A ge-related macular degeneration is the leading cause of irreversible blindness in people 50 years of age or older in the developed world. 1,2 More than 8 million Americans have age-related macular degeneration, and the overall prevalence of advanced age-related macular degeneration is projected to increase by more than 50% by the year 2020. 3 Recent advances in clinical research have led not only to a better understanding of the genetics and pathophysiology of age-related macular degeneration but also to new therapies designed to prevent and help treat it. This article reviews the clinical and histopathological features of agerelated macular degeneration, as well as its genetics and epidemiology, and discusses current management options and research advances. Nor m a l R e t ina l A rchi tec t ur eThe macula is the central, posterior portion of the retina (Fig. 1A). It contains the densest concentration of photoreceptors within the retina and is responsible for central high-resolution visual acuity, allowing a person to see fine detail, read, and recognize faces. Posterior to the photoreceptors lies the retinal pigment epithelium. It is part of the blood-ocular barrier and has several functions, including photoreceptor phagocytosis, nutrient transport, and cytokine secretion. Posterior to the retinal pigment epithelium lies Bruch's membrane, a semipermeable exchange barrier that separates the retinal pigment epithelium from the choroid, which supplies blood to the outer layers of the retina (Fig. 1B). 4 Ch a nge s w i th AgeWith age, one change that occurs within the eye is the focal deposition of acellular, polymorphous debris between the retinal pigment epithelium and Bruch's membrane. These focal deposits, called drusen, are observed during funduscopic examination as pale, yellowish lesions and may be found in both the macula and peripheral retina ( Fig. 2A). Drusen are categorized as small (<63 μm in diameter), medium (63 to 124 μm), or large (>124 μm) on the basis of studies that classified the grade of age-related macular degeneration. 5,6 On ophthalmoscopic examination, the diameter of large drusen is roughly equivalent to the caliber of a retinal vein coursing toward the optic disk. Drusen are also categorized as hard or soft on the basis of the appearance of their margins. Hard drusen have discrete margins; conversely, soft drusen generally have indistinct edges, are usually large, and can be confluent. 5Pathoph ysiol ogy of Age-R el ated M acul a r Degener ationThe clinical hallmark and usually the first clinical finding of age-related macular degeneration is the presence of drusen. In most cases of age-related macular degen-The New England Journal of Medicine Downloaded from nejm.org at MICHIGAN STATE UNIV LIB on March 17, 2013. For personal use only. No other uses without permission.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10 −75), ARMS2 (P < 10 −59), C2/CFB (P < 10 −20), C3 (P < 10 −9 ), and CFI (P < 10 −6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10 −7; CETP, P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 × 10 −3) and ABCA1 (P = 5.6 × 10 −4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.genome-wide association study | single nucleotide polymorphism A ge-related macular degeneration (AMD) is a progressive neurodegenerative disease and a common cause of blindness in the elderly population, particularly in developed countries (1). The disease affects primarily the macular region of the retina, which is necessary for sharp central vision. An early hallmark of AMD is the appearance of drusen, which are extracellular deposits of proteins and lipids under the retinal pigment epithelium (RPE). As the disease progresses, drusen grow in size and number. In advanced stages of AMD, atrophy of the RPE (geographic atrophy) and/or development of new blood vessels (neovascularization) result in death of photoreceptors and central vision loss.

Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-␣ (TNF-␣) may contribute to the disease process, although its role in vivo and its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-␣, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-␣ injections in normal mice mimicked these effects. Conversely, an anti-TNF-␣-neutralizing antibody or deleting the genes encoding TNF-␣ or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-␣ provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-␣ signaling or inflammation, therefore, may be helpful in treating glaucoma.

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte–mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

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