Original article
Age-Related Macular Degeneration Revisited – Piecing the Puzzle: The LXIX Edward Jackson Memorial Lecture

https://doi.org/10.1016/j.ajo.2012.10.018Get rights and content

Purpose

To present the current understanding of age-related macular degeneration (AMD) pathogenesis, based on clinical evidence, epidemiologic data, histopathologic examination, and genetic data; to provide an update on current and emerging therapies; and to propose an integrated model of the pathogenesis of AMD.

Design

Review of published clinical and experimental studies.

Methods

Analysis and synthesis of clinical and experimental data.

Results

We are closer to a complete understanding of the pathogenesis of AMD, having progressed from clinical observations to epidemiologic observations and clinical pathologic correlation. More recently, modern genetic and genomic studies have facilitated the exploration of molecular pathways. It seems that AMD is a complex disease that results from the interaction of genetic susceptibility with aging and environmental factors. Disease progression also seems to be driven by a combination of genetic and environmental factors.

Conclusions

Therapies based on pathophysiologic features have changed the paradigm for treating neovascular AMD. With improved understanding of the underlying genetic susceptibility, we can identify targets to halt early disease and to prevent progression and vision loss.

Section snippets

The Natural History of Age-Related Macular Degeneration

The earliest clinical manifestations of AMD are drusen and pigmentary changes in the macula (Figure 1, Top row). Drusen are focal deposits of extracellular debris that typically form between the retinal pigment epithelium (RPE) and Bruch membrane, and are described clinically by their size and contour.8, 9 Small drusen (<63 μm) are not indicative of AMD and can be seen in the eyes of healthy young and middle-aged adults.10, 11 Intermediate drusen (63 to 125 μm) and large drusen (>125 μm) are

Pathogenesis: An Evolving Story

Our understanding of AMD and its pathogenesis has changed over decades of observation. Although there has been progress, there are still missing pieces in the puzzle, and any attempt at a unified model will meet with disagreement. Nevertheless, formulating a model is a worthwhile exercise and a prerequisite to developing biologically based therapies. However, before developing a model based on current knowledge, it is useful to review the pathogenesis of AMD from a historical perspective.

Senile

Genetics of Age-Related Macular Degeneration

Clinical observations, epidemiologic data, clinicopathologic correlations, and biochemical studies have provided a large body of evidence on which to base models of AMD pathogenesis. The recent revolution in genetic and genomic studies has contributed significantly to our understanding of AMD pathogenesis—in some cases confirming factors identified by other means, and in other cases, identifying new pathways.

Clinical Management of Age-Related Macular Degeneration

The major breakthroughs of the early part of this century have been treatments for neovascular AMD. Therapy for neovascular AMD has progressed from laser photocoagulation to surgery, radiation, and steroids; then to photodynamic therapy (PDT); and finally to anti-VEGF therapy. Current investigations in neovascular AMD are focused on additional antiangiogenic strategies, neuroprotection, and long-term delivery. Ultimately, a better strategy is to attack AMD earlier in the disease to halt

An Integrated Model of Age-Related Macular Degeneration

Clinical observations, imaging, and histopathologic evidence provided the insights for the first attempts to formulate a model of AMD. Epidemiologic observations and biochemical approaches offered further insights into the pathogenic processes. More recently, molecular biology and genetics have increased our understanding, and we may be closer to being able to formulate an integrated model of AMD. The genetic studies suggest that some genes determine the major underlying risk, and others may

Conclusions

Major advances in the treatment of AMD have been based on targeting key components in the pathogenesis of the disease. By interfering with VEGF, the key driver of neovascularization and vascular permeability, we were able to halt neovascular disease in most patients and to improve vision in many. However, neovascularization represents only one of the advanced states of the disease process. Clearly, a greater impact could be achieved by targeting factors earlier in disease pathogenesis, which

Joan W. Miller, MD, FARVO, is the Henry Willard Williams Professor of Ophthalmology and Chair of Ophthalmology at Harvard Medical School. She also serves as and Chief of Ophthalmology at Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital. Her research focuses on ocular neovascular disorders, including age-related macular degeneration (AMD) and diabetic retinopathy. She pioneered the development of the first pharmacologic therapy for AMD, and her research formed the basis of

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    Joan W. Miller, MD, FARVO, is the Henry Willard Williams Professor of Ophthalmology and Chair of Ophthalmology at Harvard Medical School. She also serves as and Chief of Ophthalmology at Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital. Her research focuses on ocular neovascular disorders, including age-related macular degeneration (AMD) and diabetic retinopathy. She pioneered the development of the first pharmacologic therapy for AMD, and her research formed the basis of current antiangiogenic therapies for neovascular AMD.

    Supplemental Material available at AJO.com.

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