Early AMD is usually asymptomatic and clinically presents with drusen and RPE changes consisting of focal hyper- or hypopigmentation.

The main characteristic of late AMD is severe loss of vision.

The late stages of AMD have two different forms (dry and wet), although both forms may occur simultaneously in the same eye. Over time, dry AMD may develop to wet AMD.

Patients with dry AMD have poor visual acuity, hyperpigmented RPE spots (usually juxtafoveal), and an area with visible choroidal vessels. Choroidal vessels are visible because the RPE cells over them have become atrophic. As these areas become confluent, they take on an appearance referred to as geographic atrophy. No neovascularization is present.

Wet AMD is characterized by the presence of CNVM. Patients with wet AMD may experience a sudden onset of decreased visual acuity, metamorphopsia, and paracentral scotoma. Clinical findings include subretinal fluid, subretinal or sub-RPE hemorrhages, subretinal or intraretinal lipids, pigmentary subretinal ring, RPE irregularities and detachment, gray-white subretinal lesions, and cystoid macular edema (3).

According to the 2005-2008 NHANES (National Health and Nutrition Examination Survey) (1), the most AMD-compatible lesions were found in persons aged 60 or older in all the three ethnic groups studied (non-Hispanic Black, non-Hispanic White, and Mexican American). The incidence of early AMD is similar for non-Hispanic White persons aged 40 to 59 years (3%) and Mexican American persons aged 40 to 59 years (2.7%). The incidence of early AMD is lowest in non-Hispanic Black persons. Late AMD was more prevalent in non-Hispanic White persons.

The estimated total prevalence of any AMD in the US population aged 40 or older was 6.5%. Of a total of 7.2 million persons having any kind of AMD, 0.89 million (95% CI, 552,000-1.2 million) were estimated to have late AMD (see Ref. (1) for more details).

The most important risk factor for AMD is age, but over the years, many factors, including genetic, demographic, behavioral, dietary, and other factors, have been studied as risk or protective factors for AMD. The AREDS (Age-Related Eye Disease Study) was a clinical trial sponsored by the National Eye Institute, one of the National Institutes of Health in the United States. The trial was designed to investigate the natural history and risk factors for AMD and cataracts and to evaluate the effect of high doses of antioxidants and zinc on the progression in patients with AMD. This study describes the demographic, behavioral, medical, and nonretinal factors associated with progression to neovascular AMD and central geographic atrophy (CGA).

Of all the studied factors, only a few were statistically associated with AMD. Subjects with advanced AMD, relative to the early AMD group, tend to be older, have fewer years of formal education, smoke more, have higher body mass index (BMI), have higher blood pressure, be myopic, have a history of angina, be more likely to have a lens opacity, and be less likely with hormone replacement therapy. Neovascular AMD was associated with white race and smoking more than 10 pack-years. CGA was associated with fewer years of formal education, being obese (higher BMI), smoking more than 10 pack-years, and not using antiacids (4).

There were also some other weak associations, such as diabetes, use of nonsteroidal anti-inflammatory agents, and hormone replacement therapy, that were reported in other studies (5,6,7,8,9,10,11,12,13,14) but not fully demonstrated on AREDS. Of note, hormone replacement therapy was reported to be a protective factor in some patients with specific polymorphisms in ARMS2 (HtrA serine peptidase 1) (15).

In contrast to risk factors for progression to neovascular AMD and CGA, black race (16,17); increased intake of docosahexanoic acid (18), monounsaturated fatty acids (19), fish (20,21,22), and dark green leafy vegetables (23); and higher levels of serum carotenoids (24) were associated with a lower risk of progression.

Complement factor H (CFH), an important regulator of the alternative pathway, was the first complement protein to be implicated in the pathogenesis of AMD. Physiologically, CFH binds C3b and accelerates the decay of the alternative C3 convertase (C3bBb) and acts as cofactor for the inactivation of C3b by complement factor I (CFI) (37). CFH is produced locally in the eye by the RPE cells (38) and accumulates in the drusen, sub-RPE space, RPE, interphotoreceptor matrix, and choroid (38,39). Environmental factors vary CFH production by the RPE cells. In vitro studies show an increase in RPE CFH production by interferon gamma (40) and reduction in conditions of oxidative stress (38).

The CFH gene is located at chromosome position 1q23. Mutations of this gene manifest as dominant mendelian disorders (41). In 2005, three groups simultaneously (27,42,43) reported a nonsynonymous SNP in the CFH gene (rs1061170), resulting in a substitution of tyrosine by histidine at position 402 of the polypeptide (Y402H), which was important in the development of AMD. This change alters the ligand binding site of CRP (C-reactive protein), heparin, M protein, and glycosaminoglycans, probably leading to a reduced binding to cell surfaces and therefore impaired regulation of the alternative C3 convertase (44). A meta-analysis (45) suggested that this variant (Y402H) is a contributing factor in over half of all cases of AMD. Other SNPs throughout the CFH gene, including the SNP 162 V (38), resulting in substitution of isoleucine with valine residue within the C3b binding site, have been associated with AMD (32,38,41,46,47,48,49,50) and AMD progression (51,52,53,54,55).

Some authors (56,57,58) proposed that the SNP A/A in the allele rs3024997 and G/G re2010963 in the VEGF gene are associated with a better response to antiangiogenic (bevacizumab) therapy with regard to visual acuity outcomes. In a more recent study (59), using a multivariate data analysis and a higher number of patients, this SNP was not found to be associated with a different response to antiangiogenic therapy.

PR cells translate light into electric activity that can be understood by the brain and central nervous system.
Anatomically, PR cells have four different regions: the outer segment (OS), the inner segment, the cell body, and the synaptic terminal. The OS of the PR is composed of membranous disks, which have a high concentration of visual pigment. Rhodopsin, the visual pigment of rods, is a G protein-coupled receptor that when stimulated by a photon of light undergoes a conformational change initiating a series of biochemical steps leading to the onset of the electric activity (3). Numerous studies of the human and animal retina show that excessive light exposure leads to photochemical injury causing damage to the outer segment of the PR. Excessive light exposure is considered to be an environmental factor associated with AMD (60), but the magnitude of this risk is hard to evaluate and is controversial. Even under normal light conditions, the PR incurs significant oxidative stress, due to the great energy requirement for visual phototransduction (61). This stimulation increases the oxygen-reactive species, damaging DNA and other macromolecular complexes important for the PR survival (62,63). For a longterm survival of the PR cells, it is important to have a healthy RPE participating in the visual cycle, renewing the PR OSs and producing the interphotoreceptor cell matrix (3).

The RPE is a postmitotic, cuboidal monolayer of cells located between the neural retina and the Bruch’s membrane. Physiologically, it has a very high metabolic rate and performs several important functions for the retina. Of all the functions of the RPE, the most important for understanding AMD (64) are the following:

The reconstitution of the visual pigment rhodopsin occurs mainly in the RPE cells, through many intermediate steps. This mechanism has a key role for normal function of both cones and rods, transforming the all-trans-retinyl esters into 11-cis-retinal (65). As a phagocytic system, the RPE is essential for the renewal of PRs (66). Each PR has hundreds of disks in its outer segment. These disks are formed by plasma membrane, containing transmembrane protein rhodopsin, which is positioned in combination with four phospholipids and docosahexanoic acid. The OS disks
of the PR cells are engulfed by the RPE. In the RPE, the disks fuse with lysosomes, forming phagolysosomes, where the contents are degraded. In young, healthy individuals, most of the disks are fully degraded, and lipofuscin accumulation is minimal, but over time, the self-limited phagocytic and degradative capacity of the RPE cells becomes more and more overloaded. This incompletely degraded membrane material accumulates in the form of lipofuscin in secondary lysosomes or residual bodies (67).

Lipofuscin is a yellow-brown, autofluorescent molecule that accumulates in all postmitotic cells, particularly the RPE (68,69,70,71). The presence of lipofuscin may act as a cellular aging indicator, and its quantity in tissues may be estimated by amounts of autofluorescence present. The autofluorescence from the eye fundus, mostly derived from lipofuscin, can be clinically and noninvasively quantified, allowing for an estimate of the aging degenerative process of the eye and a diagnostic and follow-up method for patients with AMD (72). Some factors increase (vitamin E deficiency) while others decrease (oxygen-free conditions and vitamin A deficiency) lipofuscin pigment formation.

The retinoid A2E is the major fluorophore of lipofuscin (73). Once it is synthesized, it cannot be eliminated by the RPE. Precursors of A2E, all-trans-retinal and ethanolamine, are formed within the PRs (74), but the fully synthesized A2E molecule arises from the phagolysosomal compartment of the RPE cells. When it reaches a critical concentration, the metabolism of phagocytized OS lipids by the RPE is impaired. Phagocytized and oxidized OS membranes are extruded by the RPE into the Bruch’s membrane, contributing to drusen formation and membrane thickening.

A2E is toxic for the RPE. It inhibits the proton pump of lysosomes (75), causing leakage of the contents of the lysosomes into the cytoplasm of RPE cells. It inhibits phagolysosomal degradation of PR phospholipids (76) and can also damage the DNA of RPE cells. A2E also accumulates in the mitochondrial membranes, decreasing mitochondrial activity and enabling the translocation of cytochrome C and AIF (apoptosis-inducing factor) to the cytosol and nucleus, respectively. Functionally, the release of cytochrome C from the inner mitochondrial membrane generates oxidative stress and decreased electron flow, leading to impaired ATP synthesis. Both mechanisms are highly relevant for apoptosis by causing leakiness of the inner mitochondrial membrane and release of the propapoptotic proteins, activating the caspase cascade. AIF is a pro-apoptotic protein, which is strictly located in the mitochondria. Its translocation to the nucleus induces apoptosis, functionally independent from caspases (77). A2E also inhibits the normal activity of the enzyme RPE65 isomerohydrolase, a key enzyme of the visual cycle, which is responsible for the isomerization of all-trans-retinyl ester to 11-cis-retinol, the precursor of 11-cis-retinal (78

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