- Email: [email protected]
Macular pigment density and aging, assessed in the normal elderly and those with cataracts and age-related macular degeneration
Macular Pigment Density and Aging, Assessed in the Normal Elderly and Those With Cataracts and Age-related Macular Degeneration THOMAS A. CIULLA, MD, AND BILLY R. HAMMOND, JR., PHD
● PURPOSE:
Increasing evidence has linked retinal lutein and zeaxanthin (termed macular pigment, MP) to the risk of age-related macular degeneration (AMD). Currently, however, studies differ regarding the question of whether MP declines with age or age has an effect in patient populations being assessed. This study assessed MP across the lifespan with an emphasis on assessing MP in a cross-section of elderly including those with lenticular or age-related macular degeneration, or both. ● DESIGN: Prospective, observational, cross-sectional study. ● METHODS: SETTING: Institution. STUDY POPULATION: Cross-sectional study of normal, cataractous, and AMD subjects tested in Indianapolis, Indiana, including 390 subjects, 22 with cataracts and 59 with age-related macular degeneration. OBSERVATIONAL PROCEDURE: MP density was measured with a one-degree diameter test field at 460 nm using a psychophysical method based on heterochromatic flicker photometry. MAIN OUTCOME MEASURES: MP optical density. ● RESULTS: MP does not appear to change as a function of age (r ⴝ ⴙ.04) when examining subjects across the lifespan (from 18 – 88 years). There was a slight tendency (slope ⴝ ⴚ.0027, r ⴝ ⴚ.11) for MP to decline when only the elderly subjects were considered, but this trend was not significant (P < .12) for any of the groups considered (normal, cataractous, or AMD). ● CONCLUSIONS: MP does not change significantly with age, even when elderly subjects with cataracts and AMD are considered. Using heterochromic flicker photometry, elderly subjects display a full range of MP density that is similar to young subjects. (Am J Ophthalmol 2004; Accepted for publication May 18, 2004. From the Retina Service, Midwest Eye Institute, Methodist Medical Plaza North, Indianapolis, Indiana (T.A.C.); and from the Vision Science Laboratory, University of Georgia, Athens, Georgia (B.R.H.). Inquiries to Thomas A. Ciulla, Retina Service, Midwest Eye Institute, Methodist Medical Plaza North, 201 Pennsylvania Parkway, Indianapolis, Indiana 46280; fax: 317-817-1898; e-mail: [email protected]
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138:582–587. © 2004 by Elsevier Inc. All rights reserved.)
A
GE-RELATED MACULAR DEGENERATION (AMD) IS
characterized by degeneration of the central macular region of the retina. The regional selectivity of this disease suggests that some unique feature of the macula accounts for this susceptibility. Probably one of the most unique and variable features of the macula is the concentration of the carotenoids, lutein and zeaxanthin, in the inner layers of the fovea.1 These dietary pigments, termed macular pigment (MP), have been shown to vary by over a factor of 10 across individuals.2 There is a large body of evidence from diverse sources suggesting that high optical density of MP may help protect the retina by filtering actinic short-wave light and through an antioxidant mechanism.3,4 Because low levels of MP might actually be a risk for AMD,5,6 identifying factors related to individual differences in MP density across the life span is of interest. Past studies have suggested a number of MP determinants (many of which are also classic risk factors for AMD) including: dietary carotenoid intake, smoking status, iris color, gender, and body fat/BMI.7 Results regarding MP determinants, however, must still be regarded as inconclusive since they do not appear to be consistently replicated across studies. Such inconsistency is probably because of true sampling variance but is also probably related to measurement issues. For example, the sample size of some studies may be insufficient to detect some relationships. Moreover, some determinants may be less significant in certain geographical areas. For example, if iris color is related to MP because of variation in light stress (i.e., bluer irises transmit more light and therefore individuals with blue irises may have higher light stress compared with individuals with brown irises),8 then iris color may be more of a significant determinant in sunny climates. It is also often difficult to compare results across laboratories that use different methods. In vivo measures of
ELSEVIER INC. ALL
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0002-9394/04/$30.00 doi:10.1016/j.ajo.2004.05.057
MP density can be made using fundus reflectometry,9 autofluorescence,10 Raman spectroscopy,11,12 as well as various psychophysical methods.13,14 Each method depends upon different assumptions and often uses different spectral and spatial stimulus conditions, which influences the interpretation of the results.15 Probably the most debatable MP determinant appears to be the effect of age on MP density. Certainly, measuring the optical characteristics of elderly eyes is more difficult than younger eyes, which may contribute to inconsistencies across studies. In a recent study using Raman spectroscopy, one group found that MP density declined by approximately 84% between the ages of 20 and 70 years.11 This group also found that the average optical density of subjects older than age 60 ranged from zero to approximately 0.05 optical density units. Thus, this study suggested that the MP density of the elderly was uniformly low. This finding was recently replicated in another study using Raman spectroscopy, which also found a sharp age-related decline (60% when comparing subjects in their 20s and 50s) in the MP of patients with inherited retinal degenerations (such as retinitis pigmentosa and choroideremia).12 In contrast, most other studies (using psychophysics,16 autoflourescence, reflectometry,9,10 and HPLC of donor retinas17) that have examined MP density vs age have found either no change or only small to moderate declines and increases, or both. All of the studies that have measured MP as a function of age have focused on MP across the entire lifespan. Moreover, these studies have not included older subjects with retinal or lenticular problems (with the exception of the Zhao and associates data noted earlier). In the present study, we provide data on MP density across the lifespan but we included a large enough elderly sample (50 – 89 years) to determine whether age-related changes in MP are more significant when older subjects are considered separately. In addition to normal subjects with relatively healthy retinas, we also assessed elderly subjects with cataracts and geographic AMD.
DESIGN THIS STUDY WAS AN OBSERVATIONAL CROSS-SECTIONAL
design.
ly.18 All patients were undergoing planned phacoemulsification and placement of a foldable acrylic posterior chamber intraocular lens for cataract of sufficient severity to interfere with their activities of daily living. The median preoperative best-corrected Snellen distance visual acuity measured 20/50. Patients were deemed eligible for this study if their near acuity could be refracted to 20/25 or better. Only the MP data before cataract removal was used for the present analysis. Fifty-nine subjects with nonexudative AMD were assessed. Data from the older subjects was compared with data from a younger sample (n ⫽ 280, age range ⫽ 18⫺50). These data from the younger sample were previously reported separately.19 All of the older subjects underwent careful ophthalmic examination before testing. Subjects were defined as having nonexudative macular degeneration according to the International Classification System, which specifies changes such as the presence of “soft drusen greater than 63 m, hyperpigmentation and/or hypopigmentation of the retinal pigment epithelium, Poor geographic atrophy of the retinal pigment epithelium”.20 Exclusion criteria used in selecting the comparison group included exudative macular degeneration in the study eye defined according to the International Classification System as the presence of “retinal pigment epithelium and associated neurosensory retinal detachment, (peri)retinal hemorrhages, or (peri) retinal fibrosis on masked analysis of fundus photos or evidence of choroidal neovascularization (CNVM) on fluorescein angiography”.20 The 29 subjects defined as “normal” did not show evidence of either nonexudative or exudative AMD as defined above. Either normal or AMD subjects were deemed ineligible if they had a history of diabetic retinopathy, ophthalmic or retinal artery occlusion, retinal vein occlusions, hypertensive retinopathy or choroidopathy, or known history of significant carotid stenosis. Additional exclusion criteria included glaucoma, optic neuropathy, macular dystrophies, ocular inflammatory disease, or retinal detachment. Additionally, subjects were excluded if they were unable to give informed consent, or had a history of allergy to fluorescein, radiographic dyes, shellfish, or iodine. Only subjects with a near visual acuity of 20/30 or better were recruited to perform heterochromatic flicker photometry. These subjects completed the psychophysical tasks with little difficulty. ● MEASUREMENT OF MACULAR PIGMENT OPTICAL DENSITY (MPOD): Heterochromic flicker photometry
METHODS A total of 110 elderly subjects were evaluated (average age ⫽ 72, SD ⫽ 8). Twenty-nine of these subjects were relatively healthy older subjects without retinal disease, but some (n ⫽ 16) had varying levels of lenticular opacities. Twenty-two subjects with cataracts severe enough to require extraction were also assessed. Data for these subjects was previously reported separate-
(HFP) was used to measure MP. This MP measurement technique has been validated on normal subjects by measuring the entire spectral absorption curve of MP and comparing it to the extinction spectrum of the macular pigments measured in excised tissue. 21 The reliability of the method has also been evaluated previously,2,21,22 and prior studies from this institution have been published in both younger (18 –50 years) and older (47– 81 years)
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populations. 18,19 Additionally, a recent study at the same institution with the identical apparatus has demonstrated that naive subjects recruited from the general population can reliably undergo testing. 19,23 In this study, 280 healthy adult volunteers, consisting of 138 men and 142 women, between the ages of 18 and 50 years, were found to have a mean MPOD measuring 0.211 ⫾ 0.13. 19,23 MP optical density was measured with a 1-degree test stimulus. Test stimuli were presented in natural view and near the center of a 6-degree, 10.5 cd/m2, 470-nm circular background. The test stimulus was alternately composed of a 460-nm measuring field (peak MP absorbance) and a 570-nm, 16.7 cd/m2, reference field (minimal MP absorbance). Light for the measuring and reference fields and the background was produced by 40-nm bandpass LEDs with peak energy at 460, 570, and 470 nm, respectively (Nichia Corp., Mountville, Pennsylvania, USA). The radiance of the LEDs was controlled by constant current, high frequency electronic pulses. The measuring and reference fields were superposed and presented out of phase at an alternation rate of 11 to 12 Hz in the foveal condition and 6 to 7 Hz in the parafoveal condition. Parafoveal stimuli were presented at an eccentricity of 4 degrees. Details regarding the densitometer used to measure MP have been published previously. 13 Details regarding the procedure and assumptions underlying the method were published previously.15 Subjects were given brief instructions on the method and a practice trial before five foveal and five parafoveal measurements were made. The foveal and parafoveal values were calculated from the average of the final five readings, and these averages were then used to calculate MPOD (which was then increased by a 15% constant to correct for the bandwidth of the source). As noted above, this protocol has been used in prior published studies from this institution. 19,23 In the younger sample without ocular disease, the right eye was assessed (n ⫽ 280, age range ⫽ 18 –50). In the 22 subjects with cataracts severe enough to require extraction, only the data from the cataractous eye were used in the analysis, and as noted above, the median preoperative best-corrected Snellen distance visual acuity measured 20/50 with a refracted near acuity of 20/25 or better. In the 59 subjects with nonexudative AMD, only the eligible eye was assessed, according the AMD inclusion and exclusion criteria noted above, and the near acuity refracted to 20/25 or better. If both eyes were deemed eligible, only the data from the right eye was used in the analysis. In the 29 elderly subjects defined as “normal” with no AMD, only the right eye was assessed. For each group of patients, the mean MP and standard deviation were calculated. Groups were compared using the Student’s t test. To analyze the relationship of MP and age, linear regression was used. 584
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RESULTS THE OVERALL MP OF THE ELDERLY SAMPLE WAS 0.26 (SD ⫽
0.19). The average MP of the normal, AMD and cataractous subjects was 0.28 (SD ⫽ 0.21), 0.26 (SD ⫽ 0.21), and 0.24 (SD ⫽ 0.16). These means were not significantly different. Nonetheless, in this study we did not attempt to analyze the diet of these subjects nor did we exclude subjects who were taking dietary supplements. To determine whether supplement use influenced the average MP values of each group, we contacted 12 of the normal subjects, all of the cataract subjects, and 29 of the AMD subjects to question them regarding supplement use. This analysis was done several months after the original measurements. Although we were unable to quantify dosage, we did discover that a significant number of the subjects (58% of the normals, 59% of the cataract subjects, and 62% of the AMD subjects) reported that they were using supplements that contained lutein at the time of our measurements. This supplement use, however, did not co-vary with age. Consequently, although it may have confounded any mean differences between the groups, it probably did not influence the age functions. As shown in Figure 1, when all of the subjects are considered together, MP does not appear to change as a function of age (r ⫽ ⫹.04). Similarly, as shown in Figure 2, although there was a slight tendency (slope ⫽ ⫺.0027, r ⫽ ⫺.11) for MP to decline when only the elderly subjects were considered, this trend was not significant (P ⬍ .12). This slight tendency to decline was seen in the normal, AMD and cataractous subjects but was not significant for any group.
DISCUSSION THESE DATA SUGGEST THAT MP DOES NOT CHANGE SIG-
nificantly with age, even when elderly subjects with cataracts and AMD are considered, although the number of patients with AMD and cataracts are relatively small in number and that no difference may be seen because of the lack of power. In general, these data are consistent with most of the literature on this topic with the exception of MP data obtained using Raman spectroscopy. Unlike most methods, however, the Raman method measures the retinal carotenoids using an absolute instead of a relative method. By using an eccentric reference, most methods are able to minimize interference by anterior structures of the eye, because the contribution from such structures is the same at both the measuring and reference sites. In contrast, the Raman method is based on an absolute signal arising directly from the carotenoid molecules themselves. (The carotenoid concentrations outside of the macula are too low to provide an eccentric reference signal.) The absolute Raman signal is therefore susceptible to interference by any structures lying between the retinal carotenoids and the collecting detector. The most significant interference OF
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FIGURE 1. Macular pigment and age. The relation between macular pigment and age is plotted for the entire sample. When all of the subjects are considered together, Macular pigment does not appear to change as a function of age (r ⴝ ⴙ.04).
at the wavelengths used by the Raman method (488 and 527 nm) probably arises from absorption and scattering by the crystalline lens,24 which is exacerbated in the elderly. Thus, unlike the Raman method, which suggests that the MP density of the elderly is uniformly low, our data show that elderly subjects, including those with cataracts and AMD, display the full range of MP density. A number of recent studies have suggested that macular pigment optical density is not effectively zero at 4 degrees for some individuals.25–27 We chose 4 degrees as a reference to be able to compare our current data on elderly subjects directly with earlier data we obtained on younger subjects.19 We also thought the task might be easier for the older subjects with a less eccentric reference. Nonetheless, a recent study measuring the spatial distribution of MP using imaging fundus reflectometry, has suggested the possibility that wider MP distributions might be positively correlated with age.26 Their data suggested that for younger subjects (age range ⫽ 22 to 30 years) MP density at 4 degrees eccentricity ranged from 0 to approximately 0.05 OD units. For older subjects (age range ⫽ 55– 83 years), however, MP density at 4 degrees ranged from approximately 0.02 to 0.10. If MP density at 4 degrees does increase with age, and 4 degrees is used as a zero reference (as we did in this study), this would result in an underestimation of MP density in the elderly subjects (e.g., of approximately 0.05 O.D. when comparing 20 and 70 year olds). As shown in Figure 1, however, our data suggest a
slight, albeit nonsignificant, increase with age. If using a 4-degree reference confounded our age analysis, this would result in a more significant trend for MP density to increase with age. The fact that the subjects with cataracts and AMD did not have particularly low average MP levels may be attributable to the fact that many of these subjects used dietary supplements containing lutein and zeaxanthin. For example, the AMD subjects who reported using supplements tended (P ⬍ .10) to have higher MP density (about 31%) compared with the subjects who reported not using supplements. This finding is preliminary, because we were not able to quantify dosage, and supplement information was obtained for only about half of the AMD subjects. This trend was also not seen in the subjects with cataracts. Nonetheless, it does raise the intriguing possibility that supplementation can increase the MP of AMD subjects. We also did not find a significant decline in MP density based on the age of the subjects with AMD and cataracts. It is unlikely that supplement use influenced this result, because supplement use did not appear to vary with age. Nevertheless, this represents a limitation of this study, and further research is warranted. Finally, we should note that our results for the AMD and cataract subjects are based on retinal measurements performed using the HFP method. This method is certainly the most common method of measuring MP density and has been used on a number of patient populations includ-
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FIGURE 2. Macular pigment and age, stratified. The relation between macular pigment optical density and age for subjects with relatively healthy retinas (open squares), AMD (open circles), and cataracts (solid squates) is plotted. Although there was a slight tendency (slope ⴝ ⴚ.0027, r ⴝ ⴚ.11) for MP to decline when only the elderly subjects were considered, this trend was not significant (P < .12).
ing patients with age-related macular degeneration,6,28 cataracts,18 choroideremia,29 and retinitis pigmentosa.30 In all cases, it appears that HFP measurements can be made expeditiously provided subjects have vision that is sufficient to allow successful completion of the task (for example, Snellen acuity of 20/80 or better). Certainly, our measurements on patient populations were made without undue difficulty and within a relatively short time frame (e.g., around 20 –30 minutes). The method does not require pupillary dilation and is one of the few methods that is relatively unaffected by significant changes in anterior optical media.13,18 Nonetheless, it is important to point out that, despite its widespread use on patient populations, the method has only been validated on normal nondiseased subjects (for example, by matching MP spectral absorption profiles measured using HFP to ex vivo extinction spectra of L and Z). Without proper validation on patient populations, MP data obtained using this method (or any other MP assessment method at the current time) must be interpreted with caution. For example, one group has shown that morphologic disturbance in the cone axons of patients with retinitis pigmentosa could lead to higher MP optical density because of an increased optical path length.31 Thus, for such patients, measured 586
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MP optical density could be high even if total amounts were significantly lower. Given the increasing interest in the use of the MP carotenoids in the early treatment and/or prevention of cataracts and AMD, proper validation of the method on these subjects is imperative.
REFERENCES 1. Snodderly DM, Brown PK, Delori FC, Auran JD. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. Invest Ophthalmol Vis Sci 1984;25:660 – 673. 2. Hammond BR, Wooten BR, Snodderly DM. Individual variations in the spatial profile of macular pigment. J Opt Soc Am A 1997;14:1187–1196. 3. Hammond BR, Wooten BR, Curran-Celentano J. Carotenoids in the retina and lens: Possible acute and chronic effects on human visual performance. Arch Biochem Biophys 2001;385:41– 46. 4. Beatty S, Boulton M, Henson D, Koh HH, Murray IJ. Macular pigment and age-related macular degeneration. Br J Ophthalmol 1999;83:867– 877. 5. Bone RA, Landrum JT, Mayne ST, Gomez CM, Tibor SE, Twaroska EE. Macular pigment in donor eyes with and OF
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6.
7.
8. 9.
10.
11.
12.
13.
14.
15.
16. 17.
18.
19.
without AMD: A case-control study. Invest Ophthalmol Vis Sci 2001;42:235–240. Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci 2001;42:439 – 446. Curran-Celentano J, Burke JD, Hammond BR. In Vivo Assessment of Retinal carotenoids: Macular pigment detection techniques and their impact on monitoring pigment status. J Nutrition 2002;132(suppl):535S–539S. Hammond BR, Fuld K, Snodderly DM. Iris color and macular pigment optical density. Exp Eye Res 1996;62:715–720. Berendschot TM, Broekmans WR, Klopping-Ketelaar, IA, Kardinaal AM, van Poppel G, van Norren D. Lens aging in relation to nutritional determinants and possible risk factors for age-related cataract. Arch Ophthalmol 2002;120:1732– 1737. Delori FC, Goger DG, Hammond BR, Snodderly DM, Burns SA. Macular pigment density measured by autofluorescence spectrometry; comparison with reflectometry and heterochromatic flicker photometry. J Opt Soc Am A 2001;18: 1212–1230. Gellerman W, Ermakov IV, Ermakov MR, McClane RW, Zhao DY, Bernstein P. In vivo resonant Raman measurement of macular carotenoid pigments in the young and the aging human retina. J Opt Soc Am A 19:1172–1186. Zhao D-Y, Wintch SW, Ermakov IV, et al. Resonance Raman measurement of macular carotenoids in retinal, choroidal, and macular dystrophies. Arch Ophthalmol 2003; 121:967–972. Wooten BR, Hammon, BR, Land R, Snodderly DM. A practical method of measuring macular pigment optical density. Invest Ophthalmol Vis Sci 1999;40:2481–2489. Davies NP, Morland AB. Color Matching in diabetes: Optical density of the crystalline lens and macular pigments. Invest Ophthalmol Vis Sci 2002;43:281–289. Hammond BR, Wooten BR. Noninvasive assessment of the macular carotenoids. In: Ciulla, TA, Regillo, CD, Harris A, editors. Retina and optic nerve imaging. Delaware: Lippincott, Williams & Wilkins, 2003:231–243. Werner JS, Donnelly SK, Kliegl, R. Aging and human macular pigment density. Vision Res 1987;27:257–268. Bone RA, Landrum JT, Fernandez L, Tarsis SL. Analysis of the macular pigment by HPLC: Retinal distribution and age study. Invest Ophthalmol Vis Sci 1988;29:843– 849. Ciulla TA, Hammond BR, Yung CW, Pratt L. Macular pigment optical density before and after cataract extraction. Invest Ophthalmol Vis Sci 2001;42:1338 –1341. Ciulla T, Curran-Celentano J, Cooper D, et al. Macular pigment optical density in a midwestern sample. Ophthalmology 2001;108:730 –737.
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20. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39:367–374. 21. Hammond BR, Fuld K. Interocular differences in macular pigment density. Invest Ophthalmol Vis Sci 1992;33:350 – 355. 22. Snodderly DM, Hammond BR. In vivo psychophysical assessment of nutritional and environmental influences on human ocular tissues, lens and macular pigment. In: Taylor, AJ, editor. Nutritional and environmental influences on vision. Boca Raton: CRC Press,1999:251–273. 23. Cooper DA, Curran-Celentano J, Ciulla TA, et al. Olestra consumption is not associated with macular pigment optical density in a cross-sectional volunteer sample in Indianapolis. J Nutr 2000;130:642– 647. 24. Wooten BR, Hammond BR. Assessment of the Raman method of measuring human macular pigment: Response to Bernstein and Gellerman. [eLetter to the Editor]. Invest Ophthalmol Vis Sci. Available at http://www.iovs.org/cgi/ eletters?lookup⫽by_date&days⫽9999. Accessed December 30, 2003. 25. Werner JS, Bieber ML, Schefrin BE. Senescence of foveal and parafoveal cone sensitivities and their relations to macular pigment density. J Opt Soc Am A 2000;17:1918 – 1932. 26. Chen SF, Chang Y, Wu JC. The spatial distribution of macular pigment in humans. Curr Eye Res 2001;6:422– 434. 27. Robson AG, Moreland J D, Pauleikhoff D, et al. Macular pigment density and distribution: comparison of fundus autofluorescence with minimum motion photometry. Vis Res 2003;43:1765–1775. 28. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic agerelated macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75:216 –230. 29. Duncan JL, Aleman TS, Gardner LM, et al. Macular pigment and lutein supplementation in choroideremia. Exp Eye Res 2002;3:371–381. 30. Aleman TS, Duncan JL, Bieber ML, et al. Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome. Invest Ophthalmol Vis Sci 2001;42:1873– 1881. 31. Alexander KR, Kilbride PE, Fishman GA, Fishman M. Macular pigment and reduced foveal short-wavelenghth sensitivity in retinitis pigmentosa. Vision Res 1987;27:1077– 1083.
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Biosketch Dr. Ciulla has served as Co-Director of the Retina Service and Associate Professor of Ophthalmology on the faculty of the Indiana University School of Medicine, prior to joining the Midwest Eye Institute. He has served as a consultant/researcher for numerous ophthalmic pharmaceutical companies, has lectured nationally and internationally, has authored nearly 100 publications, and co-edited two major textbooks. He currently participates in several national clinical treatment trials for age-related macular degeneration, diabetic retinopathy, and venous occlusions.
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Biosketch Dr. Hammond is Professor of Physiology at the University of Georgia. He has served as a consultant/researcher for numerous ophthalmic pharmaceutical companies, has lectured nationally and internationally, and is a leading authority worldwide in macular pigments and their role in age-related macular degeneration, the leading cause of blindness in industrialized countries.
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● PURPOSE:
Increasing evidence has linked retinal lutein and zeaxanthin (termed macular pigment, MP) to the risk of age-related macular degeneration (AMD). Currently, however, studies differ regarding the question of whether MP declines with age or age has an effect in patient populations being assessed. This study assessed MP across the lifespan with an emphasis on assessing MP in a cross-section of elderly including those with lenticular or age-related macular degeneration, or both. ● DESIGN: Prospective, observational, cross-sectional study. ● METHODS: SETTING: Institution. STUDY POPULATION: Cross-sectional study of normal, cataractous, and AMD subjects tested in Indianapolis, Indiana, including 390 subjects, 22 with cataracts and 59 with age-related macular degeneration. OBSERVATIONAL PROCEDURE: MP density was measured with a one-degree diameter test field at 460 nm using a psychophysical method based on heterochromatic flicker photometry. MAIN OUTCOME MEASURES: MP optical density. ● RESULTS: MP does not appear to change as a function of age (r ⴝ ⴙ.04) when examining subjects across the lifespan (from 18 – 88 years). There was a slight tendency (slope ⴝ ⴚ.0027, r ⴝ ⴚ.11) for MP to decline when only the elderly subjects were considered, but this trend was not significant (P < .12) for any of the groups considered (normal, cataractous, or AMD). ● CONCLUSIONS: MP does not change significantly with age, even when elderly subjects with cataracts and AMD are considered. Using heterochromic flicker photometry, elderly subjects display a full range of MP density that is similar to young subjects. (Am J Ophthalmol 2004; Accepted for publication May 18, 2004. From the Retina Service, Midwest Eye Institute, Methodist Medical Plaza North, Indianapolis, Indiana (T.A.C.); and from the Vision Science Laboratory, University of Georgia, Athens, Georgia (B.R.H.). Inquiries to Thomas A. Ciulla, Retina Service, Midwest Eye Institute, Methodist Medical Plaza North, 201 Pennsylvania Parkway, Indianapolis, Indiana 46280; fax: 317-817-1898; e-mail: [email protected]
582
©
2004 BY
138:582–587. © 2004 by Elsevier Inc. All rights reserved.)
A
GE-RELATED MACULAR DEGENERATION (AMD) IS
characterized by degeneration of the central macular region of the retina. The regional selectivity of this disease suggests that some unique feature of the macula accounts for this susceptibility. Probably one of the most unique and variable features of the macula is the concentration of the carotenoids, lutein and zeaxanthin, in the inner layers of the fovea.1 These dietary pigments, termed macular pigment (MP), have been shown to vary by over a factor of 10 across individuals.2 There is a large body of evidence from diverse sources suggesting that high optical density of MP may help protect the retina by filtering actinic short-wave light and through an antioxidant mechanism.3,4 Because low levels of MP might actually be a risk for AMD,5,6 identifying factors related to individual differences in MP density across the life span is of interest. Past studies have suggested a number of MP determinants (many of which are also classic risk factors for AMD) including: dietary carotenoid intake, smoking status, iris color, gender, and body fat/BMI.7 Results regarding MP determinants, however, must still be regarded as inconclusive since they do not appear to be consistently replicated across studies. Such inconsistency is probably because of true sampling variance but is also probably related to measurement issues. For example, the sample size of some studies may be insufficient to detect some relationships. Moreover, some determinants may be less significant in certain geographical areas. For example, if iris color is related to MP because of variation in light stress (i.e., bluer irises transmit more light and therefore individuals with blue irises may have higher light stress compared with individuals with brown irises),8 then iris color may be more of a significant determinant in sunny climates. It is also often difficult to compare results across laboratories that use different methods. In vivo measures of
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/04/$30.00 doi:10.1016/j.ajo.2004.05.057
MP density can be made using fundus reflectometry,9 autofluorescence,10 Raman spectroscopy,11,12 as well as various psychophysical methods.13,14 Each method depends upon different assumptions and often uses different spectral and spatial stimulus conditions, which influences the interpretation of the results.15 Probably the most debatable MP determinant appears to be the effect of age on MP density. Certainly, measuring the optical characteristics of elderly eyes is more difficult than younger eyes, which may contribute to inconsistencies across studies. In a recent study using Raman spectroscopy, one group found that MP density declined by approximately 84% between the ages of 20 and 70 years.11 This group also found that the average optical density of subjects older than age 60 ranged from zero to approximately 0.05 optical density units. Thus, this study suggested that the MP density of the elderly was uniformly low. This finding was recently replicated in another study using Raman spectroscopy, which also found a sharp age-related decline (60% when comparing subjects in their 20s and 50s) in the MP of patients with inherited retinal degenerations (such as retinitis pigmentosa and choroideremia).12 In contrast, most other studies (using psychophysics,16 autoflourescence, reflectometry,9,10 and HPLC of donor retinas17) that have examined MP density vs age have found either no change or only small to moderate declines and increases, or both. All of the studies that have measured MP as a function of age have focused on MP across the entire lifespan. Moreover, these studies have not included older subjects with retinal or lenticular problems (with the exception of the Zhao and associates data noted earlier). In the present study, we provide data on MP density across the lifespan but we included a large enough elderly sample (50 – 89 years) to determine whether age-related changes in MP are more significant when older subjects are considered separately. In addition to normal subjects with relatively healthy retinas, we also assessed elderly subjects with cataracts and geographic AMD.
DESIGN THIS STUDY WAS AN OBSERVATIONAL CROSS-SECTIONAL
design.
ly.18 All patients were undergoing planned phacoemulsification and placement of a foldable acrylic posterior chamber intraocular lens for cataract of sufficient severity to interfere with their activities of daily living. The median preoperative best-corrected Snellen distance visual acuity measured 20/50. Patients were deemed eligible for this study if their near acuity could be refracted to 20/25 or better. Only the MP data before cataract removal was used for the present analysis. Fifty-nine subjects with nonexudative AMD were assessed. Data from the older subjects was compared with data from a younger sample (n ⫽ 280, age range ⫽ 18⫺50). These data from the younger sample were previously reported separately.19 All of the older subjects underwent careful ophthalmic examination before testing. Subjects were defined as having nonexudative macular degeneration according to the International Classification System, which specifies changes such as the presence of “soft drusen greater than 63 m, hyperpigmentation and/or hypopigmentation of the retinal pigment epithelium, Poor geographic atrophy of the retinal pigment epithelium”.20 Exclusion criteria used in selecting the comparison group included exudative macular degeneration in the study eye defined according to the International Classification System as the presence of “retinal pigment epithelium and associated neurosensory retinal detachment, (peri)retinal hemorrhages, or (peri) retinal fibrosis on masked analysis of fundus photos or evidence of choroidal neovascularization (CNVM) on fluorescein angiography”.20 The 29 subjects defined as “normal” did not show evidence of either nonexudative or exudative AMD as defined above. Either normal or AMD subjects were deemed ineligible if they had a history of diabetic retinopathy, ophthalmic or retinal artery occlusion, retinal vein occlusions, hypertensive retinopathy or choroidopathy, or known history of significant carotid stenosis. Additional exclusion criteria included glaucoma, optic neuropathy, macular dystrophies, ocular inflammatory disease, or retinal detachment. Additionally, subjects were excluded if they were unable to give informed consent, or had a history of allergy to fluorescein, radiographic dyes, shellfish, or iodine. Only subjects with a near visual acuity of 20/30 or better were recruited to perform heterochromatic flicker photometry. These subjects completed the psychophysical tasks with little difficulty. ● MEASUREMENT OF MACULAR PIGMENT OPTICAL DENSITY (MPOD): Heterochromic flicker photometry
METHODS A total of 110 elderly subjects were evaluated (average age ⫽ 72, SD ⫽ 8). Twenty-nine of these subjects were relatively healthy older subjects without retinal disease, but some (n ⫽ 16) had varying levels of lenticular opacities. Twenty-two subjects with cataracts severe enough to require extraction were also assessed. Data for these subjects was previously reported separate-
(HFP) was used to measure MP. This MP measurement technique has been validated on normal subjects by measuring the entire spectral absorption curve of MP and comparing it to the extinction spectrum of the macular pigments measured in excised tissue. 21 The reliability of the method has also been evaluated previously,2,21,22 and prior studies from this institution have been published in both younger (18 –50 years) and older (47– 81 years)
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populations. 18,19 Additionally, a recent study at the same institution with the identical apparatus has demonstrated that naive subjects recruited from the general population can reliably undergo testing. 19,23 In this study, 280 healthy adult volunteers, consisting of 138 men and 142 women, between the ages of 18 and 50 years, were found to have a mean MPOD measuring 0.211 ⫾ 0.13. 19,23 MP optical density was measured with a 1-degree test stimulus. Test stimuli were presented in natural view and near the center of a 6-degree, 10.5 cd/m2, 470-nm circular background. The test stimulus was alternately composed of a 460-nm measuring field (peak MP absorbance) and a 570-nm, 16.7 cd/m2, reference field (minimal MP absorbance). Light for the measuring and reference fields and the background was produced by 40-nm bandpass LEDs with peak energy at 460, 570, and 470 nm, respectively (Nichia Corp., Mountville, Pennsylvania, USA). The radiance of the LEDs was controlled by constant current, high frequency electronic pulses. The measuring and reference fields were superposed and presented out of phase at an alternation rate of 11 to 12 Hz in the foveal condition and 6 to 7 Hz in the parafoveal condition. Parafoveal stimuli were presented at an eccentricity of 4 degrees. Details regarding the densitometer used to measure MP have been published previously. 13 Details regarding the procedure and assumptions underlying the method were published previously.15 Subjects were given brief instructions on the method and a practice trial before five foveal and five parafoveal measurements were made. The foveal and parafoveal values were calculated from the average of the final five readings, and these averages were then used to calculate MPOD (which was then increased by a 15% constant to correct for the bandwidth of the source). As noted above, this protocol has been used in prior published studies from this institution. 19,23 In the younger sample without ocular disease, the right eye was assessed (n ⫽ 280, age range ⫽ 18 –50). In the 22 subjects with cataracts severe enough to require extraction, only the data from the cataractous eye were used in the analysis, and as noted above, the median preoperative best-corrected Snellen distance visual acuity measured 20/50 with a refracted near acuity of 20/25 or better. In the 59 subjects with nonexudative AMD, only the eligible eye was assessed, according the AMD inclusion and exclusion criteria noted above, and the near acuity refracted to 20/25 or better. If both eyes were deemed eligible, only the data from the right eye was used in the analysis. In the 29 elderly subjects defined as “normal” with no AMD, only the right eye was assessed. For each group of patients, the mean MP and standard deviation were calculated. Groups were compared using the Student’s t test. To analyze the relationship of MP and age, linear regression was used. 584
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RESULTS THE OVERALL MP OF THE ELDERLY SAMPLE WAS 0.26 (SD ⫽
0.19). The average MP of the normal, AMD and cataractous subjects was 0.28 (SD ⫽ 0.21), 0.26 (SD ⫽ 0.21), and 0.24 (SD ⫽ 0.16). These means were not significantly different. Nonetheless, in this study we did not attempt to analyze the diet of these subjects nor did we exclude subjects who were taking dietary supplements. To determine whether supplement use influenced the average MP values of each group, we contacted 12 of the normal subjects, all of the cataract subjects, and 29 of the AMD subjects to question them regarding supplement use. This analysis was done several months after the original measurements. Although we were unable to quantify dosage, we did discover that a significant number of the subjects (58% of the normals, 59% of the cataract subjects, and 62% of the AMD subjects) reported that they were using supplements that contained lutein at the time of our measurements. This supplement use, however, did not co-vary with age. Consequently, although it may have confounded any mean differences between the groups, it probably did not influence the age functions. As shown in Figure 1, when all of the subjects are considered together, MP does not appear to change as a function of age (r ⫽ ⫹.04). Similarly, as shown in Figure 2, although there was a slight tendency (slope ⫽ ⫺.0027, r ⫽ ⫺.11) for MP to decline when only the elderly subjects were considered, this trend was not significant (P ⬍ .12). This slight tendency to decline was seen in the normal, AMD and cataractous subjects but was not significant for any group.
DISCUSSION THESE DATA SUGGEST THAT MP DOES NOT CHANGE SIG-
nificantly with age, even when elderly subjects with cataracts and AMD are considered, although the number of patients with AMD and cataracts are relatively small in number and that no difference may be seen because of the lack of power. In general, these data are consistent with most of the literature on this topic with the exception of MP data obtained using Raman spectroscopy. Unlike most methods, however, the Raman method measures the retinal carotenoids using an absolute instead of a relative method. By using an eccentric reference, most methods are able to minimize interference by anterior structures of the eye, because the contribution from such structures is the same at both the measuring and reference sites. In contrast, the Raman method is based on an absolute signal arising directly from the carotenoid molecules themselves. (The carotenoid concentrations outside of the macula are too low to provide an eccentric reference signal.) The absolute Raman signal is therefore susceptible to interference by any structures lying between the retinal carotenoids and the collecting detector. The most significant interference OF
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FIGURE 1. Macular pigment and age. The relation between macular pigment and age is plotted for the entire sample. When all of the subjects are considered together, Macular pigment does not appear to change as a function of age (r ⴝ ⴙ.04).
at the wavelengths used by the Raman method (488 and 527 nm) probably arises from absorption and scattering by the crystalline lens,24 which is exacerbated in the elderly. Thus, unlike the Raman method, which suggests that the MP density of the elderly is uniformly low, our data show that elderly subjects, including those with cataracts and AMD, display the full range of MP density. A number of recent studies have suggested that macular pigment optical density is not effectively zero at 4 degrees for some individuals.25–27 We chose 4 degrees as a reference to be able to compare our current data on elderly subjects directly with earlier data we obtained on younger subjects.19 We also thought the task might be easier for the older subjects with a less eccentric reference. Nonetheless, a recent study measuring the spatial distribution of MP using imaging fundus reflectometry, has suggested the possibility that wider MP distributions might be positively correlated with age.26 Their data suggested that for younger subjects (age range ⫽ 22 to 30 years) MP density at 4 degrees eccentricity ranged from 0 to approximately 0.05 OD units. For older subjects (age range ⫽ 55– 83 years), however, MP density at 4 degrees ranged from approximately 0.02 to 0.10. If MP density at 4 degrees does increase with age, and 4 degrees is used as a zero reference (as we did in this study), this would result in an underestimation of MP density in the elderly subjects (e.g., of approximately 0.05 O.D. when comparing 20 and 70 year olds). As shown in Figure 1, however, our data suggest a
slight, albeit nonsignificant, increase with age. If using a 4-degree reference confounded our age analysis, this would result in a more significant trend for MP density to increase with age. The fact that the subjects with cataracts and AMD did not have particularly low average MP levels may be attributable to the fact that many of these subjects used dietary supplements containing lutein and zeaxanthin. For example, the AMD subjects who reported using supplements tended (P ⬍ .10) to have higher MP density (about 31%) compared with the subjects who reported not using supplements. This finding is preliminary, because we were not able to quantify dosage, and supplement information was obtained for only about half of the AMD subjects. This trend was also not seen in the subjects with cataracts. Nonetheless, it does raise the intriguing possibility that supplementation can increase the MP of AMD subjects. We also did not find a significant decline in MP density based on the age of the subjects with AMD and cataracts. It is unlikely that supplement use influenced this result, because supplement use did not appear to vary with age. Nevertheless, this represents a limitation of this study, and further research is warranted. Finally, we should note that our results for the AMD and cataract subjects are based on retinal measurements performed using the HFP method. This method is certainly the most common method of measuring MP density and has been used on a number of patient populations includ-
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FIGURE 2. Macular pigment and age, stratified. The relation between macular pigment optical density and age for subjects with relatively healthy retinas (open squares), AMD (open circles), and cataracts (solid squates) is plotted. Although there was a slight tendency (slope ⴝ ⴚ.0027, r ⴝ ⴚ.11) for MP to decline when only the elderly subjects were considered, this trend was not significant (P < .12).
ing patients with age-related macular degeneration,6,28 cataracts,18 choroideremia,29 and retinitis pigmentosa.30 In all cases, it appears that HFP measurements can be made expeditiously provided subjects have vision that is sufficient to allow successful completion of the task (for example, Snellen acuity of 20/80 or better). Certainly, our measurements on patient populations were made without undue difficulty and within a relatively short time frame (e.g., around 20 –30 minutes). The method does not require pupillary dilation and is one of the few methods that is relatively unaffected by significant changes in anterior optical media.13,18 Nonetheless, it is important to point out that, despite its widespread use on patient populations, the method has only been validated on normal nondiseased subjects (for example, by matching MP spectral absorption profiles measured using HFP to ex vivo extinction spectra of L and Z). Without proper validation on patient populations, MP data obtained using this method (or any other MP assessment method at the current time) must be interpreted with caution. For example, one group has shown that morphologic disturbance in the cone axons of patients with retinitis pigmentosa could lead to higher MP optical density because of an increased optical path length.31 Thus, for such patients, measured 586
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MP optical density could be high even if total amounts were significantly lower. Given the increasing interest in the use of the MP carotenoids in the early treatment and/or prevention of cataracts and AMD, proper validation of the method on these subjects is imperative.
REFERENCES 1. Snodderly DM, Brown PK, Delori FC, Auran JD. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. Invest Ophthalmol Vis Sci 1984;25:660 – 673. 2. Hammond BR, Wooten BR, Snodderly DM. Individual variations in the spatial profile of macular pigment. J Opt Soc Am A 1997;14:1187–1196. 3. Hammond BR, Wooten BR, Curran-Celentano J. Carotenoids in the retina and lens: Possible acute and chronic effects on human visual performance. Arch Biochem Biophys 2001;385:41– 46. 4. Beatty S, Boulton M, Henson D, Koh HH, Murray IJ. Macular pigment and age-related macular degeneration. Br J Ophthalmol 1999;83:867– 877. 5. Bone RA, Landrum JT, Mayne ST, Gomez CM, Tibor SE, Twaroska EE. Macular pigment in donor eyes with and OF
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6.
7.
8. 9.
10.
11.
12.
13.
14.
15.
16. 17.
18.
19.
without AMD: A case-control study. Invest Ophthalmol Vis Sci 2001;42:235–240. Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci 2001;42:439 – 446. Curran-Celentano J, Burke JD, Hammond BR. In Vivo Assessment of Retinal carotenoids: Macular pigment detection techniques and their impact on monitoring pigment status. J Nutrition 2002;132(suppl):535S–539S. Hammond BR, Fuld K, Snodderly DM. Iris color and macular pigment optical density. Exp Eye Res 1996;62:715–720. Berendschot TM, Broekmans WR, Klopping-Ketelaar, IA, Kardinaal AM, van Poppel G, van Norren D. Lens aging in relation to nutritional determinants and possible risk factors for age-related cataract. Arch Ophthalmol 2002;120:1732– 1737. Delori FC, Goger DG, Hammond BR, Snodderly DM, Burns SA. Macular pigment density measured by autofluorescence spectrometry; comparison with reflectometry and heterochromatic flicker photometry. J Opt Soc Am A 2001;18: 1212–1230. Gellerman W, Ermakov IV, Ermakov MR, McClane RW, Zhao DY, Bernstein P. In vivo resonant Raman measurement of macular carotenoid pigments in the young and the aging human retina. J Opt Soc Am A 19:1172–1186. Zhao D-Y, Wintch SW, Ermakov IV, et al. Resonance Raman measurement of macular carotenoids in retinal, choroidal, and macular dystrophies. Arch Ophthalmol 2003; 121:967–972. Wooten BR, Hammon, BR, Land R, Snodderly DM. A practical method of measuring macular pigment optical density. Invest Ophthalmol Vis Sci 1999;40:2481–2489. Davies NP, Morland AB. Color Matching in diabetes: Optical density of the crystalline lens and macular pigments. Invest Ophthalmol Vis Sci 2002;43:281–289. Hammond BR, Wooten BR. Noninvasive assessment of the macular carotenoids. In: Ciulla, TA, Regillo, CD, Harris A, editors. Retina and optic nerve imaging. Delaware: Lippincott, Williams & Wilkins, 2003:231–243. Werner JS, Donnelly SK, Kliegl, R. Aging and human macular pigment density. Vision Res 1987;27:257–268. Bone RA, Landrum JT, Fernandez L, Tarsis SL. Analysis of the macular pigment by HPLC: Retinal distribution and age study. Invest Ophthalmol Vis Sci 1988;29:843– 849. Ciulla TA, Hammond BR, Yung CW, Pratt L. Macular pigment optical density before and after cataract extraction. Invest Ophthalmol Vis Sci 2001;42:1338 –1341. Ciulla T, Curran-Celentano J, Cooper D, et al. Macular pigment optical density in a midwestern sample. Ophthalmology 2001;108:730 –737.
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20. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39:367–374. 21. Hammond BR, Fuld K. Interocular differences in macular pigment density. Invest Ophthalmol Vis Sci 1992;33:350 – 355. 22. Snodderly DM, Hammond BR. In vivo psychophysical assessment of nutritional and environmental influences on human ocular tissues, lens and macular pigment. In: Taylor, AJ, editor. Nutritional and environmental influences on vision. Boca Raton: CRC Press,1999:251–273. 23. Cooper DA, Curran-Celentano J, Ciulla TA, et al. Olestra consumption is not associated with macular pigment optical density in a cross-sectional volunteer sample in Indianapolis. J Nutr 2000;130:642– 647. 24. Wooten BR, Hammond BR. Assessment of the Raman method of measuring human macular pigment: Response to Bernstein and Gellerman. [eLetter to the Editor]. Invest Ophthalmol Vis Sci. Available at http://www.iovs.org/cgi/ eletters?lookup⫽by_date&days⫽9999. Accessed December 30, 2003. 25. Werner JS, Bieber ML, Schefrin BE. Senescence of foveal and parafoveal cone sensitivities and their relations to macular pigment density. J Opt Soc Am A 2000;17:1918 – 1932. 26. Chen SF, Chang Y, Wu JC. The spatial distribution of macular pigment in humans. Curr Eye Res 2001;6:422– 434. 27. Robson AG, Moreland J D, Pauleikhoff D, et al. Macular pigment density and distribution: comparison of fundus autofluorescence with minimum motion photometry. Vis Res 2003;43:1765–1775. 28. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic agerelated macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75:216 –230. 29. Duncan JL, Aleman TS, Gardner LM, et al. Macular pigment and lutein supplementation in choroideremia. Exp Eye Res 2002;3:371–381. 30. Aleman TS, Duncan JL, Bieber ML, et al. Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome. Invest Ophthalmol Vis Sci 2001;42:1873– 1881. 31. Alexander KR, Kilbride PE, Fishman GA, Fishman M. Macular pigment and reduced foveal short-wavelenghth sensitivity in retinitis pigmentosa. Vision Res 1987;27:1077– 1083.
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Biosketch Dr. Ciulla has served as Co-Director of the Retina Service and Associate Professor of Ophthalmology on the faculty of the Indiana University School of Medicine, prior to joining the Midwest Eye Institute. He has served as a consultant/researcher for numerous ophthalmic pharmaceutical companies, has lectured nationally and internationally, has authored nearly 100 publications, and co-edited two major textbooks. He currently participates in several national clinical treatment trials for age-related macular degeneration, diabetic retinopathy, and venous occlusions.
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Biosketch Dr. Hammond is Professor of Physiology at the University of Georgia. He has served as a consultant/researcher for numerous ophthalmic pharmaceutical companies, has lectured nationally and internationally, and is a leading authority worldwide in macular pigments and their role in age-related macular degeneration, the leading cause of blindness in industrialized countries.
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