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Photoreceptor Degeneration in Aging and Age-related Maculopathy

Photoreceptor Degeneration in Aging and Age-related Maculopathy. Christine A. Curcio, Ph.D. Department of Ophthalmology University of Alabama School of Medicine. Outline. Macula: cells and layers Photoreceptors as bioassay Aging & ARM: photoreceptor mosaic

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Photoreceptor Degeneration in Aging and Age-related Maculopathy

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  1. Photoreceptor Degeneration in Aging and Age-related Maculopathy Christine A. Curcio, Ph.D. Department of Ophthalmology University of Alabama School of Medicine 20051028, Curcio-1

  2. Outline • Macula: cells and layers • Photoreceptors as bioassay • Aging & ARM: photoreceptor mosaic • Aging & ARM: photoreceptor function • Possible explanations • Retinoid deficiency hypothesis • Implications for basic and clinical research 20051028, Curcio-1

  3. References • Curcio CA, Owsley C, Jackson GR: Spare the rods, save in the cones in aging and age-related maculopathy. Invest Ophthalmol Vis Sci 2000, 41:2015-2018 • Curcio CA: Photoreceptor topography in ageing and age-related maculopathy. Eye 2001, 15:376-383. • Jackson GR, Owsley C, Curcio CA: Photoreceptor degeneration and dysfunction in aging and age-related maculopathy. Ageing Research Reviews 2002, 1:381-396 • Jackson GR, Curcio CA, Sloan KR, Owsley C: Photoreceptor degeneration in aging and age-related maculopathy. Edited by Penfold PL, Provis JM. Berlin, Springer-Verlag, 2005, p. pp. 45-62 20051028, Curcio-1

  4. Relative Rate of Rod and Cone Degeneration • Fundamental to each photoreceptor degeneration • Requires similar measures of rods and cones at same retinal locations in well-characterized eyes • Possible measures include numbers, morphology, imaging, and function 20051028, Curcio-1

  5. Why Study Photoreceptor Health? • Vision loss in ARM is due to dysfunction, death of photoreceptors • RPE/ Bruch’s membrane complex is vital to photoreceptors but difficult to study in vivo • Photoreceptor health is a direct bioassay of RPE/Bruch’s membrane health • Progress has been facilitated • Better understanding of dark adaptation • Grading systems for characterizing maculopathy 20051028, Curcio-1

  6. Macula: Cells and Layers 20051028, Curcio-1

  7. Photoreceptor Mosaic Jackson, Owsley, Sloan, Curcio. 2005 20051028, Curcio-1

  8. Cones Rods Macula: Photoreceptor Topography Anatomical and epidemiologic macula: 6 mm (21°) diameter Small, cone-dominated fovea Large, rod-dominated parafovea Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497 20051028, Curcio-1

  9. Macular Photoreceptor Loss in Aging Jackson, Owsley, Sloan, Curcio. 2005 20051028, Curcio-1

  10. Aging: Fovea & Parafovea 20051028, Curcio-1 Curcio. Eye 2001, 15:376

  11. Photoreceptors in ARM Rod loss > Cone loss 4/6 NE-ARM eyes 5/6 Ex-ARM eyes • 12 pairs of ARM eyes, donors 64-95 yr • 6 non-exudative (early and late) • 6 exudative • Photoreceptors counted in whole mounts • Loss relative to controls at each location • % of locations where rod loss>cone loss • Fellow eye • Histopathology, carbonic anhydrase histochemistry • Review of clinical records Curcio, Medeiros, Millican. IOVS 1996, 37:1236 Medeiros, Curcio. IOVS 2001, 42:795 20051028, Curcio-1

  12. Early ARM and Photoreceptors 20051028, Curcio-1 Curcio. Eye 2001, 15:376

  13. Photoreceptor Loss & Fundus Jackson, Owsley, Sloan, Curcio. 2005 20051028, Curcio-1

  14. ExudativeARM Curcio, Medeiros, Millican. IOVS 1996, 37:1236 Curcio. Eye 2001, 15:376 20051028, Curcio-1

  15. Rod Photoreceptors in ARM are Apoptotic Dunaief, Dentchev, Ying, Milam Arch Ophthalmol 2002, 120:1435. 20051028, Curcio-1

  16. Drusen-associated Photoreceptor Change Johnson, Lewis, Talaga, Brown, Kappel, Fisher, Anderson, Johnson, 2003, IOVS 44:4481 20051028, Curcio-1

  17. Support from Functional Studies • Large studies (99 adults, 80 early ARM patients) • Objectively characterized macular health • Rod and cone sensitivity at same retinal locations • Decrease throughout adulthood • Rod loss > cone loss in 80% of normal subjects • Declines further in early ARM, especially near fovea • Rod loss > cone loss in 87% of patients Aging: Jackson & Owsley. Vision Res. 2000;40:2467-2473. ARM: Owsley et al. IOVS 2000;41:267-273. 20051028, Curcio-1

  18. Aging:Scotopic Loss >Photopic Loss Jackson & Owsley. Vision Research 2000, 40:2467 20051028, Curcio-1

  19. Early ARM: Scotopic Loss > Photopic Loss Owsley, Jackson, Cideciyan, Huang, Fine, Ho, Maguire, Lolley, Jacobson. IOVS 2000, 41:267-273 20051028, Curcio-1

  20. Aging: Slower Dark Adaptation Jackson, Owsley, McGwin. 1999, Vision Res 39:3975 20051028, Curcio-1

  21. Early ARM: Slower Dark Adaptation Owsley, Jackson, White, Feist, Edwards. Ophthalmology 2001, 108:1196 20051028, Curcio-1

  22. Autofluorescence due to lipofuscin Human RPE Macular pigment, macaque (from Snodderly) Topographyof Effects 20051028, Curcio-1 Jackson, Owsley, Curcio. Ageing Research Reviews 2002, 1:381

  23. Summary • Slowing of rod-mediated dark adaptation • Qualitative similarity of aging and ARM effects on photoreceptor function • Earlier loss of rods relative to cones • Topographic correspondence of dysfunction and loss to RPE/ Bruch’s pathology 20051028, Curcio-1

  24. Retinoid Deficiency Hypothesis Age- and disease-related changes in Bruch’s membrane lead to reduced retinoid transfer from the blood and localized scarcity of 11-cis retinal at the photoreceptors 20051028, Curcio-1

  25. Retinoid Deficiency Hypothesis • Rod-mediated portion of dark adaptation: regenerating photopigment in visual cycle • Visual cycle: delivery of vitamin A derivative 11-cis-retinal to photoreceptors from precursors delivered from plasma • Retinoids essential for photoreceptor survival • Rods die first, then cones during vitamin A deprivation • Delayed dark adaptation occurs in vitamin A deficiency & genetic disorders affecting retinoid processing/ transport • Vitamin A supplementation improves dark adaptation in patients with Sorsby’s fundus dystrophy (thick deposits) 20051028, Curcio-1

  26. Visual Cycle (Then & Now) • Classic visual cycle: RPE supplies rods • Novel retinoid processors in cone-dominant retinas • all-trans-retinol isomerase • 11-cis-retinyl-ester synthase • 11-cis-retinol dehydrogenase • Müller cells supply cones • Are cones less vulnerable to interruptions of retinoid supply through RPE & Bruch’s membrane? 20051028, Curcio-1 Mata, Radu, Clemmons, Travis. Neuron 2002, 36:69

  27. Early Age Changes in Bruch’s SLO images of the macula Left- 543 nm, direct mode; Right- 830 nm, indirect mode 20051028, Curcio-1 Elsner, Burns, Weiter, Delori. Vision Research 1996, 36:191

  28. Our Data Indicate: • Rods are effected earlier, more severely than cones • Effects of aging and ARM are qualitatively similar • Dark adaptation slows in aging and ARM How does this tell us about aging and disease in RPE/Bruch’s membrane complex? 20051028, Curcio-1

  29. Questions for Basic Research • Effects of partial vitamin A deprivation on photoreceptor function • Further characterization of rod- and cone-specific retinoid delivery • Localizing bottleneck in retinoid delivery to rods • RPE, Bruch’s, or both? 20051028, Curcio-1

  30. Implications for Clinical Research • Use tests of rod kinetics • Detect photoreceptor dysfunction early • Monitor disease progression • Intervene early to save photoreceptors • Rods needed for everyday activities • Rods promote survival of cones 20051028, Curcio-1

  31. Acknowledgments National Eye Institute Research to Prevent Blindness, Inc. EyeSight Foundation of Alabama 20051028, Curcio-1

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