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20030601,Waterloo
Photoreceptor Topography in Aging and Age-related Maculopathy
Christine A. Curcio, Ph.D.Department of Ophthalmology
University of Alabama School of Medicine
20030601,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
20030601,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, 41:2015-2018
• 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
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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
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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
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Macula: Cells and Layers
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Photoreceptor Mosaic
Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497
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Macula: Photoreceptor Topography
Cones Rods
Anatomical and epidemiologic macula:6 mm (21°) diameterSmall, cone-dominated foveaLarge, rod-dominated parafovea
Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497
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Human Photoreceptor TopographyQuickTime™ and aGraphics decompressorare needed to see this picture.
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Curcio, Sloan, Kalina, Hendrickson. J Comp Neurol 1990, 292:497
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Aging: Fovea & Parafovea
Curcio. Eye 2001, 15:376
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PARAFOVEAL RODS
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27-37 yr 82-90 yr Difference
Topography of Age-Related Rod Loss
Curcio, Millican, Allen, Kalina. IOVS 1993, 34:3278
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Topography of Age-related Rod Loss (2)
Curcio. Eye 2001, 15:376
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Photoreceptors in ARM• 12 pairs of ARM eyes, donors 64-95 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, 37:1236Medeiros, Curcio. IOVS 2001, 42:795
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Early ARM and Photoreceptors
Curcio. Eye 2001, 15:376
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Photoreceptor Loss & Fundus
Adapted from Curcio, Medeiros, Millican. IOVS 1996, 37:1236
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ExudativeARM &
Photoreceptors
Curcio. Eye 2001, 15:376
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Rod and Cone Loss in ARM
Rod loss > Cone loss4/6 NE-ARM eyes5/6 Ex-ARM eyes
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Curcio, Medeiros, Millican. IOVS 1996, 37:1236Medeiros, Curcio. IOVS 2001, 42:795
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Apoptotic Photoreceptors in ARM are Rods
Dunaief, Dentchev, Ying, Milam
Arch Ophthalmol 2002, 120:1435.
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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.
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Aging:Scotopic Loss >Photopic Loss
Jackson & Owsley. Vision Research 2000, 40:2467
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Early ARM: Scotopic Loss > Photopic Loss
Owsley, Jackson, Cideciyan, Huang, Fine, Ho, Maguire, Lolley, Jacobson. IOVS 2000, 41:267-273
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Aging: Slower Dark Adaptation
Jackson, Owsley, McGwin. Vision Res 1999, 39:3975
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Early ARM: Slower Dark Adaptation
Owsley, Jackson, White, Feist, Edwards. Ophthalmology 2001, 108:1196
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Poor Scotopic Sensitivity/ Night Driving
From Scilley, Jackson, Cideciyan, Maguire, Jacobson, Owsley. Ophthalmology 2002, 109:1235
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Topographyof Effects
Jackson, Owsley, Curcio. Ageing Research Reviews 2002, 1:381
Autofluorescence due to lipofuscin
Human RPE
Macular pigment, macaque (from Snodderly)
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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
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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
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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)
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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
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ARM: Rods Slower than ConesQuickTime™ and aGraphics decompressorare needed to see this picture.
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Jackson, Edwards, McGwin, & Owsley (1999). IOVS 40, S739.
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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
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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?
20030601,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?
20030601,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
20030601,Waterloo
Acknowledgments
National Eye Institute
Research to Prevent Blindness, Inc.
EyeSight Foundation of Alabama
