AGE-RELATED MACULAR DEGENERATION UPDATE: A REVIEW OF PATHOGENESIS, CLINICAL FINDINGS, AND TREATMENT

BY MARCO ZARBIN, MD, PhD, FACS

Supported in part by Research to Prevent Blindness, Inc. and the New Jersey Lions Eye Research Foundation.

PAGE 2

(e.g., dark adaptation) improve with high-dose vitamin A, which may mean that impaired diffusion across Bruch's membrane is a consequence of Bruch's membrane thickening.

6) Response of the RPE. The clinical manifestations of AMD that lead to visual loss (CNVs, RPE-choriocapillaris-photoreceptor atrophy) may represent RPE responses to metabolic abnormalities induced by the changes described above.

Histopathological and clinical studies indicate that areas of choroidal ischemia often are seen near CNVs in AMD patients. For example, fluorescein angiograms of the dissection bed one week after CNV excision reveal areas of choriocapillary nonperfusion as well as larger areas of hyperfluorescence from preserved choriocapillaris. More widespread choriocapillaris nonperfusion develops later. In response to decreased oxygen delivery/metabolic "distress", the RPE may elaborate vascular endothelial growth factor (VEGF) and other substances leading to CNV growth. Frank, Lopez, Kaplan, and their coworkers have shown that the RPE and choriocapillaris in CNVs contain VEGF and basic fibroblast growth factor (bFGF). These peptides may act synergistically to promote CNVs (often both are present in the same cell).

Heriot and coworkers showed that the break in Bruch's membrane through which CNVs grow is probably a consequence and not a cause of CNVs. Bruch's membrane erosion by CNVs often begins near hard drusen, and the separation of RPE from Bruch's membrane by basal linear deposit probably permits spread of CNVs under the RPE. Despite the fact that Bruch's membrane erosion occurs in the setting of basal laminar and linear deposit, Sarks noted that it often commences beneath small hard drusen, possibly because diffusion of factors that stimulate CNV growth is greatest both where Bruch's membrane is thinnest and where the RPE is anchored most firmly to Bruch's membrane.

Perhaps RPE atrophy, followed by choriocapillaris and photoreceptor atrophy, is a response to decreased nutrients/increasing metabolic abnormalities in areas of excessive accumulation of extracellular debris. The RPE may elaborate substances that promote choriocapillaris survival. The tendency for atrophic AMD to "spare" the fovea until late in the disease might be due to photoprotection by xanthophyll.

Why does AMD mainly involve the macula? The answer is not known. Potentially relevant facts are as follows. Foulds noted that the highest turnover of outer segments involves rods just outside the fovea, which parallels the distribution of lipofuscin in the RPE. Each day, 10-15% of each rod outer segment is phagocytosed and replaced, and each RPE cell contacts ~30 photoreceptors. These findings are consistent with the observation that photoreceptor degeneration in AMD involves the rods before the cones. The RPE continuously discharges cytoplasmic material into Bruch's membrane, which could lead to pathologic changes primarily in subjacent Bruch's membrane. Subfoveolar RPE is spared from atrophy the longest, perhaps by xanthophyll, the high

cigarette smoking, which depletes antioxidant levels, reduces oxygen delivery to end organs, and promotes free radical production) could combine with inherited risk factors (e.g., mutations causing altered substrate specificity or kinetics in one or many enzymes participating in degradation of phagocytosed material) to precipitate the accumulation of material that characterizes AMD pathologically.

3) Abnormal accumulation of extracellular material. In AMD, material that accumulates between the RPE plasma and basement membranes is termed basal laminar deposit. It is composed of wide-spaced collagen (100 nm periodicity; possibly composed of type IV collagen), coated and uncoated vesicles, glycoproteins, glycosamino-glycans, laminin, and fibronectin. Sarks noted that basal laminar deposit develops first over thickened or basophilic segments of Bruch's membrane, widened intercapillary pillars, or small drusen and suggested that its accumulation is a response to altered filtration through Bruch's membrane at these sites.

Material that accumulates within inner collagenous layer of Bruch's membrane is termed basal linear deposit. Basal linear deposit consists primarily of granular and vesicular material with foci of wide-spaced collagen. The accumulation of basal linear deposit can be focal or diffuse. A cleavage plane between the RPE and Bruch's membrane tends to develop at the level of basal linear deposit. This accounts for the tendency of CNVs to grow between the inner collagenous layer of Bruch's membrane and the RPE plasma membrane in AMD, for the tendency of pigment epithelial detachments to occur (see below), and for the surgical plane of CNV dissection to be between the RPE basement membrane and the inner collagenous layer of Bruch's membrane in AMD. Macrophages and foreign body giant cells near Bruch's membrane become more common when basal linear deposit is present. Macrophages might digest Bruch's membrane and can release cytokines that stimulate CNV growth.

Experimental and human postmortem studies indicate that drusen are RPE-derived, although conflicting data exist. Sarks, Sarks, and Killingsworth and Green and coworkers described the histopathology and pathogenesis of drusen in AMD in elegant clinicopathologic studies. RPE cells gradually enlarge during aging in association with intracellular lipofuscin accumulation. A reduction in the basal infoldings of the RPE plasma membrane is associated with deposition of membranous debris between the RPE and its basement membrane. The debris may arise from a process resembling pinocytosis of the RPE cytoplasm. This material is detectable in the second decade and may represent a normal aging change. The membranous debris may extend down the intercapillary pillars to the

choriocapillaris, and the material thins in long-standing geographic atrophy, suggesting that it is the result rather than the cause of RPE degeneration. Basal laminar deposit is present during the seventh decade during normal aging. This membranous debris probably arises at least indirectly from the photoreceptors, since basal linear deposit is reduced in quantity in areas of photoreceptor atrophy and is greatly attenuated in areas of geographic atrophy.

4) Change in Bruch's membrane composition. The accumulation of material in the inner and outer collagenous layers of Bruch's membrane induces a change in Bruch's membrane composition, as the vesicular material has high lipid content.

Karwatowski and coworkers showed that crosslinking of proteins in Bruch's membrane also occurs with age. The solubility of Bruch's membrane collagen declines with age due to increased crosslinking both in the macular region and in the periphery. In contrast, the amount of non-collagen protein increases in Bruch's membrane under the macula but not in the periphery. It is not clear whether alterations in Bruch's membrane proteins are an aging change, whether these phenomena occur in an exaggerated form in AMD, whether they are associated with hypertension, or whether the change might be viewed as a sort of "atherosclerosis" of Bruch's membrane.

5) Change in Bruch's membrane permeability to nutrients, O2, hormones, etc.The water permeability of Bruch's membrane normally decreases with age. Pauleikhoff, Marshall, Bird, and coworkers showed that a decrease in permeability impairs diffusion of water-soluble plasma constituents across Bruch's membrane. The cause may be age-related protein cross-linking and/or lipid accumulation in Bruch's membrane. Serous RPE detachments probably result from the combination of: 1) increased hydrophobicity of Bruch's membrane, 2) the presence of a cleavage plane at the level of basal linear deposit (which seems associated with weakened attachment of the RPE basement membrane to the inner collagenous layer of Bruch's membrane), and 3) water accumulation external to the RPE from ion transport.

Protein deposition and crosslinking in Bruch's membrane might prevent debris (e.g., vesicles) from passing through Bruch's membrane to the choriocapillaris and result in accumulation of extracellular material in the inner aspect of Bruch's membrane. In Sorsby's fundus dystrophy (caused by a mutation in tissue inhibitor of metalloproteinases-3 [TIMP-3], an enzyme that regulates extracellular matrix metabolism), symptoms of night blindness and retinal function