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Marco A. Zarbin, MD, PhD

Arch Ophthalmol. 2004;122:598-614.

ABSTRACT
Objective  To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD).

Methods  Review of the English-language literature.

Results  Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and (5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient's susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously.

Conclusions  Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

INTRODUCTION

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Age-related macular degeneration (AMD) is the leading cause of blindness and visual disability in patients 60 years or older in the Western hemisphere.¹ The clinical presentation of AMD includes drusen, hyperplasia of the retinal pigment epithelium (RPE), geographic atrophy, and choroidal new vessels (CNVs).² Only approximately 10% to 15% of patients with AMD have severe central vision loss. Atrophic AMD, characterized by outer retinal and RPE atrophy and subjacent choriocapillaris degeneration, accounts for approximately 25% of cases with severe central vision loss.¹ Exudative AMD is characterized by CNV growth under the RPE and retina, with subsequent hemorrhage, exudative retinal detachment, disciform scarring, and retinal atrophy. Serous or hemorrhagic pigment epithelial detachment also occurs. Exudative AMD accounts for approximately 75% of cases with severe central vision loss.¹ Most patients with subfoveal choroidal neovascularization develop profound central vision loss regardless of whether the CNV has classic or occult morphologic features on angiography.^3-4 Rarely, patients have peripheral and central vision loss due to extensive subretinal and vitreous hemorrhage.

The prevalence of early AMD (ie, the presence of soft indistinct or reticular drusen or drusen with RPE degeneration or hyperpigmentation) is 18% in the population aged 65 to 74 years and 30% in the population older than 74 years.⁵ Findings from 2 population-based studies^6-7 indicate that the prevalence of geographic atrophy is 3.5% in persons older than 75 years, or approximately half the prevalence of CNVs. Since the population older than 65 years is the fastest growing segment of our society, the burden of disease will increase during the 21st century.⁸ Considering the high social and financial cost of this problem, the need for new therapies to prevent and treat exudative and atrophic maculopathy is pressing. Many different strategies are being pursued, ranging from antiangiogenic therapy to transplantation surgery. The purpose of this review is to summarize recently developed experimental and clinical biological data relevant to the pathogenesis of AMD.

AGING VS AMD

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Aging is associated with biological changes in the eye. These features of aging are present in AMD eyes and may contribute to the pathogenesis of AMD, but they do not lead inevitably to AMD. Thus, it is important to recognize aging changes in the RPE–Bruch membrane–choriocapillaris complex that occur in aged eyes without AMD.

In general, aging is associated with cumulative oxidative injury.⁹ For example, postmitotic cells such as RPE cells accumulate mitochondrial DNA deletions and rearrangements with aging.¹⁰ Verzar¹¹ recognized that aging is associated with extracellular matrix (ECM) alterations. These may include abnormalities of ECM biosynthesis; postsynthetic modifications of ECM, including degradation; altered interaction among ECM components; and changes in cell-ECM adhesion.¹² Aged human fibroblasts, for example, seem to produce structurally and functionally abnormal fibronectin that exhibits reduced binding to native types I and II collagen.¹³ Changes in the extracellular environment can induce changes in the cell phenotype.¹² Many of these changes may be under genetic control. Fibroblasts from patients with Werner syndrome, for example, exhibit each of these abnormalities.^14-16 (Werner syndrome is a condition associated with premature aging that results from a loss of function mutations in the WRN gene [which encodes a DNA helicase], which leads to rapid telomere shortening.¹⁷) Epigenetic reactions involved in aging include the Maillard reaction, uncontrolled proteolytic degradation, and free radical release. The Maillard reaction is the reaction of free reducing sugars or reactive aldehydes with free amino groups to form Schiff bases and, after Amadori rearrangements, polycyclic advanced glycation end products.¹⁸ Advanced glycation end products induce cell injury (directly or through cell surface receptors) and can induce dysregulation of tissue remodeling with enhanced deposition of ECM. Each of these features of aging is relevant when considering the aging of the retina–RPE–Bruch membrane–choriocapillaris complex and the pathogenesis of AMD (Figure 1).

View larger version (48K): [in this window] [in a new window] Figure 1. Effects of aging on cells and the extracellular matrix (ECM). Oxidative damage results in altered cell behavior, including decreased proliferation and overexpression of ECM components. Abnormal cell-ECM interactions result in programmed cell death (apoptosis), including death initiated by separation of the cell from its basement membrane (anoikis).

RPE Lipofuscin

Lipofuscin comprises a group of autofluorescent lipid-protein aggregates present in nonneuronal and neuronal tissues. As is the case for many postmitotic cells, lipofuscin accumulates in RPE cells during life. In one study,¹⁹ lipofuscin occupied 1% of the RPE cytoplasmic volume during the first decade of life and 19% of the cytoplasmic volume by age 80 years. Reduction in functional cytoplasmic volume might compromise RPE function, for example, phagocytosis,²⁰ which can lead to photoreceptor death. In the RPE, the major source of lipofuscin is the undegradable products of photoreceptor outer segment metabolism.²¹ Intralysosomal iron–catalyzed reactions generate lipofuscin. By producing reactive oxygen species, lipofuscin may induce oxidative damage in the RPE and surrounding tissues and may inhibit RPE lysosomal enzyme activity (see the bulleted list). Okubo and coworkers²² found a linear relationship between RPE autofluorescence and Bruch membrane thickness, which indicates that aging changes in the RPE and Bruch membrane may be related.

Bruch Membrane Thickness

Bruch membrane thickness seems to increase linearly with aging from approximately 2 µm at birth to approximately 4 to 6 µm in the tenth decade of life.²³ Bruch membrane thickening can arise from increased production and decreased degradation of extracellular material. As noted in the "Bruch Membrane Composition and Permeability" subsection, changes in thickness are associated with changes in protein composition, protein cross-linking, increased glycosaminoglycan size, and increased lipid content. Age-related thickening of the Bruch membrane is not confined to the inner collagenous layer. For example, native Bruch membrane collagen content increases in the outer collagenous layer during the teens. By age 40 years, wide-spaced collagen also accumulates in this layer.²⁴ Periodic acid–Schiff–positive material that resembles the contents of RPE phagosomes accumulates in the inner collagenous layer and, later, in the elastic layer.²⁵ Thus, during aging, dysfunctional RPE cells might produce abnormal quantities of ECM material, including cell fragments, collagen, and other basement membrane components.^26-27

Impaired ability to degrade the ECM might contribute to age-related Bruch membrane thickening. Matrix metalloproteinases (MMPs), for example, are zinc-dependent enzymes that catabolize ECM proteins, including collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) regulate the activity of MMPs. Retinal pigment epithelium cells produce MMPs and TIMP-3.^28-30 Inactive forms of MMP-2 and MMP-9 increase in the Bruch membrane with aging, particularly in the submacular Bruch membrane.³¹ Abnormalities in metalloproteinase activity can result in changes in Bruch membrane thickness. Mutations of TIMP-3, for example, can cause decreased TIMP-3 turnover and result in Sorsby fundus dystrophy, a condition characterized by the accumulation of abnormal extracellular material between the RPE and the inner collagenous layer of the Bruch membrane.^32-33 Bruch membrane TIMP-3 content increases with age.³⁴ Since TIMP-3 gene expression in the macular area does not increase substantially with aging,³⁵ there may be altered TIMP-3 turnover with sustained MMP inhibition during aging.

Age-related declines in choriocapillaris density and lumen diameter (see the "Choroidal Blood Flow" subsection) might also decrease clearance of debris from the Bruch membrane, which would contribute to thickening with age. In Sorsby fundus dystrophy, symptoms and retinal function improve with high-dose vitamin A therapy, suggesting that impaired diffusion across the Bruch membrane can be a consequence of Bruch membrane thickening.³⁶ (The material that accumulates in the Bruch membrane in this condition resembles the abnormal extracellular debris deposited in the Bruch membrane in AMD.)

Bruch Membrane Composition and Permeability

Various collagens, glycosaminoglycans, laminin, and fibronectin are normal constituents of the Bruch membrane (Table 1). With aging, the Bruch membrane thickens, periodic acid–Schiff staining increases, and Bruch membrane type I collagen increases.^{26, 35, 39-42} Membranous debris, filamentous material, and coated vesicles accumulate primarily in the inner collagenous layer by early adulthood and continue to do so throughout adult life.³⁹ With aging, collagen cross-linking seems to increase in the Bruch membrane, and there is a significant increase in the amount of noncollagen protein in the submacular Bruch membrane but not in the periphery, which might mean that protein-containing debris is trapped in the Bruch membrane during aging.⁴³ By late middle age, lipid deposition in the Bruch membrane is apparent.³⁹ Basal laminar deposit, which comprises mostly wide-spaced collagen⁴⁰ and other materials, including laminin, membrane-bound vesicles, and fibronectin, is present in the seventh decade of life during normal aging.^44-46 Pauleikhoff and coworkers⁴⁷ reported an age-related decline in the presence of laminin, fibronectin, and type IV collagen in the RPE basement membrane (especially over drusen). Basal linear deposit, consisting primarily of granular and vesicular material with foci of wide-spaced collagen, appears in older persons and is more specific for AMD.^{44, 48} During aging, Bruch membrane glycosaminoglycans increase in size, and heparan sulfate content increases.³⁸ Advanced glycation end products accumulate in the Bruch membrane during aging.⁴⁹ Advanced glycation end products have been shown to promote trapping of macromolecules,^50-51 and they might alter cellular trafficking through the Bruch membrane, particularly if the cells express receptors for advanced glycation end products. Molecules present in the Bruch membrane impart a negative electrostatic charge at physiologic pH.^{38, 52} Age-related changes in glycosaminoglycans might alter this charge and, as a result, the permeability properties of the Bruch membrane.³⁸

View this table: [in this window] [in a new window] Table 1. Distribution of Various Extracellular Matrix Molecules in the Human Bruch Membrane37,38

Thus, the molecular composition of the Bruch membrane and the tight junctions between RPE cells affect the movement of molecules between the choriocapillaris and the subretinal space. Most evidence indicates that the hydraulic conductivity of the Bruch membrane decreases exponentially with age in healthy individuals.^{41, 53} At any given age, the submacular Bruch membrane is affected to a greater degree than the peripheral Bruch membrane. Starita and coworkers⁴² used excimer laser ablation of different layers of the Bruch membrane to demonstrate that most of the resistance to water flow lies in the inner collagenous layer of the Bruch membrane. These investigators suggested that a high-resistance barrier develops in the Bruch membrane in older eyes, probably due to lipid and vesicular-granular debris entrapment in the Bruch membrane.

Most of the Bruch membrane hydraulic conductivity decrease occurs by age 40 years. Marshall and coworkers³⁹ noted the discrepancy between the early rapid decline in conductivity and the relatively slower rate of increase in Bruch membrane thickness. Age-related changes in Bruch membrane biochemical composition probably underlie the discrepancy. Specifically, there is increased lipidization, protein cross-linking, and protein deposition in the Bruch membrane with aging. Lipid accumulation in the Bruch membrane begins to increase substantially after age 40 years.^54-55 The rate of lipid accumulation under the macula may be higher than under the peripheral retina, perhaps due to the greater density of photoreceptors in the macula and a greater susceptibility of outer segment lipids to peroxidation in the posterior pole. Spaide and coworkers⁵⁶ found that the amount of peroxidized lipids in the Bruch membrane increased exponentially with age. The lipids seemed to be derived from long-chain polyunsaturated fatty acids normally found in the outer segments, for example, docosahexanoic acid and linoleic acid, providing support for the notion that at least some of the lipid in the Bruch membrane is of cellular origin rather than derived from the blood.

Bruch membrane morphometry indicates that the elastin layer has the highest porosity and that the inner collagenous layer has the lowest porosity.³⁹ The elastin layer seems to become increasingly porous with age.⁵⁷ This layer might normally constitute a barrier to vessel growth between the choroid and the sub-RPE space, and this age-related change might have a permissive effect on CNV growth. Marshall and coworkers³⁹ proposed that from the late teens to the late thirties, membranous debris, vesicles, and collagen accumulation cause a reduction in effective pore size in the inner collagenous layer. From the forties to the sixties, this process continues, and, abetted by substantial lipid deposition, there is an accelerated decline in hydraulic conductivity. At older ages, the deposition of basal laminar and linear deposit further reduces functional pore size. In older persons, diffusion of small and large molecules across the Bruch membrane is impaired.^58-60 Changes in protein cross-linking, noncollagenous protein deposition, and age-related lipid accumulation in the Bruch membrane may be the underlying cause.⁶¹ To the degree that hydrodynamic forces alter molecular transport across the Bruch membrane, it seems possible that hypertension would exacerbate age-related trans–Bruch membrane transport problems.

Choroidal Blood Flow

Changes in choroidal blood flow in aging and AMD have been reviewed by Lutty and coworkers.⁶² Ramrattan and coworkers²³ showed that there is a progressive decrease in the thickness of the choroid from 200 µm at birth to 80 µm by age 90 years. The choriocapillaris density and lumen diameter decrease, and the width of the intercapillary pillars increases with age.^{23, 63} In view of these histologic changes, it is not surprising that subfoveolar choroidal blood flow decreases with age.⁶⁴ Indocyanine green choriocapillaris filling, for example, is delayed in persons older than 50 years, and areas of hypofluorescence are present in the macula of patients with AMD. Laser Doppler flowmetry of the submacular choriocapillaris demonstrates decreased choroidal blood flow and volume in individuals older than 46 years, with further reduction in patients with AMD. Guymer and coworkers⁶⁵ pointed out that if choriocapillary endothelial cell processes, which are present in the Bruch membrane, play a role in clearing debris from the Bruch membrane, then an age-related loss of choriocapillaries could play a causal role in Bruch membrane thickening during aging. Alternatively, as the RPE produces substances that help maintain normal choriocapillary density and anatomy,⁶⁶ Bruch membrane thickening might cause age-related choriocapillary changes by impairing diffusion of these substances to the choriocapillaris.

Aging and Oxidative Stress

Aging is associated with increased oxidative damage.^{9, 67} Plasma glutathione levels decrease, and oxidized glutathione levels increase, for example, with age.⁶⁸ Plasma levels of vitamin C and vitamin E also decrease with age.^69-70 Lipid peroxidation seems to increase with aging.^71-72 The susceptibility of RPE cells to oxidative damage increases with aging. For example, RPE cell vitamin E levels and catalase activity decrease with aging.^73-74 Macular pigment optical density decreases with aging.⁷⁵ Retinal pigment epithelium cell lipofuscin content, which enhances susceptibility to oxidative damage, increases with aging. In addition, RPE cells that experience phototoxicity exhibit membrane blebbing,⁷⁶ a phenomenon observed in aging and AMD eyes (see the "Evidence of Oxidative Damage in AMD" and "Inflammation" subsections). One study⁷⁷ reported that RPE density decreases approximately 0.3% per year throughout life.

Oxidative damage to the RPE is a potential final common pathway for age-related retinal damage that depends on genetic predisposition, cumulative light damage, free radical injury, and hemodynamic abnormalities (reviewed by Winkler,⁷⁸ Beatty,⁷⁵ and Cai⁷⁹ and their colleagues). Production of reactive oxygen species is stimulated by irradiation, aging, inflammation, increased partial pressure of oxygen, air pollutants, cigarette smoke, and reperfusion injury. Oxygen-derived metabolites cause oxidative damage to cytoplasmic and nuclear elements of cells and cause changes in the ECM. Reactive oxygen species react, for example, with nucleic acids, membrane lipids, surface proteins, and integral glycoproteins.

Beatty and coworkers⁷⁵ reviewed the factors promoting reactive oxygen species formation in the retina and RPE:

• Outer segments are enriched in polyunsaturated fatty acids
  
• Oxygen tension in the photoreceptor-RPE area is close to that of arterial blood
  
• The retina is exposed to high levels of cumulative irradiation
  
• The retina and RPE contain photosensitizers: rhodopsin, lipofuscin, and cytochrome c oxidase
  
• The choriocapillaris contains blood-borne photosensitizers
  
• RPE phagocytosis is an oxidative stress
  

PATHOGENESIS OF AMD

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One model of aging vs AMD consistent with published clinical, pathological, and experimental observations is shown in Figure 2. Age-related macular degeneration involves aging changes plus additional pathological changes. In AMD and aging, oxidative stress results in RPE and, possibly, choriocapillaris injury. In AMD, and possibly in aging, RPE injury elicits an inflammatory response in the Bruch membrane and the choroid. In AMD eyes, RPE injury and inflammation foster the production of an abnormal ECM derived largely from the RPE and photoreceptor cells but also from cells in the choroid and from substances in the systemic circulation. The abnormal ECM, in turn, results in altered RPE biologic behavior and may cause further damage to the retina, RPE, and choroid. Oxidative damage to the choriocapillaris also may contribute to the pathogenesis of AMD. The factors mediating CNV growth and the development of geographic atrophy involve perturbation of RPE-choriocapillaris homeostasis. Retinal pigment epithelium death, for example, probably is the cause of choriocapillaris loss in geographic atrophy.^{66, 89} Evidence for the pathogenic role of oxidative stress, inflammation, ECM abnormalities, altered RPE biologic behavior, and genetics is considered in the following subsections.

View larger version (30K): [in this window] [in a new window] Figure 2. Aging vs age-related macular degeneration (AMD). RPE indicates retinal pigment epithelium; ECM, extracellular matrix; CNV, choroidal new vessel.

Evidence of Oxidative Damage in AMD

Clinical Studies of Antioxidants. The Age-Related Eye Disease Study,⁹⁰ a multicenter randomized clinical trial involving more than 3600 patients, demonstrated that among patients with extensive intermediate drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, advanced AMD in 1 eye, or vision loss in 1 eye due to AMD, supplementation with antioxidant vitamins (ascorbic acid, 500 mg/d; vitamin E, 400 IU/d; and beta carotene, 15 mg/d) and minerals (zinc oxide, 80 mg/d; cupric oxide, 2 mg/d) reduces the risk of developing advanced AMD from 28% to 20% and the rate of at least moderate vision loss from 29% to 23%. Zinc is essential for the function of some antioxidant enzymes (eg, superoxide dismutase, catalase, and metallothionein) and is the most abundant trace element in human eyes.⁹¹ As noted in the "Bruch Membrane Thickness" subsection, zinc also is important for MMP activity. Results of the Age-Related Eye Disease Study⁹⁰ indicate that oxidative damage plays a role in the progression of AMD in its clinically evident intermediate and late stages and that disease progression can be altered with antioxidant supplementation. Earlier trials^{68, 92-96} of zinc therapy and of dietary zinc intake gave conflicting results, possibly due to small sample size, relatively short follow-up, and/or inadequate dosing.

Other studies^{68, 92-97} have provided data regarding antioxidant status and the risk of AMD, with conflicting results in some cases. Complexities of study design (eg, the number of patients studied and reliance on historical information provided by patients), variability in diet-plasma correlation for micronutrients and antioxidants (eg, carotenoids), uncertain relationships between plasma levels of antioxidants and micronutrients and their ocular tissue levels, and the possible importance of interactions between various antioxidants and micronutrients might all underlie the variable results reported in these studies. Other data supporting the hypothesis that oxidative damage plays a role in AMD pathogenesis are as follows.

Epidemiologic Studies. Thus far, the most important risk factors for AMD (ie, those associated with at least a 2-fold increased risk) seem to be age, smoking, and race.^{6, 98-100} Regarding age, the prevalence of late AMD is approximately 0% at 50 years, 2% at 70 years, and 6% at 80 years.¹⁰¹ The effect of age on risk might indicate that oxidative damage must be gradual and cumulative for AMD to develop. Also, it might be a sign that mitochondrial DNA damage plays a role in the pathogenesis.¹⁰² Smoking depresses antioxidants (eg, decreases plasma vitamin C and carotenoids), induces hypoxia and reactive oxygen species, and alters choroidal blood flow.^103-104 Regarding the effect of race, white patients have a relatively higher risk of large drusen, pigmentary abnormalities, and exudative AMD complications compared with black patients.^{44, 105-106} Differences in melanin content may underlie, in part, the racial differences in risk of advanced AMD. Melanin is a high-molecular-weight polymer arising from enzymatic oxidation of tyrosine and dihydroxyphenylalanine and is located in melanosomes, which are membrane-bound granules. In vitro experiments indicate that melanin reduces lipofuscin accumulation in RPE cells, possibly by interacting with transition metals and scavenging radicals to function as an antioxidant.¹⁰⁷ The RPE melanin content in white and black patients is similar, but black patients have substantially more choroidal melanin than whites.¹⁰⁸ Perhaps oxidative reactions in the Bruch membrane (see the "Inflammation" subsection) or at the level of the RPE can be attenuated by choroidal melanin. Alternatively, the protective effect of race may mean that the most important oxidative reactions leading to AMD occur at the level of the choriocapillaris.¹⁰⁹ The fact that choriocapillaris density decreases with AMD is consistent with but does not prove this hypothesis (see the "Abnormal ECM" and "Altered RPE-Choriocapillaris Behavior" subsections).^{23, 89, 110}

Biochemical Studies. Antioxidants act by preventing the formation of initiating radicals, binding metal ions, and removing damaged molecules. Major antioxidants in the retina and RPE include water-soluble metabolites and enzymes (vitamin C [ascorbic acid], glutathione, catalase, glutathione peroxidase, and superoxide dismutase), lipid-soluble substances (vitamin E [-tocopherol], retinoids [vitamin A derivatives], and carotenoids), and melanin.^{75, 78-79} The antioxidant enzymes, for example, superoxide dismutase, catalase, and glutathione peroxidase, constitute the primary defense against oxidative RPE damage.¹¹¹ Antioxidant molecules, for example, ascorbic acid (vitamin C), tocopherol (vitamin E), and carotenoids, support the enzymatic systems.

The protective mechanisms against oxidative RPE damage seem to decrease with aging, and, in some cases, these changes are greatest in AMD eyes (vs age-matched control eyes). For example, RPE catalase levels decrease with aging and with AMD.^{73, 112} Metallothionein is an acute-phase reactant protein that scavenges hydroxyl radicals, and there is an age-related decrease in submacular RPE metallothionein content.¹¹³ Plasma glutathione reductase is reduced substantially in patients with AMD.¹¹⁴ Frank and coworkers¹¹² found that heme oxygenase-1 and heme oxygenase-2 immunoreactivity tended to decrease with increasing age, especially in RPE lysosomes of neovascular AMD eyes. Oxidative stress probably causes pathologic up-regulation of lysosomal heme oxygenase-1 and possibly heme oxygenase-2. These investigators found that copper-zinc superoxide dismutase immunoreactivity increases in the cytoplasm of submacular RPE in eyes with AMD and CNVs. The Pathologies Oculaires Liées à l'Age Study¹¹⁵ found that higher plasma levels of glutathione peroxidase were associated with a significantly increased prevalence of late but not early AMD. Beatty and coworkers⁷⁵ pointed out that extracellular glutathione peroxidase is believed to act as an extracellular antioxidant, which may be relevant for oxidative reactions occurring in the Bruch membrane and the choriocapillaris (see the "Inflammation" subsection).

Carotenoids, especially lutein and zeaxanthin, compose the macular pigment. The primary direct antioxidant function of carotenoids is to scavenge singlet oxygen, but they also quench the triplet state of photosensitizers and retard the peroxidation of membrane phospholipids.^116-117 Factors associated with increased risk for AMD and increased risk for low macular pigment density include age, cigarette smoking, female sex, light iris color, and increasing lens density,^118-121 but not all clinical studies confirm the association between low macular pigment density and increased risk for AMD.¹²² Two postmortem studies^123-124 revealed decreased retinal lutein and zeaxanthin levels in AMD eyes vs control eyes. Increasing age and advanced AMD in the fellow eye have been associated with a relative absence of macular pigment.¹²⁵

Findings from in vitro and in vivo animal studies indicate that basal laminar deposit may form as a result of free radical–induced lipid peroxidation of RPE cell membranes with subsequent membrane blebbing and accumulation of blebs as basal laminar deposit–like material in the sub-RPE space.¹²⁶ Advanced glycation end products occur at sites of oxidant stress with hydroxyl radical formation. Advanced glycation end products occur in soft drusen, in basal laminar and basal linear deposits, and in the cell cytoplasm of RPE associated with CNVs.^{88, 127} When RPE cell lines are grown on a matrix modified by advanced glycation end products, they express genes (eg, transforming growth factor ₂) that might promote Bruch membrane thickening.¹²⁸ Advanced glycation end products induce increased expression of cytokines known to occur in CNVs.¹²⁷ Carboxymethyl lysine, a product of lipoprotein peroxidation or sequential oxidation and glycation, is present in drusen and CNVs.^{88, 129} One study⁸⁸ of drusen protein composition reported oxidative protein modifications in TIMP-3 and vitronectin. Also, carboxyethyl pyrrole protein adducts, which are uniquely generated from the oxidation of docosahexaenoate-containing lipids, were present and were much more abundant in drusen from AMD vs age-matched control donors. (As noted previously herein, docosahexaenoate lipid is abundant in photoreceptor outer segments.) The collocation of lipofuscin-induced autofluorescence and drusen suggests an etiologic relationship between the two, but this collocation has not been observed in all studies.^130-131 Genetic defects (eg, in antioxidant enzymes), dietary or uptake deficiencies in antioxidants, or exposure to noxious agents (eg, cigarette smoking) could enhance oxidative RPE damage during life and predispose to AMD and other signs of aging.

Inflammation

Anatomic studies^132-135 provided initial evidence for the role of inflammation in CNV formation in AMD. Subsequently, molecular evidence for the role of inflammation in AMD pathogenesis has been developed and summarized by Hageman,¹³⁶ Johnson,¹³⁷ and Anderson¹³⁸ and their coworkers. Protein components of drusen include immunoglobulin and components of the complement pathway associated with immune complex deposition (eg, C5b-9 complex), molecules involved in the acute-phase response to inflammation (eg, amyloid P component and ₁-antitrypsin), proteins that modulate the immune response (eg, vitronectin, clusterin, apolipoprotein E, membrane cofactor protein, and complement receptor 1), major histocompatibility complex class II antigens, and HLA-DR and cluster differentiation antigens.^139-142 Cellular components of drusen include RPE blebs, lipofuscin, and melanin, as well as choroidal dendritic cells.^{136, 143-146} Hageman and coworkers¹³⁶ postulated that choroidal dendritic cells are activated and recruited by injured RPE (eg, via monocyte chemotactic protein) and oxidized proteins and lipids in the Bruch membrane. A similar process occurs in atherosclerosis. The RPE cells respond to control dendritic cell activation by secreting proteins that modulate the immune response, including vitronectin, apolipoprotein E, and membrane cofactor protein.¹³⁷ Johnson and coworkers^{137, 147} pointed out that the cytoplasmic accumulation of vitronectin, apolipoprotein E, and other drusen-associated molecules suggests that the cells are subjected to a chronic sublethal complement attack. These researchers recognized that complement attack can result in the elimination of surface-associated membrane attack complexes (by shedding or endocytosis of cell membrane) and in the formation of extracellular deposits of immune complexes and complement intermediates. Penfold and coworkers¹⁴⁸ reported an increase in major histocompatibility complex class II immunoreactivity on retinal vascular elements and morphologic changes in microglia in eyes with incipient AMD. These immunologic changes seemed to be related to early pathological changes in RPE pigmentation and drusen formation. Evidence of inflammatory cell involvement in the later stages of AMD includes the presence of multinucleated giant cells and leukocytes in the choroid of AMD eyes^149-151 and in excised CNVs.^152-153 Macrophages and foreign body giant cells near the Bruch membrane become more common when basal linear deposit is present.¹⁵¹ Activated macrophages and other inflammatory cells secrete enzymes that can damage cells and degrade the Bruch membrane, and, by releasing cytokines, inflammatory cells might foster CNV growth into the sub-RPE space.^154-155 Thus, in AMD eyes, breaks in the Bruch membrane probably are the result and not the cause of CNVs.¹⁵⁶ In some systems, ECM degradation is associated with free radical release.^157-158

Poorly degradable RPE debris and Bruch membrane components (eg, wide-spaced collagen) might stimulate chronic inflammation.^{27, 46, 150, 159} Hageman and coworkers¹³⁶ suggested that activation of choroidal dendritic cells might initiate an autoimmune response to retinal and/or RPE antigens or to neoantigens created within the Bruch membrane. Despite the RPE and retina being immune-privileged tissues,¹⁶⁰ antiretinal and anti–RPE antibodies have been detected in the serum of patients with AMD.^{136, 161-162} Johnson and coworkers¹³⁷ pointed out that complement activation and associated inflammatory events occur in diseases exhibiting cellular degeneration and accumulation of abnormal tissue deposits, for example, atherosclerosis and Alzheimer disease.¹⁶³ In these diseases, damaged cells and highly insoluble protein deposits and extracellular debris activate the classical and alternative complement pathways, resulting in chronic direct and bystander cellular damage with attendant cell surface blebbing, endocytosis, and up-regulation of defense proteins. The Alzheimer amyloid peptide co-localizes with activated complement components in a substructural vesicular component with drusen.¹⁶⁴

Intravitreal corticosteroids reduce the incidence of laser-induced CNVs in primates, possibly by altering inflammatory cell activity and/or numbers in the choroid.¹⁶⁵ Other potential mechanisms include reduction of vascular endothelial growth factor (VEGF) expression (see the "Biochemical Features of CNV Growth" subsection) and down-regulation of intercellular adhesion molecule 1,^166-167 which is constitutively expressed on RPE and choroidal endothelial cells and mediates leukocyte adhesion and diapedesis during inflammation.^168-169

Abnormal ECM

The RPE deposits cytoplasmic material into the Bruch membrane throughout life, possibly to eliminate cytoplasmic debris or as a response to chronic inflammation (see the "Inflammation" subsection).^{143, 170-172} Histologically, AMD eyes exhibit abnormal extracellular material in 2 locations: (1) between the RPE plasmalemma and the RPE basement membrane and (2) external to the RPE basement membrane within the collagenous layers of the Bruch membrane. The former material is termed basal laminar deposit, and the latter material is termed basal linear deposit.⁴⁴ Although basal laminar deposit persists in areas of geographic atrophy, basal linear deposit disappears, which is consistent with the notion that basal linear deposit arises mostly from the RPE-photoreceptor complex.¹⁷³ Basal linear deposit may be more specific to AMD than basal laminar deposit.⁴⁸ Soft drusen can represent focal accentuations of basal linear deposit in the presence or absence of diffuse basal linear deposit–associated thickening of the inner aspects of the Bruch membrane.^{44, 174} Soft drusen can also represent a localized accumulation of basal laminar deposit in an eye with diffuse basal laminar deposit.¹⁷⁴ Thus, the abnormal ECM of AMD eyes includes basal laminar deposit, basal linear deposit, and their clinically evident manifestation, soft drusen.

Drusen represent the earliest clinical finding in AMD. Drusen composition and origin have been analyzed extensively.^{34, 56, 127, 136, 138, 140, 175-177} Small (ie, <63-µm-diameter) drusen generally do not signify the presence of AMD.^{5, 26, 44, 178} Excessive numbers of small hard drusen, however, can predispose to RPE atrophy at a relatively young age.¹⁷⁹ Soft drusen are usually pale yellow and large (63 µm in diameter), with poorly demarcated boundaries. Many different molecules have been identified in drusen, including glycoconjugates¹⁸⁰ containing mannose, sialic acid, N-acetylglucosamine, and -galactose (Table 2). Abnormal constituents of the ECM probably underlie the increased blue-green autofluorescence of the Bruch membrane in AMD eyes.¹⁸¹

View this table: [in this window] [in a new window] Table 2. Some Molecular Constituents of Drusen

Most of the molecular constituents of drusen are synthesized by RPE, neural retina, or choroidal cells, but some are derived from extraocular sources.^{56, 127, 136, 176-177,182} Several investigators^183-184 have noted that drusen tend to be distributed near the collecting venules of choriocapillaris lobules, which has led to the hypothesis that drusen are derived from the choroidal vasculature. An alternative explanation is that RPE cell susceptibility to metabolic derangement depends, to some degree, on the location of a given cell with respect to the underlying choriocapillaris lobule.

A variety of drusen constituents (eg, vitronectin, apolipoproteins B and E, complement, and lipid) are present in atherosclerotic plaques, which may reflect the association of some atherosclerosis risk factors with the development of AMD. Amyloid P component, C5, and ₁-antitrypsin are acute-phase reactants (ie, up-regulated expression in response to inflammation), and vitronectin, C5, and apolipoprotein E have roles in mediating immune responses. These findings have led to the suggestion that immune complex–mediated damage to RPE cells plays a role in the initiating events of drusen formation, as noted herein. It may be that terminal complement activation promotes drusen breakdown by enzymatic digestion and phagocytosis.¹⁴⁰ An immune response directed against RPE-derived antigens might be the trigger for drusen formation.

Although MMPs and TIMPs are present in plasma,¹⁸⁵ immunohistochemical studies of MMP and TIMP indicate that at least some MMPs and TIMPs in the Bruch membrane are derived from the RPE (see the "Bruch Membrane Thickness" subsection). Changes in MMPs and their inhibitors indicate that in AMD, RPE dysfunction could result in abnormal MMP activity, which could contribute to the exaggerated development of an abnormal ECM (compared with age-matched controls). For example, TIMP-3 is present in drusen,^{34, 186} and TIMP-3 levels seem to be increased in drusen and in the Bruch membrane of AMD eyes.³⁴ Binding of TIMP-3 to advanced glycation end products, which are present in the Bruch membrane and drusen (see the "Role of the ECM in CNV Growth" subsection), may lead to TIMP-3 accumulation in AMD eyes.^{33, 187} Leu and coworkers¹⁸⁶ noted that MMP immunoreactivity was present only on the surface of drusen. In situ zymography demonstrated that metal ion–dependent gelatinase activity was absent in drusen cores. Leu and coworkers¹⁸⁶ suggested that the lack of proteolysis in drusen cores might contribute to drusen formation and AMD progression, perhaps in the same way that Sorsby fundus dystrophy mutations, which do not result in loss of TIMP-3 function, foster accumulation of an abnormal ECM.^{33, 186}

In patients with AMD, delayed choroidal perfusion (as visualized with fluorescein and indocyanine green angiography) and psychophysical retinal functional abnormalities may result from the diffusion barrier created by a thickened, lipid-laden Bruch membrane.^{58, 188-190}

Altered RPE-Choriocapillaris Behavior

The accumulation of extracellular debris alters Bruch membrane composition (ie, increased lipid and protein content) and permeability (eg, decreased permeability to water-soluble constituents in plasma, decreased amino acid transport, and possibly decreased bulk flow of extruded RPE-derived cytoplasmic debris across the Bruch membrane).^{43, 53, 59-61} These changes may lead to impaired diffusion of waste products from and of hormones and nutrients to the RPE, including oxygen and vitamin A.¹³³ In response to this metabolic distress, the RPE probably produces substances that stimulate CNV growth. Several investigators^191-193 have shown that RPE cells associated with CNVs produce VEGF and basic fibroblast growth factor, which may act synergistically to stimulate new blood vessel growth. Macrophages and foreign body giant cells, possibly recruited by activated choroidal dendritic cells, may digest the Bruch membrane and be a source of cytokines that also stimulate CNV growth. Sarks and colleagues¹⁹⁴ noted that activated choroidal capillaries were observed only beneath thinned regions of the Bruch membrane. Sarks observed that Bruch membrane erosion often commences beneath small hard drusen and posited that this phenomenon occurs because angiogenic factors diffuse most readily to the choriocapillaris in these loci rather than through nearby areas containing substantial membranous debris.¹⁹⁴ Choroidal capillaries adjacent to CNVs are often narrowed or absent, which may be a manifestation of RPE dysfunction.^{66, 89, 195-196} This fact may underlie the clinical finding that pulsatile ocular blood flow is lower in eyes with CNVs compared with contralateral eyes with drusen.¹⁹⁷

Biochemical Features of CNV Growth. The RPE may constitutively control angiogenesis beneath the retina.¹⁹⁸ The RPE, for example, produces VEGF in vivo under physiologic conditions.¹⁹⁹ VEGF is secreted as a homodimeric protein that is expressed in ischemic retina and stimulates endothelial cell proliferation in blood vessels. The RPE-derived VEGF may maintain the fenestrated choriocapillaris endothelium. Much evidence implicates VEGF in CNV formation. High concentrations of VEGF and VEGF receptors are in CNVs, surrounding tissue, and RPE cells.^{191, 193, 200} Levels of VEGF are increased in cadaver AMD eyes,²⁰⁰ in the vitreous of patients with AMD,²⁰¹ and in the plasma of patients with AMD.²⁰² Also, VEGF is present in fibroblastic cells and transdifferentiated RPE of surgically removed CNVs.¹⁹¹ Laser-induced CNVs (in rats and monkeys) are associated with increased VEGF messenger RNA (mRNA) in the RPE, choroidal vascular endothelial cells, and fibroblasts. Intravitreal anti-VEGF antibody fragment (rhuFab VEGF) prevents laser-induced CNVs in monkeys and decreases leakage from already-formed CNVs.²⁰³ PKC 412, an inhibitor of protein kinase C and the kinases of VEGF and platelet-derived growth factor receptors, prevents laser-induced CNVs in mice.²⁰⁴

Increased VEGF expression seems to be sufficient for CNV formation. Schwesinger and coworkers²⁰⁵ showed that transgenic mice with RPE cells that overexpress VEGF are associated with increased VEGF in the RPE, Bruch membrane, and choroid; increased leukostasis in the choroidal vasculature, probably from up-regulation of intercellular adhesion molecule-1; and intrachoroidal new vessels that do not penetrate the intact Bruch membrane. This result suggests that the presence of increased RPE-derived VEGF must be coupled with some additional factor(s) to develop "typical" sub-RPE and/or subretinal CNVs. The need for RPE–Bruch membrane damage may explain why rats undergoing subretinal injection of adenovirus vector that transfects RPE exhibit CNVs.²⁰⁶

Retinal pigment epithelium cells also produce pigment epithelial–derived factor (PEDF), a 50-kDa protein.²⁰⁷ In addition to neuroprotective effects, PEDF potently inhibits angiogenesis.²⁰⁸ Oxidative stress may alter the balance between RPE VEGF and PEDF production.²⁰⁹ Increased RPE PEDF production inhibits laser-induced CNV growth and induces regression of established CNV in a murine model.^210-211

Tie-1 and Tie-2 are receptor tyrosine kinases that play a role in the later stages of angiogenesis.²¹² Angiopoietins are approximately 75-kDa secreted proteins that target endothelial cell–specific Tie-2 receptors and promote neovascularization in vascular beds, including the retina. Stimulated by angiopoietin-1 (Ang-1), Tie-2 plays a major role in recruiting and sustaining periendothelial support cells (eg, pericytes), resulting in the formation of multicellular vascular structures from simple endothelial tubes.^213-214 Angiopoietin-2 (Ang-2) blocks these functions and, in so doing, may allow vascular remodeling and angiogenesis via stimulatory cytokines, such as VEGF (eg, by reducing endothelial-matrix contact or by dissociating pericytes from endothelial cells).²¹³ Thus, Ang-1 promotes maturation and stabilization of vessels, and Ang-2 might allow endothelial cells to respond to angiogenic signals.^213-214 Cultured RPE cells express Ang-1 and Ang-2 mRNA, and VEGF up-regulates RPE Ang-1 mRNA and Ang-1 protein secretion.²¹⁵ In one study,²¹⁶ Ang-1, Ang-2, and Tie-2 immunoreactivity were present in CNVs from AMD eyes. Angiopoietin-1, Ang-2, and VEGF localization were similar, including localization in RPE and vascular cells. Angiopoietin-2 and VEGF immunoreactivity was abundant in highly vascularized regions of the CNVs. Tie-2 immunoreactivity was present in vascular structures and RPE cells. Angiopoietin-1 probably modulates the effect of VEGF on endothelial cells during CNV formation. Retinal pigment epithelium–derived Ang-1 may modulate interactions between endothelial cells and leukocytes during choroidal angiogenesis.

Hypoxia up-regulates Ang-2 mRNA in bovine retinal capillary endothelial cells.²¹⁷ Hypoxia also up-regulates VEGF levels (ie, up-regulates VEGF mRNA transcription and increases mRNA stabilization). It is not proved that the documented abnormalities in choroidal blood flow in AMD eyes are sufficient to induce this hypoxia response in the RPE-choroid. Also, it is not proved that the documented thickening, lipidization, and protein cross-linking of the Bruch membrane in AMD alter oxygen diffusion to the RPE photoreceptors. How might oxidative damage and hypoxia play a role in AMD pathogenesis? Perhaps initial oxidative damage leads to excessive formation of an abnormal ECM. Thickened Bruch membrane, combined with factors such as smoking, might then create a relatively hypoxic environment. Relatively minor changes in the diffusion properties of the Bruch membrane or in choroidal blood flow might have seemingly disproportionate effects on the RPE and photoreceptors since the photoreceptors usually consume 90% to 100% of the oxygen delivered by the choriocapillaris.²¹⁸ (In the dark-adapted macaque monkey, the oxygen tension near the level of the inner segments is approximately 8 mm Hg vs approximately 50 to 80 mm Hg in the choroid.) Hypoxia could then result in RPE death and geographic atrophy or in stimulation of CNV growth by hypoxic RPE.

Role of the ECM in CNV Growth. Sarks et al¹⁹⁴ and Campochiaro and coworkers²¹⁹ suggested that abnormalities of the RPE ECM may promote a proangiogenic phenotype that fosters CNV growth; CNV growth probably is affected by the nature and quantity of extracellular debris in the sub-RPE space. The risk of CNVs in AMD, for example, increases with increasing number, size, and confluence of drusen. Vitronectin, fibronectin, and advanced glycation end products are molecular constituents of drusen and stimulate production of angiogenic factors in model systems.^220-221 Peroxidized lipids, which accumulate in the Bruch membrane, not only alter Bruch membrane hydraulic conductivity but also stimulate the production of substances that promote neovascularization.⁵⁶ Also, ECM molecules can stimulate or inhibit angiogenesis by binding to integrins or by altering integrin expression on endothelial cells (Table 3).^{204, 209, 219, 222-223}

View this table: [in this window] [in a new window] Table 3. Some Stimulators and Inhibitors of Ocular Neovascularization*

Matrix metalloproteinases and urokinase plasminogen activator break down the ECM during angiogenesis.^224-225 Matrix metalloproteinase-2 and MMP-9 mRNA, for example, are present in excised CNV specimens,²²⁶ and MMP-2 mRNA is increased in laser-induced CNVs in rats.²²⁷ Degradation of ECM presumably releases and/or activates proangiogenic factors. Proangiogenic factors stimulate proteolytic activity, migration, proliferation, and tube formation in endothelial cells.

Biological Basis of Geographic Atrophy. Choriocapillaris density decreases with aging and with AMD. The average choroidal blood flow is lower in patients with dry AMD vs age-matched controls.^228-229 An area dilution analysis technique applied to indocyanine green angiography demonstrated delayed and heterogeneous choroidal filling in nonneovascular AMD eyes compared with age-matched control eyes.²³⁰ In AMD, the usual pattern of sinusoidal capillary lobules (ie, a central arteriole feeding a sinusoid that drains into peripheral venules) is replaced by a tubular capillary network, which has a lower surface area–volume ratio.¹¹⁰ This change might be due to primary damage to the choriocapillaris endothelium (eg, oxidative damage mediated by protoporphyrins); might follow the loss of RPE cells (eg, secondary to chronic oxidative damage), with attendant loss of VEGF and other trophic factors⁶⁶; or might arise from a combination of these processes. Photoreceptor death follows RPE cell loss.^{132, 231}

The biological basis of geographic atrophy in AMD has been reviewed by Sunness.²³² The presence of drusen measuring 250 µm or greater and pigmentary abnormalities are risk factors for the development of geographic atrophy. Increased fundus autofluorescence precedes the development and enlargement of geographic atrophy in AMD.²³³ The dominant fluorophores of fundus autofluorescence are part of RPE lipofuscin granules. Thus, excessive RPE lipofuscin accumulation may play a critical role in geographic atrophy pathogenesis in AMD. Histologically, lipofuscin-laden RPE cells are present at the junction of atrophic and normal retina in AMD eyes. The RPE appears increasingly abnormal near the area of atrophy.^{44, 179} Clinical studies²³³ indicate that the area of increased autofluorescence is larger than would be predicted from histologic studies, but no direct clinicopathologic correlation has been made yet. The loss of RPE-derived VEGF might result in the choriocapillaris atrophy seen with atrophic AMD.⁸⁹

Geographic atrophy tends to develop near the fovea, but it tends to spare the foveal center until the later stages of the disease.^{231, 234-235} One explanation for this observation is as follows.^{21, 231, 236} The highest turnover of outer segments involves rods just outside the fovea, which parallels the distribution of lipofuscin in the RPE. Each RPE cell contacts approximately 45 photoreceptor cells, and each rod outer segment is fully phagocytosed and replaced approximately every 10 days. The RPE continuously discharges cytoplasmic material into the Bruch membrane,²⁷ which could lead to pathological changes, primarily in the subjacent Bruch membrane. Atrophy of the RPE may be a response to decreased nutrients/increasing metabolic abnormalities in areas of excessive accumulation of extracellular debris. Subfoveolar RPE is spared from atrophy the longest, perhaps by macular pigment,²³⁷ the high cone density in the foveola, and possibly other factors. It may be that the subfoveolar RPE is the longest-lived source of neovascular signal(s) in this metabolically distressed region, thus accounting for the tendency of CNVs to grow toward the foveola initially and after laser photocoagulation. Choroidal new vessels do not seem to arise from within areas of geographic atrophy but instead tend to arise under adjacent areas in which the RPE-retina seems relatively preserved or under the fovea, if spared.²³⁵

Among patients with CNVs in one eye and geographic atrophy in the fellow eye, the cumulative incidence of CNVs in the eye with geographic atrophy is 30% to 50% at approximately 5-years' follow-up.²³⁷ Results of histopathologic studies^{26, 44} indicate that CNVs are present in approximately one third of cases with geographic atrophy. Thus, it seems unlikely that patients with AMD-associated geographic atrophy and AMD-associated CNVs have 2 different diseases.

Role of Genetics

Findings from genetics studies (reviewed by Yates and Moore²³⁸) indicate that there is high concordance for AMD among monozygotic twins and relatively lower concordance among dizygotic twins. Age-related macular degeneration is more likely in first-degree relatives than in age-matched controls.²³⁹ One study²⁴⁰ of monozygotic twins found a genetic effect for the phenotypes of age-related maculopathy (ie, the early stages of AMD), soft drusen, pigmentary changes, and 20 or more hard drusen. The inheritability of age-related maculopathy was estimated to be 45%. During the next few years, molecular biology studies probably will identify mutations in specific genes that alter the risk of developing AMD.²⁴¹ At this time, it seems likely that AMD is a polygenic disorder with multiple genes conferring susceptibility to and resistance from the disease. Characterization of the genetic defects underlying the diseases to which we refer currently as AMD may provide an opportunity to identify subtypes of AMD with different disease-causing molecular defects. This approach to nosology may permit better design of clinical trials of therapy, which in turn would enable physicians to provide the proper treatment (especially prophylaxis) at the proper time for any given patient.

Genetic mutations have been identified as the causes of diseases that resemble AMD. Kuntz and coworkers²⁴² observed that degenerations associated with lipid/mineral deposits in the Bruch membrane are often autosomal dominant and that patients are often asymptomatic until adulthood. Genetic factors probably play a role in the development of geographic atrophy in AMD. Zermatt macular dystrophy, for example, is associated with a dominant mutation of the RDS/peripherin gene and is associated with atrophy.²⁴³ A mutation in epidermal growth factor–containing fibrillin-like ECM protein-1 (EFEMP1) causes Malattia Leventinese and Doyne honeycomb retinal dystrophy, which are associated with drusen formation.²⁴⁴ EFEMP1 is expressed in the RPE and retina and encodes a protein homologous to a family of ECM glycoproteins known as fibulins. ABCR gene mutations have been associated with an increased risk of atrophic AMD, but findings from some studies^245-246 indicate that the detected mutations may simply be polymorphisms (ie, mutations that can occur in healthy individuals and do not confer an increased risk) among patients with a common disease. ABCR, or rim protein, is a transmembrane protein that may be involved in retinoid transport. As noted in the "Bruch Membrane Thickness" subsection, mutations in TIMP-3 cause Sorsby fundus dystrophy, which is associated accumulation of abnormal extracellular material in the Bruch membrane, patchy choroidal filling on fluorescein angiography, and CNVs. Despite the similarities between Sorsby fundus dystrophy and AMD, there are differences (eg, younger age of CNV development in the former), and TIMP-3 mutations do not seem to cause AMD.^247-248 Although lysosomal storage diseases due to single gene defects in metabolism are characterized by accumulations of intracellular material in the RPE, their resemblance to AMD is modest.²⁴⁹ Cai and coworkers⁷⁹ noted that Cockayne syndrome may be a more relevant disease model. In this condition, nucleotide excision repair and transcriptional repair are deficient, which permits cumulative damage to nuclear and mitochondrial genomes throughout life and premature aging.²⁵⁰ In analogy with mitochondrial myopathies, Cai and coworkers⁷⁹ suggested that AMD probably results from progressive damage to the retina and RPE throughout life. Functional capacity (eg, against oxidative damage) in healthy individuals exceeds the threshold below which disease becomes apparent clinically. Genetic background interacts with exposure to environmental risk and protective factors to determine age at disease onset for a given individual. Genetics might affect the susceptibility to develop AMD in the following way.²⁵¹ Cellular production of ECM is genetically controlled. Epigenetic factors can alter the ECM, for example, formation of advanced glycation end products. The matrix and matrix degradation products regulate cell phenotype via membrane receptors. The consequences of these interactions can cause disease and/or aging. For example, advanced glycation end products can trigger free radical release and seem to play a role in the accumulation of abnormal extracellular material in Alzheimer disease.²⁵²

Most AMD cases may not be caused by a single gene defect, even if genes play a major role in determining susceptibility to the disease (eg, by affecting melanin content, antioxidant enzyme activity, and/or MMP activity). Nonetheless, an important benefit of identifying a gene that causes AMD (even if it were to account only for a small fraction of the total patient population) or a condition that very strongly resembles AMD or just a particular aspect of the disease is that one might then construct a biochemical pathway "framework" in which other causes of the disease might be understood and various treatment strategies might be developed.²⁵³ The evidence summarized in this review may provide some insight into the nature of the biochemical pathways involved in AMD pathogenesis and a context in which identified mutations can be studied. The evolution of technologies such as serial analysis of gene expression and microarray analysis may accelerate the identification of genes conferring susceptibility to or protection against AMD and foster the development of complex animal models exhibiting more than 1 gene defect.²⁵⁴

IMPLICATIONS FOR DEVELOPMENT OF THERAPY

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Chronic diseases often require a stepwise approach to treatment, and progressive steps usually are associated with increasing degrees of risk to the patient. Generally, the initial approach is prophylaxis, followed by medical therapy, and then surgical therapy. Examples that illustrate this sequence include diabetes mellitus (eg, weight control oral hypoglycemic agents insulin therapy pancreatic islet cell transplantation) and atherosclerosis (eg, diet restriction + exercise cholesterol-lowering agents coronary artery stenting and/or bypass surgery). Age-related macular degeneration is a chronic disease; thus, the goal of AMD research should be to develop treatments for the early and later stages of the disease, as patients will seek care at different stages of the disease and will vary in their response to therapy.

Currently, most treatments for AMD benefit patients with advanced stages of the disease (eg, laser photocoagulation, photodynamic therapy, and surgery for CNVs). Lanchoney and coworkers²⁵⁵ showed that the addition of a 25% effective bilateral preventive treatment to the conventional laser photocoagulation treatment regimen for CNVs would reduce the rate of legal blindness in the population with bilateral soft drusen relative to current laser treatment by approximately 40% (from 2.24% to 1.34%). Preventive treatment given to the fellow eye after CNVs develop would have substantially less impact (approximately 20% reduction). Thus, treatments for the earlier stages of AMD, even if only modestly effective, can have a great impact on the incidence of AMD-induced blindness.

Better knowledge of AMD pathogenesis will permit the design of effective therapy for earlier stages of the disease. The first proven "early" treatment for AMD is oral therapy with antioxidant vitamins and minerals. Other approaches also may be effective. Dimethyl fumarate, for example, is enriched in apples, increases glutathione, and protects RPE cells from peroxide-induced damage in vitro.²⁵⁶ Other more potent inducers of glutathione synthesis, such as oltipraz or sulforaphane, have been tested in preclinical trials for cancer prevention.²⁵⁷ Ahir and coworkers²⁵⁸ showed that in vitro "transplantation" of cultured RPE cells, which express active MMP-2 and MMP-9, results in improved Bruch membrane hydraulic conductivity. Lipofuscin accumulation in RPE cells can be reduced by treatment with lutein, zeaxanthin, lycopene, or -tocopherol²⁵⁹ or reversed by centrophenoxine treatment.²⁶⁰ The role of chronic inflammation in AMD pathogenesis has led to the consideration of anti-inflammatory therapy as treatment for the early stages of the disease.^{136, 138}

Better knowledge of the biological changes underlying AMD will also foster the development of sight-restoring treatments for the late stages of AMD. For example, anti-inflammatory therapy, anti-VEGF therapy, PEDF therapy, anti–Tie-2 therapy (either via ligation of free Ang-1 or via high-level expression of Ang-2, especially in the face of VEGF inhibition), or control of TIMP and MMP expression may permit control of CNV growth without retinal, RPE, or choriocapillary damage.^{210, 261-266} More precise characterization of AMD-induced Bruch membrane ECM abnormalities probably will permit the design of more effective cellular transplantation surgery, which might serve as a treatment for exudative and atrophic AMD.^267-269 Neurotrophic agents, which promote neuron survival, might be useful for preserving vision in patients with atrophic and exudative manifestations of AMD.²⁷⁰ Gene therapy with PEDF might be an example of combined therapy, in which the treatment inhibits CNV growth and promotes photoreceptor survival via a neurotrophic effect (see the "Biochemical Features of CNV Growth" subsection).

CONCLUSIONS

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Five general concepts relevant to the cell biology of AMD have been described (Figure 2). First, AMD involves aging changes plus additional pathological events. Second, in aging and AMD, oxidative stress causes RPE and, possibly, choriocapillaris injury. Third, in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response in the Bruch membrane and the choroid. Fourth, in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal ECM. This abnormal ECM causes altered diffusion of nutrients to the retina and RPE, which may precipitate further RPE and retinal damage. Fifth, the abnormal ECM results in altered RPE-choriocapillaris behavior, leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or to CNV growth. In this pathogenetic sequence of events, environment and genetics can alter any given patient's susceptibility to the disease. Manipulation of environmental variables (eg, antioxidant levels) provides an opportunity for early therapeutic intervention. Gene and/or cellular therapy provide an opportunity for later, sight-restoring treatment. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or CNVs may operate simultaneously. Additional experimentation with in vitro and in vivo models will prove or refute the concept of linear progression and will establish the identities of the various pathways that lead to CNVs and geographic atrophy.

Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease, as results from the Age-Related Eye Disease Study⁹⁰ and the Verteporfin in Photodynamic Therapy study⁴ imply. Many unanswered questions regarding AMD pathogenesis remain. For example, if Bruch membrane permeability change plays in the evolution of AMD, is it reversible? If oxidative damage precipitates the development of geographic atrophy and CNV growth, what additional factors determine the development of atrophy vs CNV in any given patient or location within a given eye? For any given patient, can a risk profile and a "prophylactic treatment" plan be established based on genotype analysis? The development of transgenic animal models of AMD and better in vivo RPE–Bruch membrane imaging modalities will accelerate progress in answering these questions. It seems that multiple genes confer susceptibility to and resistance from AMD. Thus, animal models exhibiting multiple genetic changes may be needed to consistently reproduce all aspects of AMD. New techniques, such as serial analysis of gene expression, may be critical for the identification of these genes. Until such complex animal models are developed, there probably will be an ongoing need for simpler animal models and for in vitro models of specific aspects of AMD so that the development of effective therapies for different stages of AMD can continue.

AUTHOR INFORMATION

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Corresponding author and reprints: Marco A. Zarbin, MD, PhD, The Institute of Ophthalmology and Visual Science, New Jersey Medical School, 90 Bergen St, Suite 6100, Newark, NJ 07103-2499 (e-mail: zarbin{at}njmsa.umdnj.edu).

Submitted for publication February 6, 2002; final revision received July 15, 2003; accepted August 4, 2003.

This study was supported in part by Research to Prevent Blindness Inc, New York, NY, the New Jersey Lions Eye Research Foundation, Newark, and the Eye Institute of New Jersey, Newark.

From the Institute of Ophthalmology and Visual Science at the New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark. The author has no relevant financial interest in this article.

REFERENCES

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J. Biol. Chem. 2008;283:24770-24780.
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Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids
Agbaga et al.
Proc. Natl. Acad. Sci. USA 2008;105:12843-12848.
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An Hypothesis to Account for the Renewal of Outer Segments in Rod and Cone Photoreceptor Cells: Renewal as a Surrogate Antioxidant
Winkler
IOVS 2008;49:3259-3261.
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Vascular adhesion protein-1 blockade suppresses choroidal neovascularization
Noda et al.
FASEB J. 2008;22:2928-2935.
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Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells: A POTENTIAL LINK BETWEEN OXIDATIVE STRESS AND UP-REGULATION OF INTERLEUKIN-8
Fernandes et al.
J. Biol. Chem. 2008;283:20745-20753.
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Focal Macular Electroretinograms in Eyes with Wet-type Age-Related Macular Degeneration
Nishihara et al.
IOVS 2008;49:3121-3125.
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Age-Related Macular Degeneration
Jager et al.
NEJM 2008;358:2606-2617.
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Racial Differences and Other Risk Factors for Incidence and Progression of Age-Related Macular Degeneration: Salisbury Eye Evaluation (SEE) Project
Chang et al.
IOVS 2008;49:2395-2402.
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Increased Choroidal Neovascularization following Laser Induction in Mice Lacking Lysyl Oxidase-like 1
Yu et al.
IOVS 2008;49:2599-2605.
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Estrogen Receptor Alpha and Matrix Metalloproteinase 2 Polymorphisms and Age-related Maculopathy in Older Women
Seitzman et al.
Am J Epidemiol 2008;167:1217-1225.
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Reduction of Endogenous Angiogenesis Inhibitors in Bruch's Membrane of the Submacular Region in Eyes With Age-Related Macular Degeneration
Bhutto et al.
Arch Ophthalmol 2008;126:670-678.
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Associations of Plasma-Soluble Fas Ligand with Aging and Age-Related Macular Degeneration
Jiang et al.
IOVS 2008;49:1345-1349.
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Inflammation in the pathogenesis of age-related macular degeneration
Kanda et al.
Br J Ophthalmol 2008;92:448-450.
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Elastin Gene Polymorphisms in Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Kondo et al.
IOVS 2008;49:1101-1105.
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N-(4-hydroxyphenyl) Retinamide Augments Laser-Induced Choroidal Neovascularization in Mice
Sreekumar et al.
IOVS 2008;49:1210-1220.
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Inducible Expression of Cre Recombinase in the Retinal Pigmented Epithelium
Le et al.
IOVS 2008;49:1248-1253.
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Studies with an Orally Bioavailable {alpha}V Integrin Antagonist in Animal Models of Ocular Vasculopathy: Retinal Neovascularization in Mice and Retinal Vascular Permeability in Diabetic Rats
Santulli et al.
J. Pharmacol. Exp. Ther. 2008;324:894-901.
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Complement-Associated Deposits in the Human Retina
Seth et al.
IOVS 2008;49:743-750.
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The Protective Effect of Functional Connexin43 Channels on a Human Epithelial Cell Line Exposed to Oxidative Stress
Hutnik et al.
IOVS 2008;49:800-806.
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A hCXCR1 transgenic mouse model containing a conditional color-switching system for imaging of hCXCL8/IL-8 functions in vivo
Zheng et al.
J. Leukoc. Biol. 2007;82:1247-1256.
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Confocal Raman microscopy can quantify advanced glycation end product (AGE) modifications in Bruch's membrane leading to accurate, nondestructive prediction of ocular aging
Glenn et al.
FASEB J. 2007;21:3542-3552.
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Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits
Swaroop et al.
Hum Mol Genet 2007;16:R174-R182.
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The Importance of Bcl-xL in the Survival of Human RPE Cells
Zhang et al.
IOVS 2007;48:3846-3853.
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High-Resolution In Vivo Imaging of the RPE Mosaic in Eyes with Retinal Disease
Roorda et al.
IOVS 2007;48:2297-2303.
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Fundus autofluorescence in exudative age-related macular degeneration
McBain et al.
Br J Ophthalmol 2007;91:491-496.
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Relationship of Basal Laminar Deposit and Membranous Debris to the Clinical Presentation of Early Age-Related Macular Degeneration
Sarks et al.
IOVS 2007;48:968-977.
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Estrogen Receptor {alpha} Gene Polymorphisms Associated with Incident Aging Macula Disorder
Boekhoorn et al.
IOVS 2007;48:1012-1017.
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Novel n-3 Fatty Acid Oxidation Products Activate Nrf2 by Destabilizing the Association between Keap1 and Cullin3
Gao et al.
J. Biol. Chem. 2007;282:2529-2537.
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CTRP5 Is a Membrane-Associated and Secretory Protein in the RPE and Ciliary Body and the S163R Mutation of CTRP5 Impairs Its Secretion
Mandal et al.
IOVS 2006;47:5505-5513.
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Retinal Pigment Epithelial Cells Synthesize Laminins, Including Laminin 5, and Adhere to Them through {alpha}3- and {alpha}6-Containing Integrins
Aisenbrey et al.
IOVS 2006;47:5537-5544.
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Activation of Caspase-8 and Caspase-12 Pathways by 7-Ketocholesterol in Human Retinal Pigment Epithelial Cells
Luthra et al.
IOVS 2006;47:5569-5575.
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Iron Induced Oxidative Damage As a Potential Factor in Age-Related Macular Degeneration: The Cogan Lecture
Dunaief
IOVS 2006;47:4660-4664.
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Age-Related Macular Degeneration
de Jong
NEJM 2006;355:1474-1485.
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Analysis of CFH, TLR4, and APOE Polymorphism in India Suggests the Tyr402His Variant of CFH to be a Global Marker for Age-Related Macular Degeneration.
Kaur et al.
IOVS 2006;47:3729-3735.
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Adenovirally Transduced Bone Marrow Stromal Cells Differentiate into Pigment Epithelial Cells and Induce Rescue Effects in RCS Rats.
Arnhold et al.
IOVS 2006;47:4121-4129.
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Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue.
Maminishkis et al.
IOVS 2006;47:3612-3624.
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Dietary Fatty Acids and the 5-Year Incidence of Age-Related Maculopathy
Chua et al.
Arch Ophthalmol 2006;124:981-986.
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Characterization of Native Retinal Fluorophores Involved in Biosynthesis of A2E and Lipofuscin-associated Retinopathies
Bui et al.
J. Biol. Chem. 2006;281:18112-18119.
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The proteome of central and peripheral retina with progression of age-related macular degeneration.
Ethen et al.
IOVS 2006;47:2280-2290.
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Inhibitory effects of lutein on endotoxin-induced uveitis in lewis rats.
Jin et al.
IOVS 2006;47:2562-2568.
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A 76-year-old man with macular degeneration.
Arroyo
JAMA 2006;295:2394-2406.
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Bone Marrow-Derived Cells Home to and Regenerate Retinal Pigment Epithelium after Injury
Harris et al.
IOVS 2006;47:2108-2113.
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Should corticosteroids be considered as part of the standard care with photodynamic therapy?
Zarbin
Arch Ophthalmol 2006;124:563-571.
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Light-induced Oxidation of Photoreceptor Outer Segment Phospholipids Generates Ligands for CD36-mediated Phagocytosis by Retinal Pigment Epithelium: A POTENTIAL MECHANISM FOR MODULATING OUTER SEGMENT PHAGOCYTOSIS UNDER OXIDANT STRESS CONDITIONS
Sun et al.
J. Biol. Chem. 2006;281:4222-4230.
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EphrinA1 Inhibits Vascular Endothelial Growth Factor-Induced Intracellular Signaling and Suppresses Retinal Neovascularization and Blood-Retinal Barrier Breakdown
Ojima et al.
Am. J. Pathol. 2006;168:331-339.
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Impaired expression of thrombospondin-1 in eyes with age related macular degeneration
Uno et al.
Br J Ophthalmol 2006;90:48-54.
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Dietary Intake of Antioxidants and Risk of Age-Related Macular Degeneration
van Leeuwen et al.
JAMA 2005;294:3101-3107.
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Soluble EphB4 Regulates Choroidal Endothelial Cell Function and Inhibits Laser-Induced Choroidal Neovascularization
He et al.
IOVS 2005;46:4772-4779.
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(R)-{alpha}-Lipoic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Damage
Voloboueva et al.
IOVS 2005;46:4302-4310.
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Inflammatory Markers in Age-Related Maculopathy: Cross-sectional Analysis From the Muenster Aging and Retina Study
Dasch et al.
Arch Ophthalmol 2005;123:1501-1506.
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Correlation between Inactive Cathepsin D Expression and Retinal Changes in mcd2/mcd2 Transgenic Mice
Zhang et al.
IOVS 2005;46:3031-3038.
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Late-Onset Macular Degeneration and Long Anterior Lens Zonules Result from a CTRP5 Gene Mutation
Ayyagari et al.
IOVS 2005;46:3363-3371.
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The relation between C reactive protein and age related macular degeneration in the Cardiovascular Health Study
McGwin et al.
Br J Ophthalmol 2005;89:1166-1170.
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MOSAICISM OF THE RETINAL PIGMENT EPITHELIUM: seeing the small picture
Burke and Hjelmeland
Mol. Interv. 2005;5:241-249.
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Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy
Conley et al.
Hum Mol Genet 2005;14:1991-2002.
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The Retinal Pigment Epithelium in Visual Function
Strauss
Physiol. Rev. 2005;85:845-881.
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Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration
Zareparsi et al.
Hum Mol Genet 2005;14:1449-1455.
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Association of HLA Class I and Class II Polymorphisms with Age-Related Macular Degeneration
Goverdhan et al.
IOVS 2005;46:1726-1734.
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Automated Detection of Macular Drusen Using Geometric Background Leveling and Threshold Selection
Smith et al.
Arch Ophthalmol 2005;123:200-206.
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