Abstract

We have used resonant Raman scattering spectroscopy as a novel, noninvasive, in vivo optical technique to measure the concentration of the macular carotenoid pigments lutein and zeaxanthin in the living human retina of young and elderly adults. Using a backscattering geometry and resonant molecular excitation in the visible wavelength range, we measure the Raman signals originating from the single- and double-bond stretch vibrations of the π-conjugated molecule’s carbon backbone. The Raman signals scale linearly with carotenoid content, and the required laser excitation is well below safety limits for macular exposure. Furthermore, the signals decline significantly with increasing age in normal eyes. The Raman technique is objective and quantitative and may lead to a new method for rapid screening of carotenoid pigment levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness in the elderly in the United States.

© 2002 Optical Society of America

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2001 (5)

Age Related Eye Disease Study Research Group, “A randomized, placebo controlled clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss,” Arch. Ophthalmol. 119, 1417–1436 (2001).
[CrossRef]

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

I. V. Ermakov, R. W. McClane, W. Gellermann, P. S. Bernstein, “Resonant Raman detection of macular pigment levels in the living human retina,” Opt. Lett. 26, 202–204 (2001).
[CrossRef]

F. C. Delori, D. G. Goger, B. R. Hammond, D. M. Snodderly, S. A. Burns, “Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry,” J. Opt. Soc. Am. A 18, 1212–1230 (2001).
[CrossRef]

2000 (10)

J. S. Werner, M. L. Bieber, B. E. Schefrin, “Senescence of foveal and parafoveal cone sensitivities and their relations to macular pigment density,” J. Opt. Soc. Am. A 17, 1918–1932 (2000).
[CrossRef]

C. J. Hammond, H. Sneider, T. D. Spector, C. E. Gilbert, “Factors affecting pupil size after dilatation: the Twin Eye Study,” Br. J. Ophthamol. 84, 1173–1176 (2000).
[CrossRef]

J. Dillon, L. Zheng, J. C. Merriam, E. R. Gaillard, “Transmission spectra of light to the mammalian retina,” Photochem. Photobiol. 71, 225–229 (2000).
[CrossRef] [PubMed]

E. R. Gaillard, L. Zheng, J. C. Merriam, J. Dillon, “Age-related changes in the absorption characteristics of the primate lens,” Invest. Ophthalmol. Visual Sci. 41, 1454–1459 (2000).

B. R. Hammond, M. Caruso-Avery, “Macular pigment optical density in a southwestern sample,” Invest. Ophthalmol. Visual Sci. 41, 1492–1497 (2000).

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

L. M. Rapp, S. S. Maple, J. H. Choi, “Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina,” Invest. Ophthalmol. Visual Sci. 41, 1200–1209 (2000).

S. Beatty, H.-H. Koh, D. Henson, M. Boulton, “The role of oxidative stress in the pathogenesis of age-related macular degeneration,” Surv. Ophthalmol. 45, 115–134 (2000).
[CrossRef] [PubMed]

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

1999 (4)

J. D. M. Gass, “The Müller cell cone, an overlooked part of the anatomy of the fovea centralis,” Arch. Ophthalmol. 117, 821–823 (1999).
[CrossRef] [PubMed]

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

T. Berendshot, J. van de Kraats, D. van Norren, “Three methods to measure macular pigment compared in a lutein intake study,” Invest. Ophthalmol. Visual Sci. Suppl. 39, S314 (1999).

J. Sebag, R. R. Ansari, S. Dunker, K. I. Suh, “Dynamic light scattering of diabetic vitreopathy,” Diabetes Technol. Ther. 1, 169–176 (1999).
[CrossRef]

1998 (4)

B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Preservation of visual sensitivity of older subjects: association with macular pigment density,” Invest. Ophthalmol. Visual Sci. 39, 397–406 (1998).

P. S. Bernstein, M. D. Yoshida, N. B. Katz, R. W. McClane, W. Gellermann, “Raman detection of macular carotenoid pigments in intact human retina,” Invest. Ophthalmol. Visual Sci. 39, 2003–2011 (1998).

A. E. Elsner, S. A. Burns, E. Beausencourt, J. J. Weiter, “Foveal cone photopigment distribution: small alterations associated with macular pigment distribution,” Invest. Ophthalmol. Visual Sci. 39, 2394–2404 (1998).

D. Schweitzer, M. Hammer, M. Scibor, “Imaging spectrometry in ophthalmology: principle and applications in microcirculation and in investigation of pigments,” Invest. Ophthalmol. Visual Sci. 39, 2001–2011 (1998).

1997 (5)

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

J. T. Landrum, R. A. Bone, M. D. Kilburn, “The macular pigment: a possible role in protection from age-related macular degeneration,” Adv. Pharmacol. 38, 537–556 (1997).
[CrossRef] [PubMed]

B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Individual variations in the spatial profile of human macular pigment,” J. Opt. Soc. Am. A 14, 1187–1196 (1997).
[CrossRef]

1996 (2)

A. E. Elsner, S. A. Burns, J. J. Weiter, F. C. Delori, “Infrared imaging of subretinal structures in the human ocular fundus,” Vision Res. 36, 191–201 (1996).
[CrossRef] [PubMed]

J. van de Kraats, T. T. J. M. Berendshot, D. van Norren, “The pathways of light measured in fundus reflectometry,” Vision Res. 36, 2229–2247 (1996).
[CrossRef] [PubMed]

1995 (1)

D. M. Snodderly, “Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins,” Am. J. Clin. Nutr. Suppl. 62, 1448S–1461S (1995).

1994 (1)

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

1993 (1)

Eye Disease Case Control Study Group, “Antioxidant status and neovascular age-related macular degeneration,” Arch. Ophthalmol. (Chicago) 111, 104–109 (1993).
[CrossRef]

1992 (2)

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, G. W. Hughes, R. H. Webb, “Reflectometry with a scanning laser ophthalmoscope,” Appl. Opt. 31, 3697–3710 (1992).
[CrossRef] [PubMed]

1991 (2)

D. M. Snodderly, G. J. Handelman, A. A. Adler, “Distribution of individual macular pigment carotenoids in central retina of macaque and squirrel monkeys,” Invest. Ophthalmol. Visual Sci. 32, 268–279 (1991).

A. P. Shreve, J. K. Trautman, T. G. Owens, A. C. Albrecht, “Determination of the S2 lifetime of β-carotene,” Chem. Phys. Lett. 178, 89 (1991).
[CrossRef]

1989 (3)

P. E. Kilbride, K. R. Alexander, M. Fishman, G. A. Fishman, “Human macular pigment assessed by imaging fundus reflectometry,” Vision Res. 29, 663–674 (1989).
[CrossRef] [PubMed]

D. van Norren, J. van de Kraats, “Imaging retinal densitometry with a confocal scanning ophthalmoscope,” Vision Res. 29, 1825–1830 (1989).
[CrossRef]

F. C. Delori, K. P. Pflibsen, “Spectral reflectance of the human ocular fundus,” Appl. Opt. 28, 1061–1077 (1989).
[CrossRef] [PubMed]

1988 (4)

R. A. Weale, “Age and the transmittance of the human crystalline lens,” J. Physiol. 395, 577–587 (1988).

P. A. Sample, F. D. Esterson, R. N. Weinreb, R. M. Boynton, “The aging lens: in vivo assessment of light absorption in 84 human eyes,” Invest. Ophthalmol. Visual Sci. 29, 1306–1311 (1988).

R. A. Bone, J. T. Landrum, L. Fernandez, S. L. Tarsis, “Analysis of macular pigment by HPLC: retinal distribution and age study,” Invest. Ophthalmol. Visual Sci. 29, 843–849 (1988).

Y. Koyama, I. Takatsuka, M. Nakata, M. Tasumi, “Raman and infrared spectra of the all-trans, 7-cis, 9-cis, 13-cis, and 15-cis isomers of β-carotene: key bands distinguishing stretched or terminal-bent configurations from central-bent configurations” J. Raman Spectrosc. 19, 37–49 (1988).
[CrossRef]

1987 (2)

1986 (1)

D. van Norren, L. F. Tiemeijer, “Spectral reflectance of the human eye,” Vision Res. 26, 313–320 (1986).
[CrossRef] [PubMed]

1985 (1)

R. A. Bone, J. T. Landrum, S. L. Tarsis, “Preliminary identification of the human macular pigment,” Vision Res. 25, 1531–1535 (1985).
[CrossRef] [PubMed]

1984 (1)

D. M. Snodderly, J. D. Auran, F. C. Delori, “The macular pigment, I: absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas,” Invest. Ophthalmol. Visual Sci. 25, 660–673 (1984).

1980 (3)

R. H. Webb, G. W. Hughes, O. Pomerantzeff, “Flying spot TV ophthalmoscope,” Appl. Opt. 19, 2991–2997 (1980).
[CrossRef] [PubMed]

F. C. Delori, J. S. Parker, M. A. Mainster, “Light levels in fundus photography and fluorescein angiography,” Vision Res. 20, 1099–1104 (1980).
[CrossRef] [PubMed]

L. Apt, A. Henrick, “Pupillary dilatation with single eyedrop mydriatic combinations,” Am. J. Ophthalmol. 89, 553–559 (1980).
[PubMed]

1974 (1)

V. M. Reading, R. A. Weale, “Macular pigment and chromatic aberration,” J. Am. Optom. Assoc. 64, 231–234 (1974).

1962 (1)

E. A. Boettner, J. R. Wolter, “Transmission of the ocular media,” Invest. Ophthalmol. Visual Sci. 1, 776–783 (1962).

1961 (1)

A. C. Albrecht, “On the theory of Raman intensities,” J. Chem. Phys. 34, 1476–1484 (1961).
[CrossRef]

Adler, A. A.

D. M. Snodderly, G. J. Handelman, A. A. Adler, “Distribution of individual macular pigment carotenoids in central retina of macaque and squirrel monkeys,” Invest. Ophthalmol. Visual Sci. 32, 268–279 (1991).

Adler, A. J.

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
[CrossRef] [PubMed]

Ajani, U. A.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Albrecht, A. C.

A. P. Shreve, J. K. Trautman, T. G. Owens, A. C. Albrecht, “Determination of the S2 lifetime of β-carotene,” Chem. Phys. Lett. 178, 89 (1991).
[CrossRef]

A. C. Albrecht, “On the theory of Raman intensities,” J. Chem. Phys. 34, 1476–1484 (1961).
[CrossRef]

Alexander, K. R.

P. E. Kilbride, K. R. Alexander, M. Fishman, G. A. Fishman, “Human macular pigment assessed by imaging fundus reflectometry,” Vision Res. 29, 663–674 (1989).
[CrossRef] [PubMed]

Ansari, R. R.

J. Sebag, R. R. Ansari, S. Dunker, K. I. Suh, “Dynamic light scattering of diabetic vitreopathy,” Diabetes Technol. Ther. 1, 169–176 (1999).
[CrossRef]

Apt, L.

L. Apt, A. Henrick, “Pupillary dilatation with single eyedrop mydriatic combinations,” Am. J. Ophthalmol. 89, 553–559 (1980).
[PubMed]

Auran, J. D.

D. M. Snodderly, J. D. Auran, F. C. Delori, “The macular pigment, I: absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas,” Invest. Ophthalmol. Visual Sci. 25, 660–673 (1984).

Balashov, N.

W. Gellermann, M. D. Yoshida, R. W. McClane, N. Balashov, P. S. Bernstein, “Raman detection of pigments in the human retina,” in Optical Biopsy II, R. R. Alfano, A. Katzir, eds., Proc. SPIE3250, 8–17 (1998).
[CrossRef]

Barker, F. M.

W. Schalch, P. Dayhaw-Barker, F. M. Barker, “The carotenoids of the human retina,” in Nutritional and Environmental Influences on the Eye, A. Taylor, ed. (CRC, Boca Raton, Fla., 1999), pp. 215–250.

Beatty, S.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

S. Beatty, H.-H. Koh, D. Henson, M. Boulton, “The role of oxidative stress in the pathogenesis of age-related macular degeneration,” Surv. Ophthalmol. 45, 115–134 (2000).
[CrossRef] [PubMed]

Beausencourt, E.

A. E. Elsner, S. A. Burns, E. Beausencourt, J. J. Weiter, “Foveal cone photopigment distribution: small alterations associated with macular pigment distribution,” Invest. Ophthalmol. Visual Sci. 39, 2394–2404 (1998).

Berendshot, T.

T. Berendshot, J. van de Kraats, D. van Norren, “Three methods to measure macular pigment compared in a lutein intake study,” Invest. Ophthalmol. Visual Sci. Suppl. 39, S314 (1999).

Berendshot, T. T. J. M.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

J. van de Kraats, T. T. J. M. Berendshot, D. van Norren, “The pathways of light measured in fundus reflectometry,” Vision Res. 36, 2229–2247 (1996).
[CrossRef] [PubMed]

Bernstein, P. S.

I. V. Ermakov, R. W. McClane, W. Gellermann, P. S. Bernstein, “Resonant Raman detection of macular pigment levels in the living human retina,” Opt. Lett. 26, 202–204 (2001).
[CrossRef]

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

P. S. Bernstein, M. D. Yoshida, N. B. Katz, R. W. McClane, W. Gellermann, “Raman detection of macular carotenoid pigments in intact human retina,” Invest. Ophthalmol. Visual Sci. 39, 2003–2011 (1998).

W. Gellermann, R. W. McClane, N. B. Katz, P. S. Bernstein, “Method and apparatus for noninvasive measurement of carotenoids and related chemical substances in biological tissue,” U.S. patent6,205,354, March20, 2001.

W. Gellermann, M. D. Yoshida, R. W. McClane, N. Balashov, P. S. Bernstein, “Raman detection of pigments in the human retina,” in Optical Biopsy II, R. R. Alfano, A. Katzir, eds., Proc. SPIE3250, 8–17 (1998).
[CrossRef]

P. S. Bernstein, N. B. Katz, “The role of ocular free radicals in age-related macular degeneration,” in Environmental Stressors: Effects on Lung, Skin, Eye and Immune System Function, J. Fuchs, L. Packer, eds. (Marcel Dekker, New York, 2000), pp. 423–456.

P. S. Bernstein, W. Gellermann, R. W. McClane, “Measurement of macular carotenoid levels in the human retina using Raman spectroscopy,” U.S. patent5,873,831, February23, 1999.

Bieber, M. L.

Blair, N.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Boettner, E. A.

E. A. Boettner, J. R. Wolter, “Transmission of the ocular media,” Invest. Ophthalmol. Visual Sci. 1, 776–783 (1962).

Bone, R. A.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

J. T. Landrum, R. A. Bone, M. D. Kilburn, “The macular pigment: a possible role in protection from age-related macular degeneration,” Adv. Pharmacol. 38, 537–556 (1997).
[CrossRef] [PubMed]

R. A. Bone, J. T. Landrum, L. Fernandez, S. L. Tarsis, “Analysis of macular pigment by HPLC: retinal distribution and age study,” Invest. Ophthalmol. Visual Sci. 29, 843–849 (1988).

R. A. Bone, J. T. Landrum, S. L. Tarsis, “Preliminary identification of the human macular pigment,” Vision Res. 25, 1531–1535 (1985).
[CrossRef] [PubMed]

Boulton, M.

S. Beatty, H.-H. Koh, D. Henson, M. Boulton, “The role of oxidative stress in the pathogenesis of age-related macular degeneration,” Surv. Ophthalmol. 45, 115–134 (2000).
[CrossRef] [PubMed]

Boulton, M. E.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

Boynton, R. M.

P. A. Sample, F. D. Esterson, R. N. Weinreb, R. M. Boynton, “The aging lens: in vivo assessment of light absorption in 84 human eyes,” Invest. Ophthalmol. Visual Sci. 29, 1306–1311 (1988).

Burns, S. A.

F. C. Delori, D. G. Goger, B. R. Hammond, D. M. Snodderly, S. A. Burns, “Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry,” J. Opt. Soc. Am. A 18, 1212–1230 (2001).
[CrossRef]

A. E. Elsner, S. A. Burns, E. Beausencourt, J. J. Weiter, “Foveal cone photopigment distribution: small alterations associated with macular pigment distribution,” Invest. Ophthalmol. Visual Sci. 39, 2394–2404 (1998).

A. E. Elsner, S. A. Burns, J. J. Weiter, F. C. Delori, “Infrared imaging of subretinal structures in the human ocular fundus,” Vision Res. 36, 191–201 (1996).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, G. W. Hughes, R. H. Webb, “Reflectometry with a scanning laser ophthalmoscope,” Appl. Opt. 31, 3697–3710 (1992).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, F. C. Delori, R. H. Webb, “Quantitative reflectometry with the SLO,” in Laser Scanning Ophthalmoscopy and Tomography, J. E. Nasemann, R. O. W. Burk, eds. (Quintessenz-Verlag, Berlin, 1990), pp. 109–121.

Burton, T. C.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Carden, D.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

Caruso-Avery, M.

B. R. Hammond, M. Caruso-Avery, “Macular pigment optical density in a southwestern sample,” Invest. Ophthalmol. Visual Sci. 41, 1492–1497 (2000).

Carvalho, L. S.

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

Choi, J. H.

L. M. Rapp, S. S. Maple, J. H. Choi, “Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina,” Invest. Ophthalmol. Visual Sci. 41, 1200–1209 (2000).

Dayhaw-Barker, P.

W. Schalch, P. Dayhaw-Barker, F. M. Barker, “The carotenoids of the human retina,” in Nutritional and Environmental Influences on the Eye, A. Taylor, ed. (CRC, Boca Raton, Fla., 1999), pp. 215–250.

Delori, F. C.

F. C. Delori, D. G. Goger, B. R. Hammond, D. M. Snodderly, S. A. Burns, “Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry,” J. Opt. Soc. Am. A 18, 1212–1230 (2001).
[CrossRef]

A. E. Elsner, S. A. Burns, J. J. Weiter, F. C. Delori, “Infrared imaging of subretinal structures in the human ocular fundus,” Vision Res. 36, 191–201 (1996).
[CrossRef] [PubMed]

F. C. Delori, K. P. Pflibsen, “Spectral reflectance of the human ocular fundus,” Appl. Opt. 28, 1061–1077 (1989).
[CrossRef] [PubMed]

R. W. Webb, G. W. Hughes, F. C. Delori, “Confocal scanning laser ophthalmosope,” Appl. Opt. 26, 1492–1499 (1987).
[CrossRef] [PubMed]

D. M. Snodderly, J. D. Auran, F. C. Delori, “The macular pigment, I: absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas,” Invest. Ophthalmol. Visual Sci. 25, 660–673 (1984).

F. C. Delori, J. S. Parker, M. A. Mainster, “Light levels in fundus photography and fluorescein angiography,” Vision Res. 20, 1099–1104 (1980).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, F. C. Delori, R. H. Webb, “Quantitative reflectometry with the SLO,” in Laser Scanning Ophthalmoscopy and Tomography, J. E. Nasemann, R. O. W. Burk, eds. (Quintessenz-Verlag, Berlin, 1990), pp. 109–121.

F. C. Delori, “Macular pigment density measured by reflectometry and fluorophotometry,” in Ophthalmic and Visual Optics and Noninvasive Assessment of the Visual System, Vol. 3 of 1993 OSA Technical Digest Series (Optical Society of America, Washington, D.C., 1993), pp. 240–243.

Dillon, J.

J. Dillon, L. Zheng, J. C. Merriam, E. R. Gaillard, “Transmission spectra of light to the mammalian retina,” Photochem. Photobiol. 71, 225–229 (2000).
[CrossRef] [PubMed]

E. R. Gaillard, L. Zheng, J. C. Merriam, J. Dillon, “Age-related changes in the absorption characteristics of the primate lens,” Invest. Ophthalmol. Visual Sci. 41, 1454–1459 (2000).

Dratz, E. A.

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
[CrossRef] [PubMed]

Dunker, S.

J. Sebag, R. R. Ansari, S. Dunker, K. I. Suh, “Dynamic light scattering of diabetic vitreopathy,” Diabetes Technol. Ther. 1, 169–176 (1999).
[CrossRef]

Edwards, R. B.

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

Elsner, A. E.

A. E. Elsner, S. A. Burns, E. Beausencourt, J. J. Weiter, “Foveal cone photopigment distribution: small alterations associated with macular pigment distribution,” Invest. Ophthalmol. Visual Sci. 39, 2394–2404 (1998).

A. E. Elsner, S. A. Burns, J. J. Weiter, F. C. Delori, “Infrared imaging of subretinal structures in the human ocular fundus,” Vision Res. 36, 191–201 (1996).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, G. W. Hughes, R. H. Webb, “Reflectometry with a scanning laser ophthalmoscope,” Appl. Opt. 31, 3697–3710 (1992).
[CrossRef] [PubMed]

A. E. Elsner, S. A. Burns, F. C. Delori, R. H. Webb, “Quantitative reflectometry with the SLO,” in Laser Scanning Ophthalmoscopy and Tomography, J. E. Nasemann, R. O. W. Burk, eds. (Quintessenz-Verlag, Berlin, 1990), pp. 109–121.

Ermakov, I. V.

I. V. Ermakov, R. W. McClane, W. Gellermann, P. S. Bernstein, “Resonant Raman detection of macular pigment levels in the living human retina,” Opt. Lett. 26, 202–204 (2001).
[CrossRef]

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

Esterson, F. D.

P. A. Sample, F. D. Esterson, R. N. Weinreb, R. M. Boynton, “The aging lens: in vivo assessment of light absorption in 84 human eyes,” Invest. Ophthalmol. Visual Sci. 29, 1306–1311 (1988).

Farber, M. D.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Fernandez, L.

R. A. Bone, J. T. Landrum, L. Fernandez, S. L. Tarsis, “Analysis of macular pigment by HPLC: retinal distribution and age study,” Invest. Ophthalmol. Visual Sci. 29, 843–849 (1988).

Fishman, G. A.

P. E. Kilbride, K. R. Alexander, M. Fishman, G. A. Fishman, “Human macular pigment assessed by imaging fundus reflectometry,” Vision Res. 29, 663–674 (1989).
[CrossRef] [PubMed]

Fishman, M.

P. E. Kilbride, K. R. Alexander, M. Fishman, G. A. Fishman, “Human macular pigment assessed by imaging fundus reflectometry,” Vision Res. 29, 663–674 (1989).
[CrossRef] [PubMed]

Friedes, L. M.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Gaillard, E. R.

E. R. Gaillard, L. Zheng, J. C. Merriam, J. Dillon, “Age-related changes in the absorption characteristics of the primate lens,” Invest. Ophthalmol. Visual Sci. 41, 1454–1459 (2000).

J. Dillon, L. Zheng, J. C. Merriam, E. R. Gaillard, “Transmission spectra of light to the mammalian retina,” Photochem. Photobiol. 71, 225–229 (2000).
[CrossRef] [PubMed]

Gass, J. D. M.

J. D. M. Gass, “The Müller cell cone, an overlooked part of the anatomy of the fovea centralis,” Arch. Ophthalmol. 117, 821–823 (1999).
[CrossRef] [PubMed]

Gellermann, W.

I. V. Ermakov, R. W. McClane, W. Gellermann, P. S. Bernstein, “Resonant Raman detection of macular pigment levels in the living human retina,” Opt. Lett. 26, 202–204 (2001).
[CrossRef]

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

P. S. Bernstein, M. D. Yoshida, N. B. Katz, R. W. McClane, W. Gellermann, “Raman detection of macular carotenoid pigments in intact human retina,” Invest. Ophthalmol. Visual Sci. 39, 2003–2011 (1998).

W. Gellermann, R. W. McClane, N. B. Katz, P. S. Bernstein, “Method and apparatus for noninvasive measurement of carotenoids and related chemical substances in biological tissue,” U.S. patent6,205,354, March20, 2001.

W. Gellermann, M. D. Yoshida, R. W. McClane, N. Balashov, P. S. Bernstein, “Raman detection of pigments in the human retina,” in Optical Biopsy II, R. R. Alfano, A. Katzir, eds., Proc. SPIE3250, 8–17 (1998).
[CrossRef]

P. S. Bernstein, W. Gellermann, R. W. McClane, “Measurement of macular carotenoid levels in the human retina using Raman spectroscopy,” U.S. patent5,873,831, February23, 1999.

Gilbert, C. E.

C. J. Hammond, H. Sneider, T. D. Spector, C. E. Gilbert, “Factors affecting pupil size after dilatation: the Twin Eye Study,” Br. J. Ophthamol. 84, 1173–1176 (2000).
[CrossRef]

Goger, D. G.

Goldbohm, R. A.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

Gomez, C. A.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Gomez, C. M.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

Gragoudas, E. S.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Haller, J.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Hammer, M.

D. Schweitzer, M. Hammer, M. Scibor, “Imaging spectrometry in ophthalmology: principle and applications in microcirculation and in investigation of pigments,” Invest. Ophthalmol. Visual Sci. 39, 2001–2011 (1998).

Hammond, B. R.

F. C. Delori, D. G. Goger, B. R. Hammond, D. M. Snodderly, S. A. Burns, “Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry,” J. Opt. Soc. Am. A 18, 1212–1230 (2001).
[CrossRef]

B. R. Hammond, M. Caruso-Avery, “Macular pigment optical density in a southwestern sample,” Invest. Ophthalmol. Visual Sci. 41, 1492–1497 (2000).

B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Preservation of visual sensitivity of older subjects: association with macular pigment density,” Invest. Ophthalmol. Visual Sci. 39, 397–406 (1998).

B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Individual variations in the spatial profile of human macular pigment,” J. Opt. Soc. Am. A 14, 1187–1196 (1997).
[CrossRef]

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

D. M. Snodderly, B. R. Hammond, “In vivopsychophysical assessment of nutritional and environmental influences on human ocular tissues: lens and macular pigment,” in Nutritional and Environmental Influences on the Eye, A. Taylor, ed. (CRC, Boca Raton, Fla., 1999), pp. 251–273.

Hammond, C. J.

C. J. Hammond, H. Sneider, T. D. Spector, C. E. Gilbert, “Factors affecting pupil size after dilatation: the Twin Eye Study,” Br. J. Ophthamol. 84, 1173–1176 (2000).
[CrossRef]

Handelman, G. J.

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
[CrossRef] [PubMed]

D. M. Snodderly, G. J. Handelman, A. A. Adler, “Distribution of individual macular pigment carotenoids in central retina of macaque and squirrel monkeys,” Invest. Ophthalmol. Visual Sci. 32, 268–279 (1991).

Hata, T. R.

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

Henrick, A.

L. Apt, A. Henrick, “Pupillary dilatation with single eyedrop mydriatic combinations,” Am. J. Ophthalmol. 89, 553–559 (1980).
[PubMed]

Henson, D.

S. Beatty, H.-H. Koh, D. Henson, M. Boulton, “The role of oxidative stress in the pathogenesis of age-related macular degeneration,” Surv. Ophthalmol. 45, 115–134 (2000).
[CrossRef] [PubMed]

Henson, D. B.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

Hiller, R.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Hughes, G. W.

Hurst, J. S.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Joa, H.

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

Johnson, E. J.

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

Katz, N. B.

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

P. S. Bernstein, M. D. Yoshida, N. B. Katz, R. W. McClane, W. Gellermann, “Raman detection of macular carotenoid pigments in intact human retina,” Invest. Ophthalmol. Visual Sci. 39, 2003–2011 (1998).

W. Gellermann, R. W. McClane, N. B. Katz, P. S. Bernstein, “Method and apparatus for noninvasive measurement of carotenoids and related chemical substances in biological tissue,” U.S. patent6,205,354, March20, 2001.

P. S. Bernstein, N. B. Katz, “The role of ocular free radicals in age-related macular degeneration,” in Environmental Stressors: Effects on Lung, Skin, Eye and Immune System Function, J. Fuchs, L. Packer, eds. (Marcel Dekker, New York, 2000), pp. 423–456.

Khachik, F.

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

Kiefer, W.

W. Kiefer, M. Spiekermann, “Resonance Raman theories,” in Infrared and Raman Spectra, B. Schrader, ed. (VCH Verlagsgesellschaft, Weinheim, Germany, 1995), pp. 468–473.

Kilbride, P. E.

P. E. Kilbride, K. R. Alexander, M. Fishman, G. A. Fishman, “Human macular pigment assessed by imaging fundus reflectometry,” Vision Res. 29, 663–674 (1989).
[CrossRef] [PubMed]

Kilburn, M. A.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Kilburn, M. D.

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

J. T. Landrum, R. A. Bone, M. D. Kilburn, “The macular pigment: a possible role in protection from age-related macular degeneration,” Adv. Pharmacol. 38, 537–556 (1997).
[CrossRef] [PubMed]

Kliger, D. S.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Kloepping, W. A. A.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

Koh, H.-H.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

S. Beatty, H.-H. Koh, D. Henson, M. Boulton, “The role of oxidative stress in the pathogenesis of age-related macular degeneration,” Surv. Ophthalmol. 45, 115–134 (2000).
[CrossRef] [PubMed]

Koyama, Y.

Y. Koyama, I. Takatsuka, M. Nakata, M. Tasumi, “Raman and infrared spectra of the all-trans, 7-cis, 9-cis, 13-cis, and 15-cis isomers of β-carotene: key bands distinguishing stretched or terminal-bent configurations from central-bent configurations” J. Raman Spectrosc. 19, 37–49 (1988).
[CrossRef]

Krinsky, N. I.

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

Landrum, J. T.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

J. T. Landrum, R. A. Bone, M. D. Kilburn, “The macular pigment: a possible role in protection from age-related macular degeneration,” Adv. Pharmacol. 38, 537–556 (1997).
[CrossRef] [PubMed]

R. A. Bone, J. T. Landrum, L. Fernandez, S. L. Tarsis, “Analysis of macular pigment by HPLC: retinal distribution and age study,” Invest. Ophthalmol. Visual Sci. 29, 843–849 (1988).

R. A. Bone, J. T. Landrum, S. L. Tarsis, “Preliminary identification of the human macular pigment,” Vision Res. 25, 1531–1535 (1985).
[CrossRef] [PubMed]

Lewis, J. W.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Lutze, M.

Mainster, M. A.

F. C. Delori, J. S. Parker, M. A. Mainster, “Light levels in fundus photography and fluorescein angiography,” Vision Res. 20, 1099–1104 (1980).
[CrossRef] [PubMed]

Maple, S. S.

L. M. Rapp, S. S. Maple, J. H. Choi, “Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina,” Invest. Ophthalmol. Visual Sci. 41, 1200–1209 (2000).

Mayne, S. T.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

McClane, R. W.

I. V. Ermakov, R. W. McClane, W. Gellermann, P. S. Bernstein, “Resonant Raman detection of macular pigment levels in the living human retina,” Opt. Lett. 26, 202–204 (2001).
[CrossRef]

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

P. S. Bernstein, M. D. Yoshida, N. B. Katz, R. W. McClane, W. Gellermann, “Raman detection of macular carotenoid pigments in intact human retina,” Invest. Ophthalmol. Visual Sci. 39, 2003–2011 (1998).

W. Gellermann, R. W. McClane, N. B. Katz, P. S. Bernstein, “Method and apparatus for noninvasive measurement of carotenoids and related chemical substances in biological tissue,” U.S. patent6,205,354, March20, 2001.

W. Gellermann, M. D. Yoshida, R. W. McClane, N. Balashov, P. S. Bernstein, “Raman detection of pigments in the human retina,” in Optical Biopsy II, R. R. Alfano, A. Katzir, eds., Proc. SPIE3250, 8–17 (1998).
[CrossRef]

P. S. Bernstein, W. Gellermann, R. W. McClane, “Measurement of macular carotenoid levels in the human retina using Raman spectroscopy,” U.S. patent5,873,831, February23, 1999.

Menendez, E.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Merriam, J. C.

E. R. Gaillard, L. Zheng, J. C. Merriam, J. Dillon, “Age-related changes in the absorption characteristics of the primate lens,” Invest. Ophthalmol. Visual Sci. 41, 1454–1459 (2000).

J. Dillon, L. Zheng, J. C. Merriam, E. R. Gaillard, “Transmission spectra of light to the mammalian retina,” Photochem. Photobiol. 71, 225–229 (2000).
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Miller, D. T.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Moore, L. L.

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

Muir, G. J.

P. S. Bernstein, F. Khachik, L. S. Carvalho, G. J. Muir, D. Y. Zhao, N. B. Katz, “Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye,” Exp. Eye Res. 72, 215–223 (2001).
[CrossRef] [PubMed]

Murray, I. J.

S. Beatty, I. J. Murray, D. B. Henson, D. Carden, H.-H. Koh, M. E. Boulton, “Macular pigment and risk for age-related macular degeneration in subjects from a northern European population,” Invest. Ophthalmol. Visual Sci. 42, 439–446 (2001).

Nakata, M.

Y. Koyama, I. Takatsuka, M. Nakata, M. Tasumi, “Raman and infrared spectra of the all-trans, 7-cis, 9-cis, 13-cis, and 15-cis isomers of β-carotene: key bands distinguishing stretched or terminal-bent configurations from central-bent configurations” J. Raman Spectrosc. 19, 37–49 (1988).
[CrossRef]

Owens, T. G.

A. P. Shreve, J. K. Trautman, T. G. Owens, A. C. Albrecht, “Determination of the S2 lifetime of β-carotene,” Chem. Phys. Lett. 178, 89 (1991).
[CrossRef]

Parker, J. S.

F. C. Delori, J. S. Parker, M. A. Mainster, “Light levels in fundus photography and fluorescein angiography,” Vision Res. 20, 1099–1104 (1980).
[CrossRef] [PubMed]

Pershing, L. K.

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
[CrossRef] [PubMed]

Pflibsen, K. P.

Pokorny, J.

Pomerantzeff, O.

Rapp, L. M.

L. M. Rapp, S. S. Maple, J. H. Choi, “Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina,” Invest. Ophthalmol. Visual Sci. 41, 1200–1209 (2000).

Reading, V. M.

V. M. Reading, R. A. Weale, “Macular pigment and chromatic aberration,” J. Am. Optom. Assoc. 64, 231–234 (1974).

Russell, R. M.

B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

Russett, M. D.

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
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Sample, P. A.

P. A. Sample, F. D. Esterson, R. N. Weinreb, R. M. Boynton, “The aging lens: in vivo assessment of light absorption in 84 human eyes,” Invest. Ophthalmol. Visual Sci. 29, 1306–1311 (1988).

Schalch, W.

W. Schalch, P. Dayhaw-Barker, F. M. Barker, “The carotenoids of the human retina,” in Nutritional and Environmental Influences on the Eye, A. Taylor, ed. (CRC, Boca Raton, Fla., 1999), pp. 215–250.

Schefrin, B. E.

Scholz, T. A.

T. R. Hata, T. A. Scholz, I. V. Ermakov, R. W. McClane, F. Khachik, W. Gellermann, L. K. Pershing, “Non-invasive Raman spectroscopic detection of carotenoids in human skin,” J. Invest. Dermatol. 115, 441–448 (2000).
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Schweitzer, D.

D. Schweitzer, M. Hammer, M. Scibor, “Imaging spectrometry in ophthalmology: principle and applications in microcirculation and in investigation of pigments,” Invest. Ophthalmol. Visual Sci. 39, 2001–2011 (1998).

Scibor, M.

D. Schweitzer, M. Hammer, M. Scibor, “Imaging spectrometry in ophthalmology: principle and applications in microcirculation and in investigation of pigments,” Invest. Ophthalmol. Visual Sci. 39, 2001–2011 (1998).

Sebag, J.

J. Sebag, R. R. Ansari, S. Dunker, K. I. Suh, “Dynamic light scattering of diabetic vitreopathy,” Diabetes Technol. Ther. 1, 169–176 (1999).
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Seddon, J. M.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Shreve, A. P.

A. P. Shreve, J. K. Trautman, T. G. Owens, A. C. Albrecht, “Determination of the S2 lifetime of β-carotene,” Chem. Phys. Lett. 178, 89 (1991).
[CrossRef]

Siems, W. G.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Smith, V. C.

Sneider, H.

C. J. Hammond, H. Sneider, T. D. Spector, C. E. Gilbert, “Factors affecting pupil size after dilatation: the Twin Eye Study,” Br. J. Ophthamol. 84, 1173–1176 (2000).
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Snodderly, D. M.

F. C. Delori, D. G. Goger, B. R. Hammond, D. M. Snodderly, S. A. Burns, “Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry,” J. Opt. Soc. Am. A 18, 1212–1230 (2001).
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B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Preservation of visual sensitivity of older subjects: association with macular pigment density,” Invest. Ophthalmol. Visual Sci. 39, 397–406 (1998).

B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Individual variations in the spatial profile of human macular pigment,” J. Opt. Soc. Am. A 14, 1187–1196 (1997).
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B. R. Hammond, E. J. Johnson, R. M. Russell, N. I. Krinsky, K.-J. Yeum, R. B. Edwards, D. M. Snodderly, “Dietary modification of human macular pigment density,” Invest. Ophthalmol. Visual Sci. 38, 1795–1801 (1997).

D. M. Snodderly, “Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins,” Am. J. Clin. Nutr. Suppl. 62, 1448S–1461S (1995).

G. J. Handelman, D. M. Snodderly, A. J. Adler, M. D. Russett, E. A. Dratz, “Measurement of carotenoids in human and monkey retinas,” Methods Enzymol. 213, 220–230 (1992).
[CrossRef] [PubMed]

D. M. Snodderly, G. J. Handelman, A. A. Adler, “Distribution of individual macular pigment carotenoids in central retina of macaque and squirrel monkeys,” Invest. Ophthalmol. Visual Sci. 32, 268–279 (1991).

D. M. Snodderly, J. D. Auran, F. C. Delori, “The macular pigment, I: absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas,” Invest. Ophthalmol. Visual Sci. 25, 660–673 (1984).

D. M. Snodderly, B. R. Hammond, “In vivopsychophysical assessment of nutritional and environmental influences on human ocular tissues: lens and macular pigment,” in Nutritional and Environmental Influences on the Eye, A. Taylor, ed. (CRC, Boca Raton, Fla., 1999), pp. 251–273.

Sommerberg, O. G.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Spector, T. D.

C. J. Hammond, H. Sneider, T. D. Spector, C. E. Gilbert, “Factors affecting pupil size after dilatation: the Twin Eye Study,” Br. J. Ophthamol. 84, 1173–1176 (2000).
[CrossRef]

Sperduto, R. D.

J. M. Seddon, U. A. Ajani, R. D. Sperduto, R. Hiller, N. Blair, T. C. Burton, M. D. Farber, E. S. Gragoudas, J. Haller, D. T. Miller, L. A. Yannuzzi, W. Willet, “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” J. Am. Med. Assoc. 272, 1413–1420 (1994).
[CrossRef]

Spiekermann, M.

W. Kiefer, M. Spiekermann, “Resonance Raman theories,” in Infrared and Raman Spectra, B. Schrader, ed. (VCH Verlagsgesellschaft, Weinheim, Germany, 1995), pp. 468–473.

Sprague, K. E.

J. T. Landrum, R. A. Bone, H. Joa, M. D. Kilburn, L. L. Moore, K. E. Sprague, “A one year study of the macular pigment: the effect of 140 days of a lutein supplement,” Exp. Eye Res. 65, 57–62 (1997).
[CrossRef] [PubMed]

Suh, K. I.

J. Sebag, R. R. Ansari, S. Dunker, K. I. Suh, “Dynamic light scattering of diabetic vitreopathy,” Diabetes Technol. Ther. 1, 169–176 (1999).
[CrossRef]

Takatsuka, I.

Y. Koyama, I. Takatsuka, M. Nakata, M. Tasumi, “Raman and infrared spectra of the all-trans, 7-cis, 9-cis, 13-cis, and 15-cis isomers of β-carotene: key bands distinguishing stretched or terminal-bent configurations from central-bent configurations” J. Raman Spectrosc. 19, 37–49 (1988).
[CrossRef]

Tarsis, S. L.

R. A. Bone, J. T. Landrum, L. Fernandez, S. L. Tarsis, “Analysis of macular pigment by HPLC: retinal distribution and age study,” Invest. Ophthalmol. Visual Sci. 29, 843–849 (1988).

R. A. Bone, J. T. Landrum, S. L. Tarsis, “Preliminary identification of the human macular pigment,” Vision Res. 25, 1531–1535 (1985).
[CrossRef] [PubMed]

Tasumi, M.

Y. Koyama, I. Takatsuka, M. Nakata, M. Tasumi, “Raman and infrared spectra of the all-trans, 7-cis, 9-cis, 13-cis, and 15-cis isomers of β-carotene: key bands distinguishing stretched or terminal-bent configurations from central-bent configurations” J. Raman Spectrosc. 19, 37–49 (1988).
[CrossRef]

Tibor, S. E.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

Tiemeijer, L. F.

D. van Norren, L. F. Tiemeijer, “Spectral reflectance of the human eye,” Vision Res. 26, 313–320 (1986).
[CrossRef] [PubMed]

Trautman, J. K.

A. P. Shreve, J. K. Trautman, T. G. Owens, A. C. Albrecht, “Determination of the S2 lifetime of β-carotene,” Chem. Phys. Lett. 178, 89 (1991).
[CrossRef]

Twaroska, E. E.

R. A. Bone, J. T. Landrum, S. T. Mayne, C. M. Gomez, S. E. Tibor, E. E. Twaroska, “Macular pigment in donor eyes with and without AMD: a case-control study,” Invest. Ophthalmol. Visual Sci. 42, 235–240 (2000).

van de Kraats, J.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

T. Berendshot, J. van de Kraats, D. van Norren, “Three methods to measure macular pigment compared in a lutein intake study,” Invest. Ophthalmol. Visual Sci. Suppl. 39, S314 (1999).

J. van de Kraats, T. T. J. M. Berendshot, D. van Norren, “The pathways of light measured in fundus reflectometry,” Vision Res. 36, 2229–2247 (1996).
[CrossRef] [PubMed]

D. van Norren, J. van de Kraats, “Imaging retinal densitometry with a confocal scanning ophthalmoscope,” Vision Res. 29, 1825–1830 (1989).
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van Kuijk, F. J.

O. G. Sommerberg, W. G. Siems, J. S. Hurst, J. W. Lewis, D. S. Kliger, F. J. van Kuijk, “Lutein and zeaxanthin are associated with photoreceptors in the human retina,” Curr. Eye Res. 19, 502–505 (1999).

Van Norel, J.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

van Norren, D.

T. T. J. M. Berendshot, R. A. Goldbohm, W. A. A. Kloepping, J. van de Kraats, J. Van Norel, D. van Norren, “Influence of lutein supplementation on macular pigment, assessed with two objective techniques,” Invest. Ophthalmol. Visual Sci. 41, 3322–3326 (2000).

T. Berendshot, J. van de Kraats, D. van Norren, “Three methods to measure macular pigment compared in a lutein intake study,” Invest. Ophthalmol. Visual Sci. Suppl. 39, S314 (1999).

J. van de Kraats, T. T. J. M. Berendshot, D. van Norren, “The pathways of light measured in fundus reflectometry,” Vision Res. 36, 2229–2247 (1996).
[CrossRef] [PubMed]

D. van Norren, J. van de Kraats, “Imaging retinal densitometry with a confocal scanning ophthalmoscope,” Vision Res. 29, 1825–1830 (1989).
[CrossRef]

D. van Norren, L. F. Tiemeijer, “Spectral reflectance of the human eye,” Vision Res. 26, 313–320 (1986).
[CrossRef] [PubMed]

Vidal, I.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Wang, W.

R. A. Bone, J. T. Landrum, L. M. Friedes, C. A. Gomez, M. A. Kilburn, E. Menendez, I. Vidal, W. Wang, “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Exp. Eye Res. 64, 211–218 (1997).
[CrossRef] [PubMed]

Weale, R. A.

R. A. Weale, “Age and the transmittance of the human crystalline lens,” J. Physiol. 395, 577–587 (1988).

V. M. Reading, R. A. Weale, “Macular pigment and chromatic aberration,” J. Am. Optom. Assoc. 64, 231–234 (1974).

Webb, R. H.

A. E. Elsner, S. A. Burns, G. W. Hughes, R. H. Webb, “Reflectometry with a scanning laser ophthalmoscope,” Appl. Opt. 31, 3697–3710 (1992).
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R. H. Webb, G. W. Hughes, O. Pomerantzeff, “Flying spot TV ophthalmoscope,” Appl. Opt. 19, 2991–2997 (1980).
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A. E. Elsner, S. A. Burns, F. C. Delori, R. H. Webb, “Quantitative reflectometry with the SLO,” in Laser Scanning Ophthalmoscopy and Tomography, J. E. Nasemann, R. O. W. Burk, eds. (Quintessenz-Verlag, Berlin, 1990), pp. 109–121.

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B. R. Hammond, B. R. Wooten, D. M. Snodderly, “Preservation of visual sensitivity of older subjects: association with macular pigment density,” Invest. Ophthalmol. Visual Sci. 39, 397–406 (1998).

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Figures (19)

Fig. 1
Fig. 1

Molecular structures of the carotenoid pigment species β-carotene, lutein, and zeaxanthin. All molecules feature a linear, chainlike conjugated-carbon backbone consisting of nine alternating carbon single (CC) and double bonds (C=C) and four methyl groups attached as side groups. Structural differences between the molecules originate from the end groups attached to the carbon backbone. These end groups, termed ionone rings, contain an attached OH molecule in lutein and zeaxanthin, and they also differ in the location of an additional C=C bond in each ring. In lutein this leads to an effective conjugation length of 10 C=C bonds and in zeaxanthin to 11 C=C bonds.

Fig. 2
Fig. 2

Absorption (upper part) and luminescence spectra (lower part) of lutein and zeaxanthin solutions in THF. Solutions were optically thin (O.D.0.3). Luminescence spectra were measured under 488-nm excitation.

Fig. 3
Fig. 3

Configuration-coordinate diagram for lowest energy levels of carotenoid molecules, with indicated optical excitation, nonradiative relaxation, luminescence, and Raman transition channels. Note that an even-parity excited state exists in these molecules (2 1Ag), which lies below the excited state reached after optical excitation (1 1Bu). Once an excited molecule has relaxed into this even-parity state after excitation, a luminescence transition to the even-parity ground state is parity forbidden. This feature allows one to observe resonant Raman transitions without spectrally overlapping luminescence.

Fig. 4
Fig. 4

Resonant Raman spectrum of a 7-μM solution of lutein in THF, showing three major Raman peaks at 1008, 1159, and 1525 cm-1. The peaks correspond, respectively, to the rocking motions of the methyl components (CCH3) and the stretch vibrations of the carbon–carbon single bonds (CC) and double bonds (C=C). The side peak at 1030 cm-1 is an artifact and corresponds to THF. Laser excitation was at 488 nm.

Fig. 5
Fig. 5

Absorption spectrum of an excised, flat-mounted human retina in the near-UV–visible wavelength region, revealing typical absorption characteristics of carotenoid pigments near 450 nm (the retinal pigment epithelium of the retina was removed for this measurement). Note the remarkable similarity of the absorption of the biological tissue to the absorption of the carotenoid solution in Fig. 2. Dashed curve, Rayleigh scattering background; the arrows, wavelength positions of the 488- and 514.5-nm argon laser lines that are useful for resonant Raman excitation.

Fig. 6
Fig. 6

Resonance Raman spectra of a flat-mounted human retina. Spectra were observed under excitation with 488-nm argon laser light in the center (trace a), 0.5 mm away from the center (trace b), and at the periphery (trace c) of the macula. The intensity scale of trace c is expanded by a factor of 10 for clarity. Illumination conditions: 488-nm, 40-mW, 300-μm spot size, 9 s collection time. Spectra were recorded in backscattering geometry.

Fig. 7
Fig. 7

Schematics of the fiber-based, portable Raman instrument for clinical applications. The instrument consists of an argon laser (lower right) for excitation, a light-delivery and collection module, a spectrograph (upper right) and electronics. The subject looks into the light module through an eyepiece and aligns his/her head position before a measurement. See text.

Fig. 8
Fig. 8

Display of a typical Raman measurement on the computer monitor. The spectral displays (center and center right) consist of plots of signal intensity (counts) versus pixel number of the CCD camera array. The spectrum in the center shows the unprocessed spectrum of a measurement and includes fluorescence background as well as superimposed Raman peaks. The spectrum on the right shows the Raman spectrum after polynomial fit of the fluorescent background and subtraction of that background. The window at center bottom shows the Raman peak heights of the CC single-bond and C=C double-bond vibration, the magnitudes of the background signals, and the ratios of Raman to background signals at corresponding pixels.

Fig. 9
Fig. 9

Raman scattering of lutein PVDF samples attached to the “macula” of a model eye. Upper part, schematic of the model eye, which consists of two hemispheres with internal meniscus lens and glass ball. Middle part, Raman spectra in the carotenoid-stretching vibration range for three increasing concentrations: 5.5 (a), 11 (b), and 22 (c) ng/sampled area. Bottom part, Raman signal of C=C double bond peak versus concentration, showing linear dependence with near-unity correlation coefficient.

Fig. 10
Fig. 10

Experimental setup for Raman measurements of primate retinas. An instrument similar to that shown in Fig. 7 is interfaced to a fundus camera to permit viewing of the animal’s retina while targeting the macula with a pilot laser beam before a measurement.

Fig. 11
Fig. 11

Views of illuminated primate retinas (four images) showing physiological structures, along with associated fluorescence-background-subtracted Raman spectra (right). Top two images, views when the laser is turned off (left) and when the laser is illuminating the retina between the optic nerve and the fovea (right). Bottom two images, corresponding views when the fovea is targeted. See text.

Fig. 12
Fig. 12

Correlation of Raman signals, obtained for the C=C double-bond vibration at 1525 cm-1, with the carotenoid content of six monkey maculae as determined by HPLC. A linear fit to the data results in a correlation coefficient of 0.68.

Fig. 13
Fig. 13

Raman spectra of a healthy human volunteer, measured with dilated pupil. Top trace, before background subtraction; bottom trace, after subtraction of fluorescence background. Excitation 488 nm, 0.5 s, 0.5 mW, 1-mm spot size on retina.

Fig. 14
Fig. 14

Repeatability of Raman measurement of macular pigments measured in two subjects, ages 26 (a) and 37 (b). Raman intensities are shown for dilated (gray bars) and undilated (black bars) pupils in each case, and measured over a two-week period in five sessions (represented by the five pairs of bars). Mean ±S.D. of 5–7 measurements for each session is shown.

Fig. 15
Fig. 15

Raman signals for left and right eyes of normal subjects, revealing symmetry of macular pigment concentrations in both eyes.

Fig. 16
Fig. 16

Variation of the Raman signal with pupil diameter for two subjects (circles), showing approximately twofold increase of the Raman signal after full pupil dilation. Above ∼7-mm pupil diameter, signals stay constant. Dashed curve, theoretically expected variation of the signal with pupil diameter.

Fig. 17
Fig. 17

Raman macular pigment measurement of 212 normal eyes as a function of subject age, revealing statistically significant decrease of macular pigment concentration with age. Solid circles represent subjects with clear prosthetic intraocular lenses. Mean ±S.D. of the best three out of five measurements are shown. Data are not corrected for decrease of ocular transmission with age. See text.

Fig. 18
Fig. 18

Pupil sizes of subjects enrolled in the clinical trial, showing mean pupil diameter and standard deviation grouped in decades of age.

Fig. 19
Fig. 19

Schematic representation of ocular media and fundus tissue layers (adapted from Ref. 28; not to scale). ILM, inner limiting membrane; PhR, photoreceptors; RPE, retinal pigment epithelium; BM, Bruch’s membrane; CC, choriocapillaris; CS, choroidal stroma.

Equations (3)

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Is=N(Ei)σR(if )IL,
σR(if )=8π9λs4jαijlLαjflsωij-ωL-iΓj+αjilLαjflsωjf-ωL-iΓj2,
TL=0.86TL1[1+0.02(A-32)],

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