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

,Waterloo 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

,Waterloo 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:

,Waterloo 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

,Waterloo 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

,Waterloo Macula: Cells and Layers

,Waterloo Photoreceptor Mosaic Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497

,Waterloo 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

,Waterloo Human Photoreceptor Topography Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497

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

,Waterloo yr82-90 yrDifference Topography of Age-Related Rod Loss Curcio, Millican, Allen, Kalina. IOVS 1993, 34:3278

,Waterloo Topography of Age-related Rod Loss (2) Curcio. Eye 2001, 15:376

,Waterloo Photoreceptors in ARM 12 pairs of ARM eyes, donors yr –6 non-exudative (early and late) –6 exudative Photoreceptor counted in whole mounts –Loss relative to controls at each location –% of locations where rod loss>cone loss Histopathology, histochemistry in fellow eye Review of clinical records Curcio, Medeiros, Millican. IOVS 1996, 37:1236 Medeiros, Curcio. IOVS 2001, 42:795

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

,Waterloo Photoreceptor Loss & Fundus Adapted from Curcio, Medeiros, Millican. IOVS 1996, 37:1236

,Waterloo Exudative ARM & Photoreceptors Curcio. Eye 2001, 15:376

,Waterloo Rod and Cone Loss in ARM Rod loss > Cone loss 4/6 NE-ARM eyes 5/6 Ex-ARM eyes Curcio, Medeiros, Millican. IOVS 1996, 37:1236 Medeiros, Curcio. IOVS 2001, 42:795

,Waterloo Apoptotic Photoreceptors in ARM are Rods Dunaief, Dentchev, Ying, Milam Arch Ophthalmol 2002, 120:1435.

,Waterloo 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:

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

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

,Waterloo Aging: Slower Dark Adaptation Jackson, Owsley, McGwin. Vision Res 1999, 39:3975

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

,Waterloo Poor Scotopic Sensitivity/ Night Driving From Scilley, Jackson, Cideciyan, Maguire, Jacobson, Owsley. Ophthalmology 2002, 109:1235

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

,Waterloo 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

,Waterloo 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

,Waterloo 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)

,Waterloo Visual Cycle (Then & Now) Mata, Radu, Clemmons, Travis. Neuron 2002, 36:69 Classic visual cycle: RPE and rods Recent evidence: Müller cells supply cones Cones are less vulnerable to interruptions of vitamin A supply through RPE & Bruch’s membrane

,Waterloo ARM: Rods Slower than Cones +20 min+30 min Jackson, Edwards, McGwin, & Owsley (1999). IOVS 40, S739.

,Waterloo 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

,Waterloo 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?

,Waterloo 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?

,Waterloo 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

,Waterloo Acknowledgments National Eye Institute Research to Prevent Blindness, Inc. EyeSight Foundation of Alabama