):216–230. Abstract | Full-Text PDF (6757 KB) | CrossRef

13. 13Stringham JM, Hammond B. Macular pigment and visual performance under glare conditions. Optom Vis Sci. 2008;85(2):82–88. CrossRef

14. 14Aleman TS, Duncan JL, Bieber ML, et al. Macular pigment and lutein supplementation in retinitis pigmentosa and usher syndrome. Invest Ophthalmol Vis Sci. 2001;42(8):1873–1881. MEDLINE

15. 15Berendschot TT, Goldbohm RA, Klopping WA, et al. Influence of lutein supplementation on macular pigment, assessed with two objective techniques. Invest Ophthalmol Vis Sci. 2000;41(11):3322–3326. MEDLINE

16. 16Francois JL, Askew EW, Lang LC, Bernstein PS. Serum and macular response to antioxidant supplementation versus a carotenoid-rich dietary intervention in elderly. Curr Top Neutraceutical Res. 2006;4(1):69–78.

17. 17Bone RA, Landrum JT, Guerra LH, et al. Lutein and Zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans. J Nutr. 2003;133(4):992–998. MEDLINE

18. 18Bone RA. Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin. Nutr Metab. 2007;4(12):.

19. 19Cardinault N, Gorrand JM, Tyssandier V, et al. Short-term supplementation with lutein affects biomarkers of lutein status similarly in young and elderly subjects. Exp Gerontol. 2003;38(5):573–582. MEDLINE | CrossRef

20. 20Duncan JL, Aleman TS, Gardner LM, et al. Macular pigment and lutein supplementation in choroideremia. Exp Eye Res. 2002;74(3):371–381. MEDLINE | CrossRef

21. 21Francoise JL, Askew EW, Lang JC, et al. Serum and macular responses to antioxidant supplementation versus a carotenoid-rich dietary intervention in the elderly. Curr Topics Nutraceutical Res. 2006;4(1):69–78.

22. 22Johnson EJ, Chung HY, Caldarella SM, et al. The influence of supplemental lutein and docosahexaenoic acid on serum, lipoproteins, and macular pigmentation. Am J Clin Nutr. 2008;87(5):1521–1529.

23. 23Koh HH, Murray IJ, Nolan D, et al. Plasma and macular responses to lutein supplement in subjects with and without age-related maculopathy: a pilot study. Exp Eye Res. 2004;79(1):21–27. MEDLINE | CrossRef

24. 24Kopsell DA, Lefsrud MG, Kopsell DE, et al. Spinach cultigen variation for tissue carotenoid concentrations influences human serum carotenoid levels and macular pigment optical density following a 12-week dietary intervention. J Agric Food Chem. 2006;54(21):7998–8005.

25. 25Kvansakul J, Rodriguez-Carmona M, et al. Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic Physiol Opt. 2006;26(4):362–371. MEDLINE | CrossRef

26. 26Landrum JT, Bone RA, Joa H, et al. A one year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp Eye Res. 1997;65(1):57–62. MEDLINE | CrossRef

27. 27Landrum JT, Chen Y, Bone RA, et al. Serum and macular pigment response to 2.4 mg dosage of lutein (Abstract). ARVO. 2000;41(4):S60.

28. 28Morganti P, Fabrizi G, Bruno C. Protective effects of oral antioxidants on skin and eye function. Skinmed. 2004;3(6):310–316. MEDLINE | CrossRef

29. 29Richer S, Devenport J, Lang JC. LAST II: Differential temporal responses of macular pigment optical density in patients with atrophic age-related macular degeneration to dietary supplementation with xanthophylls. Optometry. 2007;78(5):213–219. Abstract | Full-Text PDF (6757 KB) | CrossRef

30. 30Rodriguez-Carmona M, Kvansakul J, Harlow JA, et al. The effects of supplementation with lutein and/or zeaxanthin on human macular pigment density and colour vision. Ophthalmic Physiol Opt. 2006;26(2):137–147. MEDLINE | CrossRef

31. 31Schalch W, Cohn W, Barker FM, et al. Xanthophyll accumulation in the human retina during supplementation with lutein or zeaxanthin—the LUXEA (LUtein Xanthophyll Eye Accumulation) study. Arch Biochem Biophys. 2007;458(2):128–135. MEDLINE | CrossRef

32. 32Schweitzer D, Lang GE, Beuermann B, et al. Objektive bestimmung der optischen dichte von xanthophyll nach supplementation von lutein. Ophtalmologe. 2002;99:270–275.

33. 33Trieschmann M, Beatty S, Nolan JM, et al. Changes in macular pigment optical density and serum concentrations of its constituent carotenoids following supplemental lutein and zeaxanthin: the LUNA study. Exp Eye Res. 2007;84(4):718–728. MEDLINE | CrossRef

34. 34Wenzel AJ, Gerweck C, Barbato D, et al. A 12-wk egg intervention increases serum zeaxanthin and macular pigment optical density in women. J Nutr. 2006;136(10):2568–2573. MEDLINE

35. 35Wenzel AJ, Sheehan JP, Gerweck C, et al. Macular pigment optical density at four retinal loci during 120 days of lutein supplementation. Ophthalm Physiol Optics. 2007;27(4):329–335.

36. 36Yolton D, DeRuyter B, Miller B, et al. Failure of oral supplement containing lutein to change macular pigment density. Abstract presented at the American Academy of Optometry Conference; December 12, 2002; San Diego, CA.

37. 37Zeimer M, Hense HW, Heimes B, et al. [The macular pigment: short- and intermediate-term changes of macular pigment optical density following supplementation with lutein and zeaxanthin and co-antioxidants. The LUNA Study]. Ophthalmologe. 2009;106(1):29–36. CrossRef

38. 38The Relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225–1232. CrossRef

39. 39Bone RA, Landrum JT, Mayne ST, et al. Macular pigment in donor eyes with and without AMD: a case-control study. Invest Ophthalmol Vis Sci. 2001;42(1):235–240. MEDLINE

40. 40Neelam K, Hogg RE, Stevenson MR, et al. Carotenoids and co-antioxidants in age-related maculopathy: design and methods. Ophthalmic Epidemiol. 2008;15(6):389–401. CrossRef

41. 41Bernstein PS, Zhao DY, Wintch SW, et al. Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients. Ophthalmology. 2002;109(10):1780–1787. Abstract | Full Text | Full-Text PDF (199 KB) | CrossRef

42. 42Cho E, Seddon JM, Rosner B, et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 2004;122(6):883–892. MEDLINE | CrossRef

43. 43Delcourt C, Carriere I, Delage M, et al. Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study. Invest Ophthalmol Vis Sci. 2006;47(6):2329–2335. MEDLINE | CrossRef

44. 44Gale CR, Hall NF, Phillips DI, et al. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2003;44(6):2461–2465. MEDLINE | CrossRef

45. 45Moeller SM, Parekh N, Tinker L, et al. Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye Disease Study (CAREDS): ancillary study of the Women's Health Initiative. Arch Ophthalmol. 2006;124(8):1151–1162. MEDLINE | CrossRef

46. 46Tan JS, Wang JJ, Flood V, et al. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115(2):334–341. Abstract | Full Text | Full-Text PDF (137 KB) | CrossRef

47. 47Vu HT, Robman L, McCarty CA, et al. Does dietary lutein and zeaxanthin increase the risk of age related macular degeneration? The Melbourne Visual Impairment Project. Br J Ophthalmol. 2006;90(3):389–390. MEDLINE | CrossRef

48. 48Hammond BR, Curran-Celentano J, Judd S, et al. Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns. Vision Res. 1996;36(13):2001–2012. MEDLINE | CrossRef

49. 49Hammond BR, Fuld K, Snodderly DM. Iris color and macular pigment optical density. Exp Eye Res. 1996;62(3):293–297. MEDLINE | CrossRef

50. 50Hammond BR, Wooten BR, Snodderly DM. Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Res. 1996;36(18):3003–3009. MEDLINE | CrossRef

51. 51Bone RA, Sparrock JM. Comparison of macular pigment densities in human eyes. Vision Res. 1971;11(10):1057–1064. MEDLINE | CrossRef

52. 52Hammond BR, Fuld K. Interocular differences in macular pigment density. Invest Ophthalmol Vis Sci. 1992;33(2):350–355. MEDLINE

53. 53Beatty S, Koh HH, Carden D, et al. Macular pigment optical density measurement: a novel compact instrument. Ophthalmic Physiol Opt. 2000;20(2):105–111. MEDLINE | CrossRef

54. 54Snodderly DM, Mares JA, Wooten BR, et al. Macular pigment measurement by heterochromatic flicker photometry in older subjects: the carotenoids and age-related eye disease study. Invest Ophthalmol Vis Sci. 2004;45(2):531–538. MEDLINE | CrossRef

55. 55Bernstein PS, Yoshida MD, Katz NB, et al. Raman detection of macular carotenoid pigments in intact human retina. Invest Ophthalmol Vis Sci. 1998;39(11):2003–2011. MEDLINE

56. 56Delori FC. Spectrophotometer for noninvasive measurement of intrinsic fluorescence and reflectance of the ocular fundus. Applied Optics. 1994;33:7439–7452. CrossRef

57. 57Beatty S, Murray IJ, Henson DB, et al. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci. 2001;42(2):439–446. MEDLINE

58. 58LaRowe TL, Mares JA, Snodderly DM, et al. Macular pigment density and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study. An ancillary study of the women's health initiative. Ophthalmology. 2008;115(5):876–877e1. Abstract | Full Text | Full-Text PDF (141 KB) | CrossRef

59. 59Obana A, Hiramitsu T, Gohto Y, et al. Macular carotenoid levels of normal subjects and age-related maculopathy patients in a Japanese population. Ophthalmology. 2008;115(1):147–157. Abstract | Full Text | Full-Text PDF (552 KB) | CrossRef

60. 60Ciulla TA. Hammond BR, Jr. Macular pigment density and aging, assessed in the normal elderly and those with cataracts and age-related macular degeneration. Am J Ophthalmol. 2004;138(4):582–587. Abstract | Full Text | Full-Text PDF (349 KB) | CrossRef

61. 61Nolan JM, Stack J, O OD, et al. Risk factors for age-related maculopathy are associated with a relative lack of macular pigment. Exp Eye Res. 2007;84(1):61–74. MEDLINE | CrossRef

PII: S1529-1839(09)00426-6

doi:10.1016/j.optm.2009.08.002

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