, Curcio-11 Photoreceptor Degeneration in Aging and Age-related Maculopathy Christine A. Curcio, Ph.D. Department of Ophthalmology University of Alabama School of Medicine

, Curcio-12 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

, Curcio-13 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: Curcio CA: Photoreceptor topography in ageing and age-related maculopathy. Eye 2001, 15: Jackson GR, Owsley C, Curcio CA: Photoreceptor degeneration and dysfunction in aging and age-related maculopathy. Ageing Research Reviews 2002, 1: 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

, Curcio-14 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

, Curcio-15 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

, Curcio-16 Macula: Cells and Layers

, Curcio-17 Photoreceptor Mosaic Jackson, Owsley, Sloan, Curcio. 2005

, Curcio-18 Macula: Photoreceptor Topography ConesRods 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

, Curcio-19 Macular Photoreceptor Loss in Aging Jackson, Owsley, Sloan, Curcio. 2005

, Curcio-110 Aging: Fovea & Parafovea Curcio. Eye 2001, 15:376

, Curcio-111 Photoreceptors in ARM 12 pairs of ARM eyes, donors 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 Rod loss > Cone loss 4/6 NE-ARM eyes 5/6 Ex-ARM eyes

, Curcio-112 Early ARM and Photoreceptors Curcio. Eye 2001, 15:376

, Curcio-113 Photoreceptor Loss & Fundus Jackson, Owsley, Sloan, Curcio. 2005

, Curcio-114 Exudative ARM Curcio. Eye 2001, 15:376 Curcio, Medeiros, Millican. IOVS 1996, 37:1236

, Curcio-115 Rod Photoreceptors in ARM are Apoptotic Dunaief, Dentchev, Ying, Milam Arch Ophthalmol 2002, 120:1435.

, Curcio-116 Drusen- associated Photoreceptor Change Johnson, Lewis, Talaga, Brown, Kappel, Fisher, Anderson, Johnson, 2003, IOVS 44:4481

, Curcio-117 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: ARM: Owsley et al. IOVS 2000;41:

, Curcio-118 Aging: Scotopic Loss > Photopic Loss Jackson & Owsley. Vision Research 2000, 40:2467

, Curcio-119 Early ARM: Scotopic Loss > Photopic Loss Owsley, Jackson, Cideciyan, Huang, Fine, Ho, Maguire, Lolley, Jacobson. IOVS 2000, 41:

, Curcio-120 Aging: Slower Dark Adaptation Jackson, Owsley, McGwin. 1999, Vision Res 39:3975

, Curcio-121 Early ARM: Slower Dark Adaptation Owsley, Jackson, White, Feist, Edwards. Ophthalmology 2001, 108:1196

, Curcio-122 Topography of Effects Jackson, Owsley, Curcio. Ageing Research Reviews 2002, 1:381 Autofluorescence due to lipofuscin Human RPE Macular pigment, macaque (from Snodderly)

, Curcio-123 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

, Curcio-124 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

, Curcio-125 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)

, Curcio-126 Visual Cycle (Then & Now) Mata, Radu, Clemmons, Travis. Neuron 2002, 36:69 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?

, Curcio-127 Early Age Changes in Bruch’s SLO images of the macula Left- 543 nm, direct mode; Right- 830 nm, indirect mode Elsner, Burns, Weiter, Delori. Vision Research 1996, 36:191

, Curcio-128 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?

, Curcio-129 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?

, Curcio-130 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

, Curcio-131 Acknowledgments National Eye Institute Research to Prevent Blindness, Inc. EyeSight Foundation of Alabama