Elsevier

Survey of Ophthalmology

Volume 48, Issue 3, May–June 2003, Pages 257-293
Survey of Ophthalmology

Major review
Age-Related Macular Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies

https://doi.org/10.1016/S0039-6257(03)00030-4Get rights and content

Abstract

Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have refined our understanding of the pathobiology of drusen, geographic atrophy, and retinal pigment epithelial detachments. Epidemiological identification of risk factors has facilitated an intelligent search for underlying mechanisms and fueled clinical investigation of behavior modification. Gene searches have not only brought us to the cusp of identifying the culpable gene loci in age-related macular degeneration, but also localized genes responsible for other macular dystrophies. Recent and ongoing investigations, often cued by tumor biology, have revealed an important role for various growth factors, particularly in the neovascular form of the condition. Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration. This in turn has culminated in preclinical and clinical trials of directed molecular interventions.

Section snippets

DRUSEN

The clinical hallmark of AMD is the appearance of drusen,144 localized deposits lying between the basement membrane of the retinal pigment epithelium (RPE) and Bruch's membrane. In the earliest stage, they may be visible ophthalmoscopically as semi-translucent punctate dots in retroillumination. As the overlying RPE thins, drusen are more obvious as yellow-white deposits; they may regress, leaving atrophy in their wake. Clinically, drusen are classified morphologically either as hard or soft.

Pathology

AMD is a degenerative disease that affects the outer neural retina, RPE, Bruch's membrane, and the choroid. The locus of the primary insult remains in dispute. The hallmarks of the disease are diffuse and focal thickening of Bruch's membrane (drusen) together with the development of hypo- and hyper-pigmented areas of RPE, the former signifying areas of RPE cell loss.154., 155., 156.

Risk Factors and Relation to Etiology

Vast epidemiological studies have shed light on various factors associated with an altered risk of AMD. Apart from aiding early detection and treatment, these risk factors may also provide insight into the etiology of the disease. Table 2 provides a list on ongoing experimental trials for AMD.

Animal Models

There are no animal models that faithfully replicate all features of clinical AMD. This, in large part, has hampered the delineation of etiology and the development of a desirable prophylactic or curative treatment. However, spontaneous and iatrogenic conditions have shed some light.

GENETICS

Much evidence points to a familial component of AMD. Twin-concordance, linkage studies, and biomolecular investigations implicating genetic factors are compelling. Genetic analyses of AMD have been hindered by the late onset of the disease, which results in limited study pedigrees, as well as the intertwined nature of multiple genetic influences acting in concert with myriad environmental provocations. Furthermore, the clinical classification of AMD may not lend itself to genetic analyses:

Therapeutic Prospects

Although an array of risk factors has been epidemiologically related to AMD, their role in the progression of the disease remains equivocal. Recent studies have helped unravel some of the molecular processes involved, but their intricate interplay and complexity make the understanding of AMD still quite elusive. Still, with a greater understanding of the etiology of AMD have come therapeutic strategies that have moved beyond the limited approach of thermal laser photocoagulation. Photodynamic

Challenges

AMD promises to remain a major threat to vision for decades to come. Current management options represent a modest advance, but do not greatly alter the unrelenting course and prognosis of the disease itself. New advances in the understanding of the molecular mechanisms underpinning photoreceptor apoptosis, geographic atrophy, CNV, and disciform scarring hopefully will unlock the door to more targeted and effective therapeutic modalities. There are several milestones that must be achieved on

Method of Literature Search

References for this review were generated by a comprehensive literature search of the electronic PubMed database (1966–2003) and of the Association for Research in Vision and Ophthalmology abstracts (1996–2002). Additional articles, unavailable on electronic archives, were selected from a review of the bibliographies of the articles generated from the above search. The literature search was not limited to the English language; foreign language publications were translated to English. To ensure

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    Supported, in part, by a Foundation Fighting Blindness Career Development Award (JA), Heed Ophthalmic Foundation (JA, BKA), AOS-Knapp Testimonial Fund (JA), University of Kentucky Physician Scientist Award (JA), Prevent Blindness America/Fight for Sight Grant-in-Aid (JA), National Eye Institute (APA), Massachusetts Lions Research Fund (APA), Falk Foundation (APA), Iaccoca Foundation (APA), and the Roberta Siegel Fund (APA). The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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