Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

whereas the fourth study was borderline significant (p = 0.11) (31). Four studies have reported null associations (72–75) and two studies have reported that statins increase the risk of ARM (76,77). There was geographical diversity across all of these studies though the demographic characteristics of the study populations were generally similar.

This heterogeneity in previous study results is somewhat expected given that some studies have determined the presence of ARM using standard techniques (i.e., fundus photography), whereas others have relied upon administrative data sources. Another problem, probably more serious, is that all of the studies to date have been secondary data analyses. That is, the data used in these analyses was not primarily collected for the purpose of testing the hypothesis in question. Such analyses are commonplace in clinical science and can yield valid results; however, because the primary variables of interest are not collected with an explicit hypothesis in mind, limitations often arise.

In the context of the studies in Table 1, perhaps one of the greatest limitations in this regard is the lack of explicit information pertaining to statins vs other cholesterollowering medications. For example, the studies by McCarthy et al. (76), Klein et al. (73), van Leeuwen et al. (74), and McGwin et al. (71) presented data with respect to cholesterol-lowering drugs (e.g., statin, cholestyramine, clofibrate, colestipol, gemfibrozil, and others related to bile sequestrants, antihyperlipidemic, and vitamin B3) and not statins in particular. The consequence of aggregating statins with other nonstatin cholesterol-lowering drugs depends on the hypothesized mechanism of action behind the relationship between statins and ARM, an issue discussed in greater detail in the subsequent section. Briefly, if the hypothesized mechanism is via a lowering of cholesterol levels, then one might expect a similar association for statins as for nonstatin drugs. However, if the mechanism of action is not solely via a lowering of cholesterol but rather attributable, at least in part, to a characteristic specific to statins, then studies combining statins and nonstatins would produce estimates that are biased towards the null. To date, only one study has simultaneously compared the relationship between statins and nonstatins and ARM (30). McGwin et al. (30) reported no reduced risk for ARM associated with nonstatin cholesterol-lowering drugs, but a significantly reduced risk associated with statin use. This evidence, albeit limited, supports the feasibility of a statin-specific effect and suggests that the null associations observed in studies that did not separate nonstatin cholesterol lowering drugs from statins might be biased towards the null. Further evidence for a non-cholesterol lowering mechanism is the lack of a consistent association between elevated cholesterol levels and the risk of ARM (78–83).

Because all of the studies were secondary analyses using existing cohorts, despite the large sample sizes, the ultimate number of subjects who developed ARM was often small, as in the case of the McCarthy et al. (31) and Klein et al. (72,73) studies. This, in turn, equates to lower statistical power to detect associations, particularly those that are modest in size.

Yet another limitation of many of the existing studies is failure to account for the temporal relationship between statin use and the onset of ARM. For example, the crosssectional studies by Hall et al. (32) and McCarthy et al. (76) documented the presence of ARM and statin use simultaneously. Our own recent work also suffered from the same limitation (71,77). Thus, we cannot be certain the extent to which the reported

statin use preceded, and by how much, the development of ARM. Despite the use of the case-control design, McGwin et al. were able to address this issue by using a nested case-control design (30). Thus, they only considered statin use that occurred prior to ARM diagnosis. As previously noted, much of the research on statins and ARM comes from secondary analysis of existing cohort studies. The cohort design will generally ensure that the primary exposure of interest is present prior to the occurrence of the primary outcome of interest. It is important to note that the follow-up time in many of these studies was relatively short, for example 5 yr in one study (73). However, given that statins did not become widespread until 1993, the follow-up time for any cohort study conducted presently would be no greater than 11 yr. Further, many of these studies did not quantify duration of statin use. Thus, the null associations may be the result of a heterogeneous mixture of shortand long-term statin users; for the former group, the short duration of time between use and potential onset of ARM may be too short to have had any potential impact on the risk of ARM. Two studies have addressed the duration issue and reported differing results. van Leeuwen et al. (74) found no association between statin use (or use of any cholesterol-lowering drugs) and ARM, regardless of the duration of use. However, there were only 25 subjects who developed ARM during the follow-up period of this study, resulting in low statistical power to detect an association. McGwin et al. also evaluated duration of statin use and documented a stronger association for past vs current users and for those who had used statins for a longer period of time (30).

Among the studies in Table 1, there are a variety of other lesser limitations that, although unlikely to account for the heterogeneity of results, hamper the ability to draw any firm conclusions from the body of research. For example, some studies relied upon self report of statin use, whereas others had independent sources of such information (e.g., pharmacy records); several studies had low response rates therefore introducing opportunity for selection bias; and finally, several studies failed to account for the impact of potentially confounding characteristics, some of which are potentially strong confounders (e.g., smoking, nutritional characteristics).

The aforementioned research described here is limited to those studies evaluating the potential role of statins in the prevention of ARM; there is an emerging body of research suggesting that statins may be an effective treatment for patients with ARM. Recently, Wilson et al. (84) evaluated the hypothesis that treatment with statins is associated with a reduced risk of choroidal neovascularization (CNV) in patients with ARM. The results of this study indicated that, in fact, statin use appeared to reduce the risk of CNV independent of other potentially confounding characteristics (e.g., smoking). This result is consistent with that from one other study wherein cholesterol-lowering medications were found to reduce the progression of ARM (31). Although indirect, this body of research provides support for a potential effect of statins on ARM.

SUMMARY

ARM is an important cause of vision impairment. The lack of effective treatments, particularly in the earliest stages of the disease, underscores the need for continued research on risk factors for preventing ARM from occurring in the first place. The evidence from observational studies for a relationship between statins and ARM is

equivocal yet there are a sufficient number of studies suggesting a protective association as well as significant limitations across all studies to leave the question open to further research. There are several mechanisms by which statins might reduce the risk of ARM. The cholesterol-lowering and anti-inflammatory properties of statins are among the most frequently mentioned mechanisms. However, additional research is needed to support or refute these mechanisms or reveal additional ones. Additional epidemiological studies are also needed. Despite the rapidly growing body of literature on the relationship between statins and ARM, all studies to date have been secondary analyses and, therefore, possessed specific limitations that likely contribute to the heterogeneity of observed results and prevent firm conclusions from being drawn. Although the evidence to date is sufficient to support the conduct of a clinical trial, there is debate regarding this issue (85,86). Thus, in the absence of support for such an endeavor, an observational study specifically design to test the association between statins and ARM is needed. Such a study would address the limitations of published studies to date, therefore providing further, perhaps more valid, results but also preliminary data required for a randomized clinical trial.

ACKNOWLEDGMENTS

Preparation of this chapter was made possible by National Institutes of Health grants R21-14071 and R01-AG04212, Research to Prevent Blindness, Inc, and the EyeSight Foundation of Alabama.

REFERENCES

1.Klein R, Klein BEK, Linton, KLP. Prevalence of age-related maculopathy: The Beaver Dam eye study. Ophthalmology 1992;99:933–943.

2.Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia: The Blue Mountains Eye Study. Ophthalmology 1995;102:1450–1460.

3.Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 1995;102:205–210.

4.Bressler NM, Bressler SB, West SK, Fine SL, Taylor HR. The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Archives of Ophthalmology 1989; 107:847–852.

5.Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Survey of Ophthalmology 1995;39:367–374.

6.Klein R, Davis MD, Magli YL, Segal P, Klein BEK, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;98:1128–1134.

7.Group, “Age-Related Eye Disease Study Research Group”(A.-r. E. D. S. R.) Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-related eye disease study report number 3. Ophthalmology 2000;107:2224–2232.

8.Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH. Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology 2002; 109:1767–1779.

9.Mangione CM, Gutierrez PR, Lowe G, Orav EJ, Seddon JM. Influence of age-related maculopathy on visual functioning and health-related quality of life. American Journal of Ophthalmology 1999;128:45–53.

10.Scott IU, Smiddy WE, Schiffman J, Feuer WJ, Pappas CJ. Quality of life of low-vision patients and the impact of low-vision services. American Journal of Ophthalmology 1999;128:54–62.

11.Scilley K, Jackson GR, Cideciyan AV, et al. Early age-related maculopathy and selfreported visual difficulty in daily life. Ophthalmology 2002;109:1235–1242.

12.Bressler NM, Bressler SB. Photodynamic therapy with verteprofin (Visudyne): impact on ophthalmology and visual science. Invest Ophthalmol Vis Sci 2000;41:624–628.

13.Age-related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol 2001;119: 1417–1436.

14.Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR, Group, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Study Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816.

15.Williams RA, Brody BL, Thomas RG, Kaplan RM, Brown SI. The psychosocial impact of macular degeneration. Arch Ophthalmol 1998;116:514–520.

16.Rovner BW, Casten RJ, Tasman WS. Effect of depression on vision function in age-related macular degeneration. Arch Ophthalmol 2002;120:1041–1044.

17.Marottoli RA, Ostfeld AM, Merrill SS, Perlman GD, Foley DJ, Cooney LM, Jr. Driving cessation and changes in mileage driven among elderly individuals. J Gerontol: Soc Sci 1993;48:S255–S260.

18.DeCarlo DK, Scilley K, Wells J, Owsley C. Driving habits and health-related quality of life in patients with age-related maculopathy. Optom Vis Sc 2003;80:207–213.

19.Scilley K, DeCarlo DK, Wells J, Owsley C. Vision-specific health-related quality of life in age-related maculopathy patients presenting for low vision services. Ophthalmic Epidemiol 2004;11:131–146.

20.Mangione CM, Lee PP, Gutierrez PR, et al. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol 2001;119:1050–1058.

21.National Advisory Eye Council National Eye Institute, National Institutes of Health. US Department of Health and Human Services. Vision research. A national plan: 1999–2003. 1999; Number 99–4120.

22.Friedman DS, O’Colman BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572.

23.Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM. Racial differences in the prevalence of age-related macular degeneration: The Baltimore Eye Survey. Ophthalmology 1999;106:1049–1055.

24.Klein R, Peto T, Bird AC, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137:486–495.

25.Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol 1999;6:125–143.

26.Gottlieb JL. Age-related macular degeneration. JAMA 2002;288:2233–2236.

27.van Leeuwen R, Klaver C, Vingerling J, Hofman A, de Jong PTVM. Epidemiology of agerelated maculopathy: a review. Eur J Epidemiol 2003;18:845–854.

28.Chan D. Cigarette smoking and age-related macular degeneration. Optom Vis Sci 1998; 75:476–484.

29.Solberg Y, Rosenr M, Belkin M. The association between cigarette smoking and ocular diseases. Surv Ophthalmol 1998;42:535–547.

30.McGwin G, Owsley C, Curcio CA, Crain RJ. The association between statin use and age related maculopathy. Br J Ophthalmol 2003;87:1121–1125.

31.McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR. Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Med J Aust 2001;175:340.

32.Hall NF, Gale CR, Syddall H, Phillips DIW, Martyn CN. Risk of macular degeneration in users of statins: cross sectional study. BMJ 2001;323:375–376.

33.Brown MS, Goldstein JL. Multivalent feedback regulation of HMG CoA reductase a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res 1980;21:505–517.

34.Comparato C, Altana C, Bellosta S, Baetta R, Paoletti R, Corsini A. Clinically relevant pleiotropic effects of statins: Drug properties or effects of profound cholesterol reduction? Nutri Metab Cardiovasc Dis 2001;11:328–343.

35.Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21:1712–1719.

36.Hennekens CH. Current perspectives on lipid lowering with statins to decrease risk of cardiovascular disease. Clin Cardiol 2001;24:2–5.

37.Miller LJ, Chacko R. The role of choesterol and stains in Alzheimer’s disease. Ann Pharmacother 2004;38:91–98.

38.Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627–1631.

39.Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme a reductase inhibitors. Arch Neurol 2000;57:1439–1443.

40.Vaughan CJ. Prevention of stroke and dementia with statin: Effects of lipid lowering. Am J Cardiol 2003;91:23B–29B.

41.Bauer DC, Mundy GR, Jamal SA, et al. Use of statins and fracture: Results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med 2004;164:146–152.

42.Yaturu S. Skeletal effects of statins. Endicr Pract 2003;9:315–320.

43.Young-Xu Y, Chan KA, Liao JK, Ravid S, Blatt CM. Long-term statin use and psychological well-being. J Am Coll Cardiol 2003;42:690–697.

44.Edwards PA, Ericsson J. Sterols and isoprenoids: Signalling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 1999;68:157–185.

45.Cucchiara B, Kasner SE. Use of statins in CNS disorders. J Neurol Sci 2001;187:81–89.

46.Fassbender K, Simons M, Bergmann C, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides A-beta-42 and A-beta-40 in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:5856–5861.

47.Sarks SH. Aging and degeneration in the macular region: A clinico-pathological study. Br J Ophthalmol 1976;60:324–341.

48.Green WR, Enger C. Age-related macular degeneration histopathologic studies: The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519–1535.

49.Malek G, Li CM, Guidry C, Medeiros NE, Curcio CA. Apolipoprotein B in cholesterolcontaining drusen and basal deposits of human eyes with age-related maculopathy. Am J Pathol 2003;162:413–425.

50.Curcio CA, Millican CL, Bailey T, Kruth H. Accumulation of cholesterol with age in human Bruch’s membrane. Invest Ophthalmol Vis Sci 2001;42:265–274.

51.Curcio C, Presley JB, Millican CL, Medeiros N. Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles. Exp Eye Res 2005;80:761–775.

52.Farkas TG, Sylvester V, Archer D, et al. The histochemistry of drusen. Am J Ophthalmol 1971;71:1206–1215.

53.Pauleikhoff D, Harper C, Marshall J, Bird A. Aging changes in Bruch’s membrane. A histochemical and morphologic study. Ophthalmology 1990;97:171–178.

54.Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol 1994;112:402–406.

55.Haimovici R, Gantz DL, Rumelt S, Freddo TF, Small DM. The lipid composition of drusen, bruch’s membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci 2001;42:1592–1599.

56.Chuan-Ming L, Chung H, Presley JB, et al. Lipoprotein-like particles and cholesteryl esters in human Bruch’s membrane: Initial characterization. Invest Ophthalmol Vis Sci 2005; 46:2576–2586.

57.Dithmar S, Sharara NA, Curcio CA, et al. Murine high-fat diet and laswer photochemical model of basal deposits in Bruch membrane. Arch Ophthalmol 2001;119:1643–1649.

58.Miceli MV, Newsome DA, Tate DJ, Jr, Sarphie TG. Pathologic changes in the retinal pigment epithelium and Bruch’s membrane of fat-fed atherogenic mice. Curr Eye Res 2000;20:8–16.

59.Dithmar S, Curcio C, Le N-A, Brown S, Grossniklaus HE. Ultrastructural changes in Bruch’s membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci 2000; 41:2035–2042.

60.Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease, Vol. 2. New York: McGraw-Hill, 2001.

61.Tabas I. Nonoxidative modifications of lipoproteins in atherogenesis. Annu Rev Nutr 1999;19:123–129.

62.Moulton KS. Plaque angiogenesis and atherosclerosis. Curr Atheroscler Rep 2001;3:225–233.

63.Campachiaro PA. Retinal and choroidal neovascularization. J Cell Physiol 2000;184: 301–310.

64.Qi JH, Ebrahem Q, Yeow K, Edwards DR, Fox PL, Anand-Apte B. Expression of Sorsby’s fundus dystrophy mutations in human reitnal pigment epithelial cells reduces matrix metallaoproteinase inhibition and may promote angiogenesis. J Biol Chem 2002; 277:13,394–13,400.

65.Grossniklaus HE, Cingle KA, Yoon YD, Ketkar N, L’hernault N, Brown S. Correlation of histologic 2-dimenstional reconstructional and confocal scanning laser microscopic imagng of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol 2000;118:625–629.

66.Killlingsworth MC, Sarks JP, Sarks SH. Macrophages related to Bruch’sm embrane in agerelated macular degeneration. Eye 1990;4:613–621.

67.Lopez PF, Sippy BD, Lambert HM, Tahck AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vacular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1996;37:855–868.

68.Hageman GS, Luthert PJ, Chong NHV, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705–732.

69.Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 2001;20:385–414.

70.Capeans C, Pineiro A, Pardo M, et al. Role of inhibitors of isoprenylation in proliferation, phenotype and apoptosis of human retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 2001;239:188–198.

71.McGwin G, Xie A, Owsley C. The use of cholesterol lowering medications and age-related macular degeneration. Ophthalmology 2005;112:488–494.

72.Klein R, Klein BEK, Jensen SC, et al. Medication use and the 5-year incidence of early agerelated maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 2001;119:1354–1359.

73.Klein R, Klein BEK, Tomany SC, Danforth LG, Cruickshanks KJ. Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 2003;121:1151–1155.

74.van Leeuwen R, Vingerling JR, Hofman A, de Jong PTVM, Stricker BHC. Cholesterol lowering drugs and risk of age related maculopathy: Prospective cohort study with cumulative exposure measurement. BMJ 2003;326:255–256.

75.van Leeuwen R, Tomany SC, Wang JJ, et al. Is medication use associated with incidence of early age-related maculopathy? Ophthalmology 2004;111:1169–1175.

76.McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR. Risk factors for agerelated maculopathy: The visual impairment project. Arch Ophthalmol 2001; 119:1455–1462.

77.McGwin G, Modjarrad K, Hall TA, Xie A, Owsley C. 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors and the presence of age-related macular degeneration in the Cardiovascular Health Study. Arch Ophthalmol 2006;124:33–37.

78.van Leeuwen R, Klaver CCW, Vingerling JR, et al. Cholesterol and age-related macular degeneration: Is there a link? Am J Ophthalmol 2004;137:750–752.

79.Tomany SC, Wang JJ, van Leeuwen R, et al. Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents. Ophthalmology 2004;111:1280–1287.

80.Eye Disease Case Control Study Group. Risk factors for neovascular age-related macular degeneration. Arch Ophthamol 1992;110:1701–1708.

81.Klein R, Klein BEK, Franke T. The relationship of cardiovascular disease and its risk factors to age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 1993; 10:406–414.

82.Delcourt C, Michel F, Colvez A, et al. Associations of cardiovascular disease and its risks factors with age-related macular degeneration: The POLA study. Ophthalmic Epidemiol 2001;8:237–249.

83.Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001;108:697–704.

84.Wilson HL, Schwartz DM, Bhatt HRF, McCulloch CE, Duncan JL. Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration. Am J Ophthalmol 2004;137:615–624.

85.Klein R, Klein BE. Do statins prevent age-related macular degeneration? Am J Ophthalmol 2004;137:747–749.

86.McGwin G, Owsley C. Statins and age-related macular degeneration. Am J Ophthalmol 2004;138:688.

and are generally considered benign when present alone. Soft drusen, sometimes postulated to form from hard drusen or from a membranous component of the basement membrane of the retinal pigment epithelium (RPE), tend to be larger in size and may be coalescent (2). They can be divided into soft distinct drusen, which have uniform reflectance throughout, and soft indistinct drusen, the reflectance of which tapers off toward the boundary and often blends with the background (2). Other types of drusen have also been noted. Reticular pseudodrusen are seen in the peripheral macula as a lacy, lobular pattern whose histopathological correlate is uncertain and are probably not drusen at all (2). There are also cuticular drusen, a descriptive term referring to small nodules in large numbers emanating from the inner portion of Bruch’s membrane (4). However, Russell et al. have differed concerning the uniqueness of cuticular drusen, and suggest that they are indistinguishable from drusen found in AMD (5).

DRUSEN AS A RISK FACTOR

Soft drusen are a clear risk factor for the development of advanced AMD. The Blue Mountain Eye Study demonstrated that the presence of drusen 125 m or larger, soft indistinct or reticular drusen, were amongst the chief risk factors for the progression to CNV (6). The Beaver Dam Eye study found there was a 100 times greater risk of developing CNV in eyes of patients with established early AMD with drusen formation or retinal pigmentary abnormalities when compared to eyes with no evidence of drusen or pigment change (7). The macular photocoagulation study (MPS) also found that large drusen, and five or more soft drusen, were risk factors for progression to advanced AMD (8). For further details on the epidemiology of drusen in AMD, please see the companion chapter by Klein.

DRUSEN COMPOSITION

Drusen composition has also been studied in greater detail recently. Studies by Hageman et al., as well as Crabb et al., have resulted in a more precise elucidation of the composition of macular drusen (9,10). Drusen are aggregates of lipids, glycolipids, proteins and other cellular elements. Following isolation of drusen from Bruch’s membrane, Crabb et al. conducted proteome analysis that isolated many common proteins in drusen including TIMP3, clusterin, vitronectin, and serum albumin (10). An intriguing group of compounds isolated were carboxyethyl pyrrole protein adducts. These adducts, a result of oxidative damage to proteins, suggest that age-related oxidative damage to tissues (vascular elements or elements intrinsic to Bruch’s membrane and the RPE) contributes to drusen formation.

DRUSEN IN OTHER DISEASES

Diseases other than AMD may present with drusen. For example, Doyne’s honeycomb macular dystrophy presents with drusen that appear as white or brownish-white deposits occupying the posterior pole in a honeycomb pattern (11). Doyne’s honeycomb and a related phenotype, Mallatia Leventinese, are caused by mutations in the EFEMP1 protein, an extracellular matrix protein, providing yet another genetic link between drusen and its etiology (12). Unlike AMD, these present in the third to fourth decade of life. Drusen can also be seen in systemic diseases such as membrano-proliferative

glomerulonephritis (13). Sometimes, choroidal melanomas will have overlying drusen (14). Nevertheless, the most common cause of drusen remains by far AMD, a disease afflicting millions of elderly.

PATHOPHYSIOLOGY OF DRUSEN

Historical Theories

Drusen were first noted by Muller (15). Muller theorized that drusen were congregate deposits of secretions from RPE membranes onto Bruch’s membrane (the “deposition theory”). Donders proposed that rather than deposits, drusen were actually just degenerated RPE cells (the “transformation theory”) (16). Both theories held paramount the role of RPE dysfunction in the generation of drusen.

Although RPE dysfunction remains a central tenet in the current understanding of drusen, inflammation, inflammatory mediators, and choriocapillaris dysfunction have recently been implicated in drusen formation.

Inflammation

Hageman et al. (9) proposed a unifying theory of drusen biogenesis that places the role of the dendritic cell, an antigen-presenting cell, as the primary instigator of drusen formation. Hageman finds that dendritic cells accumulate in areas of drusen formation at a very early stage, and after nucleation of the drusen, the subsequent inflammatory processes direct further aggregation of compounds. These include complement mediators, complement inhibitors such as vitronectin, amyloid compounds, HLA-DR, as well as coagulation factors such as Factor X, and prothrombin. Hageman argued that these inflammatory and immune compounds play a central role in drusen biogenesis, especially if combined with genetic alterations that might predispose to decreased clearance of debris. Ambati et al. described just such an alteration (17).

Inflammatory Factors and Drusen

Ambati et al. demonstrated that mice that lack a chemoattractant for macrophages develop accumulations of drusen-like material (17). These ccl/r-2 deficient mice developed an AMD-like disease in the absence of functional scavenging macrophages. These data were therefore suggestive that macrophages play a critical role in maintaining homeostasis in the environment of Bruch’s membrane and the RPE, and thereby prevent buildup of compounds leading to drusen formation.

The Vascular Theory

Further evidence recently has indicated that the anticholesterol drug family known as the statins decreases the rate of AMD progression. Wilson et al. (18) demonstrated that patients taking statins demonstrated a lower rate than controls of progression from early to advanced AMD.

This supports the notion that the choriocapillaris and vascular factors play an important role in the progression of AMD. Friedman proposed that decreased compliance of ocular tissues and progressive narrowing of the macular choriocapillaris due to infiltration with lipid result in increased intraocular vascular resistance and increased choriocapillaris pressures (19). These high pressures prohibit clearance of lipoprotein debris