OSA's Digital Library

Journal of the Optical Society of America A

Journal of the Optical Society of America A


  • Editor: Stephen A. Burns
  • Vol. 24, Iss. 5 — May. 1, 2007
  • pp: 1457–1467

Reduced-illuminance autofluorescence imaging in A B C A 4 -associated retinal degenerations

Artur V. Cideciyan, Malgorzata Swider, Tomas S. Aleman, Marisa I. Roman, Alexander Sumaroka, Sharon B. Schwartz, Edwin M. Stone, and Samuel G. Jacobson  »View Author Affiliations

JOSA A, Vol. 24, Issue 5, pp. 1457-1467 (2007)

View Full Text Article

Enhanced HTML    Acrobat PDF (926 KB)

Browse Journals / Lookup Meetings

Browse by Journal and Year


Lookup Conference Papers

Close Browse Journals / Lookup Meetings

Article Tools



The health of the retinal pigment epithelium (RPE) can be estimated with autofluorescence (AF) imaging of lipofuscin, which accumulates as a byproduct of retinal exposure to light. Lipofuscin may be toxic to the RPE, and its toxicity may be enhanced by short-wavelength (SW) illumination. The high-intensity and SW excitation light used in conventional AF imaging could, at least in principle, increase the rate of lipofuscin accumulation and/or increase its toxicity. We considered two reduced-illuminance AF imaging (RAFI) methods as alternatives to conventional AF imaging. RAFI methods use either near-infrared (NIR) light or reduced-radiance SW illumination for excitation of fluorophores. We quantified the distribution of RAFI signals in relation to retinal structure and function in patients with the prototypical lipofuscin accumulation disease caused by mutations in A B C A 4 . There was evidence for two subclinical stages of macular A B C A 4 disease involving hyperautofluorescence of both SW- and NIR-RAFI with and without associated loss of visual function. Use of RAFI methods and microperimetry in future clinical trials involving lipofuscinopathies should allow quantification of subclinical disease expression and progression without subjecting the diseased retina/RPE to undue light exposure.

© 2007 Optical Society of America

OCIS Codes
(170.1610) Medical optics and biotechnology : Clinical applications
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(170.4470) Medical optics and biotechnology : Ophthalmology
(170.4500) Medical optics and biotechnology : Optical coherence tomography
(170.4580) Medical optics and biotechnology : Optical diagnostics for medicine
(170.6280) Medical optics and biotechnology : Spectroscopy, fluorescence and luminescence

ToC Category:
Clinical Applications of Retinal Imaging

Original Manuscript: July 31, 2006
Revised Manuscript: September 21, 2006
Manuscript Accepted: September 26, 2006
Published: April 11, 2007

Virtual Issues
Vol. 2, Iss. 6 Virtual Journal for Biomedical Optics

Artur V. Cideciyan, Malgorzata Swider, Tomas S. Aleman, Marisa I. Roman, Alexander Sumaroka, Sharon B. Schwartz, Edwin M. Stone, and Samuel G. Jacobson, "Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations," J. Opt. Soc. Am. A 24, 1457-1467 (2007)

Sort:  Author  |  Year  |  Journal  |  Reset  


  1. L. Feeney, "Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies," Invest. Ophthalmol. Visual Sci. 17, 583-600 (1978).
  2. G. E. Eldred and M. L. Katz, "Fluorophores of the human retinal pigment epithelium: separation and spectral characterization," Exp. Eye Res. 47, 71-86 (1988). [CrossRef]
  3. G. E. Eldred and M. R. Lasky, "Retinal age pigments generated by self-assembling lysosomotropic detergents," Nature 361, 724-726 (1993). [CrossRef] [PubMed]
  4. J. R. Sparrow and M. Boulton, "RPE lipofuscin and its role in retinal pathobiology," Exp. Eye Res. 80, 595-606 (2005). [CrossRef] [PubMed]
  5. J. Weng, N. L. Mata, S. M. Azarian, R. T. Tzekov, D. G. Birch, and G. H. Travis, "Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice," Cell 98, 13-23 (1999). [CrossRef] [PubMed]
  6. R. A. Radu, N. L. Mata, S. Nusinowitz, X. Liu, P. A. Sieving, and G. H. Travis, "Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration," Proc. Natl. Acad. Sci. U.S.A. 100, 4742-4747 (2003). [CrossRef] [PubMed]
  7. M. Boulton, M. Rozanowska, B. Rozanowski, and T. Wess, "The photoreactivity of ocular lipofuscin," Photochem. Photobiol. Sci. 3, 759-764 (2004). [CrossRef] [PubMed]
  8. P. A. Sieving, P. Chaudhry, M. Kondo, M. Provenzano, D. Wu, T. J. Carlson, R. A. Bush, and D. A. Thompson, "Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy," Proc. Natl. Acad. Sci. U.S.A. 98, 1835-1840 (2001). [CrossRef] [PubMed]
  9. M. Golczak, V. Kuksa, T. Maeda, A. R. Moise, and K. Palczewski, "Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle," Proc. Natl. Acad. Sci. U.S.A. 102, 8162-8167 (2005). [CrossRef] [PubMed]
  10. P. Maiti, J. Kong, S. R. Kim, J. R. Sparrow, R. Allikmets, and R. R. Rando, "Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation," Biochemistry 45, 852-860 (2006). [CrossRef] [PubMed]
  11. G. H. Travis, M. Golczak, A. R. Moise, and K. Palczewski, "Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents," Annu. Rev. Pharmacol. Toxicol. 47, 8.1-8.44 (2007). [CrossRef]
  12. K. Kitagawa, S. Nishida, and Y. Ogura, "In vivo quantitation of autofluorescence in human retinal pigment epithelium," Ophthalmologica 199, 116-121 (1989). [CrossRef] [PubMed]
  13. F. C. Delori, "Spectrophotometer for noninvasive measurement of intrinsic fluorescence and reflectance of ocular fundus," Appl. Opt. 33, 7439-7452 (1994). [CrossRef] [PubMed]
  14. A. von Ruckmann, F. W. Fitzke, and A. C. Bird, "Distribution of fundus autofluorescence with a scanning laser ophthalmoscope," Br. J. Ophthamol. 79, 407-412 (1995). [CrossRef]
  15. F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Weiter, "In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics," Invest. Ophthalmol. Visual Sci. 36, 718-729 (1995).
  16. F. C. Delori, G. Staurenghi, O. Arend, C. K. Dorey, D. G. Goger, and J. J. Weiter, "In vivo measurement of lipofuscin in Stargardt's disease--fundus flavimaculatus," Invest. Ophthalmol. Visual Sci. 36, 2327-2331 (1995).
  17. C. Bellmann, F. G. Holz, O. Schapp, H. E. Volcker, and T. P. Otto, "[Topography of fundus autofluorescence with a new confocal scanning laser ophthalmoscope]," (in German) Ophthalmologe 94, 385-391 (1997). [CrossRef] [PubMed]
  18. F. G. Holz, C. Bellmann, M. Margaritidis, F. Schutt, T. P. Otto, and H. E. Volcker, "Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration," Graefe's Arch. Clin. Exp. Ophthalmol. 237, 145-152 (1999). [CrossRef]
  19. F. C. Delori, D. G. Goger, and C. K. Dorey, "Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects," Invest. Ophthalmol. Visual Sci. 42, 1855-1866 (2001).
  20. F. G. Holz, C. Bellman, S. Staudt, F. Schutt, and H. E. Volcker, "Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration," Invest. Ophthalmol. Visual Sci. 42, 1051-1056 (2001).
  21. N. Lois, G. E. Holder, C. Bunce, F. W. Fitzke, and A. C. Bird, "Phenotypic subtypes of Stargardt macular dystrophy--fundus flavimaculatus," Arch. Ophthalmol. (Chicago) 119, 359-369 (2001).
  22. C. Gerth, M. Andrassi-Darida, M. Bock, M. N. Preising, B. H. Weber, and B. Lorenz, "Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation," Graefes Arch. Clin. Exp. Ophthalmol. 240, 628-638 (2002). [CrossRef] [PubMed]
  23. R. F. Spaide, "Fundus autofluorescence and age-related macular degeneration," Ophthalmology 110, 392-329 (2003). [CrossRef] [PubMed]
  24. N. Lois, A. S. Halfyard, A. C. Bird, G. E. Holder, and F. W. Fitzke, "Fundus autofluorescence in Stargardt macular dystrophy--fundus flavimaculatus," Am. J. Ophthalmol. 138, 55-63 (2004). [CrossRef] [PubMed]
  25. J. J. Jorzik, A. Bindewald, S. Dithmar, and F. G. Holz, "Digital simultaneous fluorescein and indocyanine green angiography, autofluorescence, and red-free imaging with a solid-state laser-based confocal scanning laser ophthalmoscope," Retina 25, 405-416 (2005). [CrossRef] [PubMed]
  26. S. Schmitz-Valckenberg, A. Bindewald-Wittich, J. Dolar-Szczasny, J. Dreyhaupt, S. Wolf, H. P. Scholl, F. G. Holz, and Fundus Autofluorescence in Age-Related Macular Degeneration Study Group, "Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD," Invest. Ophthalmol. Visual Sci. 47, 2648-2654 (2006). [CrossRef]
  27. J. C. Hwang, J. W. Chan, S. Chang, and R. T. Smith, "Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration," Invest. Ophthalmol. Visual Sci. 47, 2655-2661 (2006). [CrossRef]
  28. J. S. Sunness, M. D. Ziegler, and C. A. Applegate, "Issues in quantifying atrophic macular disease using retinal autofluorescence," Retina 26, 666-672 (2006). [CrossRef] [PubMed]
  29. G. A. Fishman, S. G. Jacobson, K. R. Alexander, A. V. Cideciyan, D. G. Birch, R. G. Weleber, and D. C. Hood, "Outcome measures and their application in clinical trials for retinal degenerative disease: outline, review, and perspective," Retina 25, 772-777 (2005). [CrossRef] [PubMed]
  30. F. C. Delori, J. S. Parker, and M. A. Mainster, "Light levels in fundus photography and fluorescein angiography," Vision Res. 20, 1099-1104 (1980). [CrossRef] [PubMed]
  31. F. C. Piccolino, L. Borgia, E. Zinicola, M. Iester, and S. Torrielli, "Pre-injection fluorescence in indocyanine green angiography," Ophthalmology 103, 1837-1845 (1996). [PubMed]
  32. A. W. Weinberger, A. Lappas, T. Kirschkamp, B. A. Mazinani, J. K. Huth, B. Mohammadi, and P. Walter, "Fundus near infrared fluorescence correlates with fundus near infrared reflectance," Invest. Ophthalmol. Visual Sci. 47, 3098-3108 (2006). [CrossRef]
  33. C. N. Keilhauer and F. C. Delori, "Near-infrared autofluorescence imaging of the fundus: visualization of ocular melanin," Invest. Ophthalmol. Visual Sci. 47, 3556-3564 (2006). [CrossRef]
  34. A. V. Cideciyan, T. S. Aleman, M. Swider, S. B. Schwartz, J. D. Steinberg, A. J. Brucker, A. M. Maguire, J. Bennett, E. M. Stone, and S. G. Jacobson, "Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence," Hum. Mol. Genet. 13, 525-534 (2004). [CrossRef] [PubMed]
  35. A. V. Cideciyan, M. Swider, T. S. Aleman, A. Sumaroka, S. B. Schwartz, M. I. Roman, A. H. Milam, J. Bennett, E. M. Stone, and S. G. Jacobson, "ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina," Invest. Ophthalmol. Visual Sci. 46, 4739-4746 (2005). [CrossRef]
  36. A. V. Cideciyan, S. G. Jacobson, T. S. Aleman, D. Gu, S. E. Pearce-Kelling, A. Sumaroka, G. M. Acland, and G. D. Aguirre, "In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa," Proc. Natl. Acad. Sci. U.S.A. 102, 5233-5238 (2005). [CrossRef] [PubMed]
  37. M. M. Galloway, "Texture analysis using gray level run-lengths," Comput. Graph. Image Process. 4, 172-179 (1975). [CrossRef]
  38. S. Herlidou, R. Grebe, F. Grados, N. Leuyer, P. Fardellone, and M. E. Meyer, "Influence of age and osteoporosis on calcaneus trabecular bone structure: a preliminary in vivo MRI study by quantitative texture analysis," Magn. Reson. Imaging 22, 237-243 (2004). [CrossRef] [PubMed]
  39. S. G. Jacobson, T. S. Aleman, A. V. Cideciyan, A. Sumaroka, S. B. Schwartz, E. A. M. Windsor, E. I. Traboulsi, E. Heon, S. J. Pittler, A. H. Milam, A. M. Maguire, K. Palczewski, E. M. Stone, and J. Bennett, "Identifying photoreceptors in blind eyes due to RPE65 mutations: prerequisite for human gene therapy success," Proc. Natl. Acad. Sci. U.S.A. 102, 6177-6182 (2005). [CrossRef] [PubMed]
  40. S. G. Jacobson, A. V. Cideciyan, A. Sumaroka, T. S. Aleman, S. B. Schwartz, E. A. M. Windsor, A. J. Roman, E. M. Stone, and I. M. MacDonald, "Remodeling of the human retina in choroideremia--Rab Escort Protein 1 (REP-1) mutations," Invest. Ophthalmol. Visual Sci. 47, 4113-4120 (2006). [CrossRef]
  41. Y. Huang, A. V. Cideciyan, G. I. Papastergiou, E. Banin, S. L. Semple-Rowland, A. H. Milam, and S. G. Jacobson, "Relation of optical coherence tomography to microanatomy in normal and rd chickens," Invest. Ophthalmol. Visual Sci. 39, 2405-2416 (1998).
  42. A. E. Elsner, S. A. Burns, J. J. Weiter, and F. C. Delori, "Infrared imaging of sub-retinal structures in the human ocular fundus," Vision Res. 36, 191-205 (1996). [CrossRef] [PubMed]
  43. F. C. Delori, D. G. Goger, C. Keilhauer, P. Salvetti, and G. Staurenghi, "Bimodal spatial distribution of macular pigment: evidence of a gender relationship," J. Opt. Soc. Am. A 23, 521-538 (2006). [CrossRef]
  44. R. W. Knighton, S. G. Jacobson, and C. M. Kemp, "The spectral reflectance of the nerve fiber layer of the macaque retina," Invest. Ophthalmol. Visual Sci. 30, 2392-2402 (1989).
  45. R. Allikmets, N. Singh, H. Sun, N. F. Shroyer, A. Hutchinson, A. Chidambaram, B. Gerrard, L. Baird, D. Stauffer, A. Peiffer, A. Rattner, P. Smallwood, Y. Li, K. L. Anderson, R. A. Lewis, J. Nathans, M. Leppert, M. Dean, and J. R. Lupski, "A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy," Nat. Genet. 15, 236-246 (1997). [CrossRef] [PubMed]
  46. A. Martinez-Mir, E. Paloma, R. Allikmets, C. Ayuso, T. del Rio, M. Dean, L. Vilageliu, R. Gonzalez-Duarte, and S. Balcells, "Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR," Nat. Genet. 18, 11-12 (1998). [CrossRef] [PubMed]
  47. F. P. Cremers, D. J. van de Pol, M. van Driel, A. I. den Hollander, F. J. van Haren, N. V. Knoers, N. Tijmes, A. A. Bergen, K. Rohrschneider, A. Blankenagel, A. J. Pinckers, A. F. Deutman, and C. B. Hoyng, "Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR," Hum. Mol. Genet. 7, 355-362 (1998). [CrossRef] [PubMed]
  48. G. A. Fishman, E. M. Stone, S. Grover, D. J. Derlacki, H. L. Haines, and R. R. Hockey, "Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene," Arch. Ophthalmol. (Chicago) 117, 504-510 (1999).
  49. A. R. Webster, E. Heon, A. J. Lotery, K. Vandenburgh, T. L. Casavant, K. T. Oh, G. Beck, G. A. Fishman, B. L. Lam, A. Levin, J. R. Heckenlively, S. G. Jacobson, R. G. Weleber, V. C. Sheffield, and E. M. Stone, "An analysis of allelic variation in the ABCA4 gene," Invest. Ophthalmol. Visual Sci. 42, 1179-1189 (2001).
  50. G. A. Fishman, E. M. Stone, D. A. Eliason, C. M. Taylor, M. Lindeman, and D. J. Derlacki, "ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy," Arch. Ophthalmol. (Chicago) 121, 851-855 (2003).
  51. T. S. Aleman, A. V. Cideciyan, E. A. M. Windsor, S. B. Schwartz, L. M. Gardner, J. M. Emmons, K. G. Duncan, J. D. Steinberg, E. M. Stone, and S. G. Jacobson, "Macular pigment in ABCA4-associated retinal degenerations: response to lutein supplementation," Invest. Ophthalmol. Visual Sci. 47, E-Abstract 5810 (2006).
  52. J. Hopkins, A. Walsh, and U. Chakravarthy, "Fundus autofluorescence in age-related macular degeneration: an epiphenomenon?" Invest. Ophthalmol. Visual Sci. 47, 2269-2271 (2006). [CrossRef]
  53. D. Sliney, D. Aron-Rosa, F. Delori, F. Fankhauser, R. Landry, M. Mainster, J. Marshall, B. Rassow, B. Stuck, S. Trokel, T. M. West, M. Wolffe, and International Commission on Non-Ionizing Radiation Protection, "Adjustment of guidelines for exposure of the eye to optical radiation from ocular instruments: statement from a task group of the International Commission on Non-Ionizing Radiation Protection (ICNIRP)," Appl. Opt. 44, 2162-2176 (2005). [CrossRef]
  54. D. M. Paskowitz, M. M. Lavail, and J. L. Duncan, "Light and inherited retinal degeneration," Br. J. Ophthamol. 90, 1060-1066 (2006). [CrossRef]
  55. U. Schraermeyer, "Does melanin turnover occur in the eyes of adult vertebrates?" Pigment Cell Res. 6, 193-204 (1993). [CrossRef]
  56. J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, "Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes," Invest. Ophthalmol. Visual Sci. 27, 145-152 (1986).
  57. D. Gibbs, S. M. Azarian, C. Lillo, J. Kitamoto, A. E. Klomp, K. P. Steel, R. T. Libby, and D. S. Williams, "Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes," J. Cell. Sci. 117, 6473-6483 (2004). [CrossRef]
  58. P. Kayatz, G. Thumann, T. T. Luther, J. F. Jordan, K. U. Bartz-Schmidt, P. J. Esser, and U. Schraermeyer, "Oxidation causes melanin fluorescence," Invest. Ophthalmol. Visual Sci. 42, 241-246 (2001).
  59. G. S. Tucker, "Refractile bodies in the inner segments of cones in the aging human retina," Invest. Ophthalmol. Visual Sci. 27, 708-715 (1986).
  60. M. Iwasaki and H. Inomata, "Lipofuscin granules in human photoreceptor cells," Invest. Ophthalmol. Visual Sci. 29, 671-679 (1988).
  61. C. D. Birnbach, M. Jarvelainen, D. E. Possin, and A. H. Milam, "Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus," Ophthalmology 101, 1211-1219 (1994). [PubMed]
  62. N. Fishkin, Y. P. Jang, Y. Itagaki, J. R. Sparrow, and K. Nakanishi, "A2-rhodopsin: a new fluorophore isolated from photoreceptor outer segments," Org. Biomol. Chem. 1, 1101-1105 (2003). [CrossRef] [PubMed]

Cited By

Alert me when this paper is cited

OSA is able to provide readers links to articles that cite this paper by participating in CrossRef's Cited-By Linking service. CrossRef includes content from more than 3000 publishers and societies. In addition to listing OSA journal articles that cite this paper, citing articles from other participating publishers will also be listed.


Fig. 1 Fig. 2 Fig. 3
Fig. 4

« Previous Article  |  Next Article »

OSA is a member of CrossRef.

CrossCheck Deposited