to loss of elasticity that involves also the adjacent choriocapillaris, impeding the diffusion between the retinal pigment epithelium and choroidal vessels. This undoubtedly contributes to a further decline in metabolic transfer capacity from the circulation to the photoreceptor outer segments that includes also decreased transport of vitamin A, resulting in slowing of dark adaptation and visual cycle pigment regeneration [45].

RETINAL FUNCTION CHANGES

Aging is associated with a decline in visual function evident in most elderly individuals. Visual acuity is usually well maintained but other psychophysical tests such as contrast sensitivity, color discrimination, visual fields, and dark adaptation sensitivity indicate an age-related loss [46–49]. Preretinal factors (i.e., crystalline lens opacification, progressive optical aberrations, loss of pupillary reactivity) may alter the way in which the visual signal is propagated to the retina [50]. However, neural loss is considered to be the major contributor to visual function loss in the elderly [51].

Visual field sensitivity undergoes a gradual reduction and is particularly visible at increasing visual field eccentricities [52]. In studies in which photopic and scotopic vision are examined, scotopic visual sensitivity loss is typically more severe than photopic sensitivity loss [53], and dark adaptation is delayed in the elderly [54, 55]. A number of neural causes for this visual deficit have been suggested, including agingrelated delays in rhodopsin regeneration [54], changes in the metabolic support structures of the retina [56], rod loss, ganglion cell loss [6], as well as postreceptoral and cortical dysfunction in the neural pathway [57]. Alterations of the retinal pigment epithelium and the Bruch’s membrane that impede the passage of vitamin A or other molecules to the rod photoreceptors are also discussed as a source for the scotopic sensitivity impairment in the aging retina [45, 53].

Electrophysiological studies reported similar age-related changes. Standard Ganzfeld electroretinography commonly presents a significant increase in implicit times with a decrease in a-wave (photoreceptor responses) and b-wave amplitudes (bipolar and Müller cell responses) [58, 59]. Multifocal electroretinography is a more recent technique and allows obtaining electroretinogram responses in smaller localized retinal areas (multiple, spatially localized electroretinograms) at the posterior pole of the eye. Results obtained with this technique indicate similarly increased implicit times and decreased amplitudes [60, 61]. However, this decline in visual function is thought to be caused not solely by neural changes but may be the result also of preretinal modifications. Multifocal oscillatory potentials reflect the inner retinal function. Kurtenbach and Weiss described a linear decrease in amplitude and increase in latency [62] and suggested an age-related impairment that occurs at or before the inner retina.

AGE-RELATED MACULAR DISEASE

Age-related macular disease (AMD) is the leading cause of legal blindness among the elderly in Western nations [63]. This disease is characterized by a progressive loss of central vision. The pathogenesis is poorly understood, but it is thought to be a multifactorial disease.

Both retinal aging and AMD are part of a continuous deterioration process. All of the previously described age-related changes in the physiology of the retina may contribute to a pathological state of aging as being influenced by a variety of initiating, promoting, or inhibiting genetically and exogenous factors.

Early changes of AMD are described as drusen and pigmentary changes at the posterior pole of the eye [64]. Patients with these changes usually do not report any symptoms, and visual acuity may be normal. However, late stages of this disease are in general combined with irreversible degeneration of the neurosensory retina and dismal visual prognosis. The growth of choroidal neovascularization or, alternatively, geographic atrophy of the retinal pigment epithelium may lead to a retinal scotoma in the central visual field (macula), compromising many important everyday tasks [65].

Aside from age, cardiovascular disease, history of smoking, female sex, level of pigmentation, environment (exposure to UV light and to oxidative damage), and nutrition are considered important risk factors for AMD [66, 67]. Smoking is thought to reduce the antioxidant level in the retina and subsequently may alter the protection mechanisms against reactive oxygen species. Atherosclerotic vascular changes may contribute to a reduced metabolic transfer and waste disposition between the choroid and the retinal pigment epithelium. AMD seems to be not merely the result of a nonspecific aging process. Results from epidemiological research and twin studies propose a primarily polygenic etiology for AMD [68, 69]. Different ethnic groups have independent profiles with different phenotypic responses. A correlation with certain alleles of apoprotein E (apoE) and AMD is discussed. The presence of the epsilon 4 allele seems to be associated with a reduced risk for AMD. Variants of complement factor H (CFH) are coupled with an up to sevenfold increased risk for AMD [70, 71]. This gene encodes a major inhibitor of the alternative complement pathway, strengthening the hypothesis that the immune system plays an important role in the pathogenesis of AMD. Furthermore, the phenotypic similarity with monogenic diseases suggests potential gene candidates.

The ABCA4 gene is responsible for Stargardt’s macular dystrophy and may be involved in certain forms of AMD, sharing the phenotype of retinotoxic lipofuscin accumulation in retinal pigment epithelium cells [72]. Lipofuscin fluorophores are formed in large part as a by-product of the visual cycle. Radu and colleagues were able to show that treatment with 13-cis retinoic acid (known as isotretinoin or Accutane) slows rhodopsin regeneration due to its inhibition of RPE65, an essential protein for the operation of the visual cycle, and of 11-cis-RDH. The 13-cis retinoic acid inhibits accumulation of A2E, but its daily administration risks systemic toxicity and teratogenicity, so there is a need to develop other treatment forms that may prove to be safe for long-term therapy in lipofuscin-related retinal degenerations [73]. The same group presented another therapeutic approach that aims to regulate serum retinol by N-(4-hydroxyphenyl) retinamide (HPR). This molecule has been widely used already as a chemotherapeutic agent for a variety of cancers and is known to reduce reversibly serum retinol and retinol-binding protein levels. In a recent study on ABCA4 knockout mice, HPR was able to block the formation of A2E and other lipofuscin fluorophores with no deleterious effects on visual function or retinal morphology [74].

Maiti and colleagues were able to prevent the formation of lipofuscin by inhibiting the visual cycle function with chronic treatment of specific, nonretinoid isoprenoid compounds.

These molecules serve as antagonists of RPE65 and thus block the regeneration of 11-cis retinal, the chromophore of rhodopsin [75]. To date, these treatments have been applied only in animal models but may represent future candidates for preventing the onset of lipofuscin-sensitive forms of macular degeneration, such as geographic atrophy in AMD.

Nutritional supplementation with antioxidants in patients with early forms of AMD is considered helpful in slowing the progression in a subset of patients with early retinal changes of intermediate severity into advanced disease with central vision loss [66]. Macular pigments are thought to protect the retina both by filtering high-energy blue light and by serving an antioxidant function. Recent evidence suggests that the photochemical reactions against which the macular pigments zeaxanthin and lutein (xanthophylls) protect may also include those initiated by A2-PE, a bis-retinoid compound that is the immediate precursor of the lipofuscin fluorophore A2E [76–78].

In contrast, currently available treatment possibilities aim only to stabilize visual acuity. They can be applied solitarily for the exudative form of AMD and seek to inhibit the growth of choroidal neovascularization. The mechanisms that trigger the development of choroidal neovascularization in AMD are still not completely understood. An imbalance between proangiogenic and antiangiogenic factors that controls the angiogenesis is discussed. Major progress in recent years allows us now to use antiangiogenic drugs in the treatment of choroidal neovascularization. These drugs are currently under investigation in clinical trials. They are based on the events that occur sequentially during the angiogenic response: antagonizing proangiogenic activities (primarily vascular endothelial growth factor: Macugen® and Lucentis®), administration of angiogenic inhibitors (adenovirus encoding the pigment epithelium-derived factor), or the use of indirect angiogenesis inhibitors (Evizon® and Retaane®) [79–81].

CONCLUSIONS

The physiology of the retina involves a large number of complex mechanisms in which the functions of many cell types depend on interactions with other cell types, particularly interactions between photoreceptors and the underlying retinal pigment epithelium. Studies of monogenic retinal diseases such as retinitis pigmentosa and Stargardt’s disease have helped improve greatly our understanding of retinal physiology.

The pathological aging of the retina is an even more complex phenomenon. Novel treatment approaches try to modify risk factors and to prevent disease progression. However, to date no curative treatment is known for patients with AMD. To foster the development of preventive measures and of more effective treatments, an improved understanding of AMD pathogenesis has become a major public health mission in industrialized countries.

High-resolution visual acuity is often considered to be the most important indicator in measuring quality of vision but underestimates the degree of vision function loss that is suffered by many older individuals under the nonoptimal viewing conditions encountered in daily life. Results from psychophysical and electrophysiological studies suggest functional changes that affect many different retinal cell types during the aging process. More advanced visual function tests are mandatory for assessing retinal function loss in the natural course of aging as well in the assessment of novel and successful therapies for pathological aging, such as AMD.

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