20051028, Curcio-1 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

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

20051028, Curcio-1 9

Macular Photoreceptor Loss in Aging

Jackson, Owsley, Sloan, Curcio. 2005

20051028, Curcio-1 10

Aging: Fovea & Parafovea

Curcio. Eye 2001, 15:376

QuickTime™ and aGraphics decompressorare needed to see this picture. 1234520406080100Con

es x

10^

4Age, yearsDonorsPatientsFOVEAL CONES24681020406080100Rod

s x1

0^5

Age, yearsPARAFOVEAL RODS

20051028, Curcio-1 11

Photoreceptors in ARM• 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 recordsCurcio, Medeiros, Millican. IOVS 1996, 37:1236Medeiros, Curcio. IOVS 2001, 42:795

Rod loss > Cone loss4/6 NE-ARM eyes5/6 Ex-ARM eyes

20051028, Curcio-1 12

Early ARM and Photoreceptors

Curcio. Eye 2001, 15:376

20051028, Curcio-1 13

Photoreceptor Loss & Fundus

Jackson, Owsley, Sloan, Curcio. 2005

20051028, Curcio-1 14

ExudativeARM

Curcio. Eye 2001, 15:376

QuickTime™ and aGraphics decompressorare needed to see this picture. -3-2.5-2-1.5-1-0.500.500.511.522.533.5Diff

eren

ce fr

om c

ontr

ols

Distance from edge of lesion, mmConesRodsCurcio, Medeiros, Millican. IOVS 1996, 37:1236

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

Topographyof Effects

Jackson, Owsley, Curcio. Ageing Research Reviews 2002, 1:381

Autofluorescence due to lipofuscin

Human RPE

Macular pigment, macaque (from Snodderly)

QuickTime™ and aGraphics decompressorare needed to see this picture. DBCA0123456012345Les

ion

prev

alen

ce, %

Distance from foveal center, mm-0.200.20.40.60.811.2Lo

g ph

otor

ecep

tor

loss

RodsCones00.20.40.60.811.2012345N

orm

aliz

ed

Distance from foveal center, mmAutofluorescenceMacular pigment00.20.40.60.811.2Log

sens

itivi

ty lo

ssScotopicPhotopicRPE/ Bruch's membrane pathology

20051028, Curcio-1 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)

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?

20051028, Curcio-1 27

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

20051028, Curcio-1 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