Decreased Thickness and Integrity of the Macular Elastic Layer of Bruch's Membrane Correspond to the

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. In its severest form, choroidal neovessels breach the macular Bruch's membrane, an extracellular matrix compartment comprised of elastin and collagen laminae, and grow into the retina. We sought to determine whether structural properties of the elastic lamina (EL) correspond to the region of the macula that is predilected toward degeneration in AMD. Morphometric assessment of the macular and extramacular regions of 121 human donor eyes, with and without AMD, revealed a statistically significant difference in both the integrity (P < 0.0001) and thickness (P < 0.0001) of the EL between the macular and extramacular regions in donors of all ages. The EL was three to six times thinner and two to five times less abundant in the macula than in the periphery. The integrity of the macular EL was significantly lower in donors with early-stage AMD (P = 0.028), active choroidal neovascularization (P = 0.020), and disciform scars (P = 0.003), as compared to unaffected, age-matched controls. EL thickness was significantly lower only in individuals with disciform scars (P = 0.008). The largest gaps in macular EL integrity were significantly larger in all categories of AMD (each P < 0.0001), as compared to controls. EL integrity, thickness, and gap length in donors with geographic atrophy did not differ from those of controls. These structural properties of the macular EL correspond spatially to the distribution of macular lesions associated with AMD and may help to explain why the macula is more susceptible to degenerative events that occur in this disease.

[1]  C. Curcio,et al.  Accumulation of cholesterol with age in human Bruch's membrane. , 2001, Investigative ophthalmology & visual science.

[2]  Thomas J. Liesegang,et al.  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.Hageman GS,∗ Luthert PJ, Chong NHV, Johnson LV, Anderson DH, Mullins RF. Prog Ret Eye Res 2001:20:705–732. , 2002 .

[3]  R. Pruett,et al.  Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy , 1994, Nature Genetics.

[4]  M. Gillies,et al.  Immunological and Aetiological Aspects of Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[5]  R. Klein,et al.  The association of cataract and cataract surgery with the long-term incidence of age-related maculopathy: the Beaver Dam eye study. , 2002, Archives of ophthalmology.

[6]  A. Bird,et al.  [Biochemical and histochemical analysis of age related lipid deposits in Bruch's membrane]. , 1994, Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft.

[7]  P. Campochiaro,et al.  VEGF is major stimulator in model of choroidal neovascularization. , 2000, Investigative ophthalmology & visual science.

[8]  Hans E. Grossniklaus,et al.  Characteristics of Drusen and Bruch's membrane in postmortem eyes with age-related macular degeneration. , 1997 .

[9]  J. Alvarado,et al.  Studies on the human macula. IV. Aging changes in Bruch's membrane. , 1967, Archives of ophthalmology.

[10]  Hogan Mj Bruch's membrane and disease of the macula. Role of elastic tissue and collagen. , 1967 .

[11]  P. Campochiaro,et al.  Inducible expression of vascular endothelial growth factor in adult mice causes severe proliferative retinopathy and retinal detachment. , 2002, The American journal of pathology.

[12]  N. Lee,et al.  Successful photodynamic therapy for subretinal neovascularisation due to Sorsby’s fundus dystrophy: 1 year follow up , 2003, The British journal of ophthalmology.

[13]  W. Green,et al.  Bruch's membrane age-related changes vary by region. , 1987, Current eye research.

[14]  D. Easty,et al.  Preparation of Bruch's membrane and analysis of the age-related changes in the structural collagens. , 1995, The British journal of ophthalmology.

[15]  G. Hageman,et al.  Molecular composition of drusen as related to substructural phenotype. , 1999, Molecular vision.

[16]  G. Nackman,et al.  Elastin degradation products induce adventitial angiogenesis in the Anidjar/Dobrin rat aneurysm model. , 1997, Surgery.

[17]  K. Bartz-Schmidt,et al.  Clinicopathological correlation in exudative age-related macular degeneration: recurrent choroidal neovascularization , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[18]  P. Henkind,et al.  Ultrastructure of Bruch's membrane after krypton laser photocoagulation. I. Breakdown of Bruch's membrane. , 1986, Archives of ophthalmology.

[19]  A. Bird,et al.  TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy. , 2000, Investigative ophthalmology & visual science.

[20]  R. Phipps Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Marshall,et al.  Age-related alterations in the diffusional transport of amino acids across the human Bruch's-choroid complex. , 2002, Journal of the Optical Society of America. A, Optics, image science, and vision.

[22]  S. Tyagi,et al.  Responses of vascular smooth muscle cell to extracellular matrix degradation , 1999, Journal of cellular biochemistry.

[23]  R. D'Amato,et al.  Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. , 2001, The American journal of pathology.

[24]  P T de Jong,et al.  Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging. , 1994, Investigative ophthalmology & visual science.

[25]  Robert F. Mullins,et al.  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 , 2001, Progress in Retinal and Eye Research.

[26]  M. Zarbin,et al.  Age-Related Macular Degeneration: Review of Pathogenesis , 1998, European journal of ophthalmology.

[27]  W R Green,et al.  Pathologic Features of Senile Macular Degeneration , 1985, Ophthalmology.

[28]  M. Mochizuki,et al.  Long-term visual prognosis of choroidal neovascularization in high myopia: a comparison between age groups. , 2002, Ophthalmology.

[29]  A C Bird,et al.  The relationships of age changes in retinal pigment epithelium and Bruch's membrane. , 1999, Investigative ophthalmology & visual science.

[30]  J. Handa,et al.  Increase in the advanced glycation end product pentosidine in Bruch's membrane with age. , 1999, Investigative ophthalmology & visual science.

[31]  A Hofman,et al.  Risk factors for age-related macular degeneration: Pooled findings from three continents. , 2001, Ophthalmology.

[32]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[33]  W. Green,et al.  Ocular histoplasmosis: clinicopathologic correlation of 3 cases. , 1977, Survey of ophthalmology.

[34]  I J Constable,et al.  Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. , 2000, The American journal of pathology.

[35]  S. Ryan,et al.  Subretinal neovascularization. Natural history of an experimental model. , 1982, Archives of ophthalmology.

[36]  Hollenberg Mj,et al.  The fine structure of Bruch's membrane in the human eye. , 1969 .

[37]  M. Kamei,et al.  TIMP-3 in Bruch's membrane: changes during aging and in age-related macular degeneration. , 1999, Investigative ophthalmology & visual science.

[38]  M. Goldberg Editorial: Bruch's membrane and vascular growth. , 1976, Investigative ophthalmology.

[39]  W R Green,et al.  Age-related Macular Degeneration Histopathologic Studies: The 1992 Lorenz E. Zimmerman Lecture , 1993, Ophthalmology.

[40]  W. Green,et al.  Granulomatous reaction to Bruch's membrane in age-related macular degeneration. , 1994, Archives of ophthalmology.

[41]  W. Heriot,et al.  Choroidal neovascularization can digest Bruch's membrane. A prior break is not essential. , 1984, Ophthalmology.

[42]  A. Hendrickson,et al.  The morphological development of the human fovea. , 1984, Ophthalmology.

[43]  K. Niemi,et al.  OCULAR FINDINGS IN FOUR SIBLINGS WITH PSEUDOXANTHOMA ELASTICUM , 1983, Acta ophthalmologica.

[44]  S. Russell,et al.  Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  J. Lim,et al.  Iatrogenic choroidal neovascularization. , 1999, Survey of ophthalmology.

[46]  S. Sarks,et al.  Ageing and degeneration in the macular region: a clinico-pathological study. , 1976, The British journal of ophthalmology.

[47]  G. Soubrane,et al.  Etiology of choroidal neovascularization in young patients. , 1996, Ophthalmology.

[48]  L. V. Johnson,et al.  A potential role for immune complex pathogenesis in drusen formation. , 2000, Experimental eye research.

[49]  Robert F Mullins,et al.  A role for local inflammation in the formation of drusen in the aging eye. , 2002, American journal of ophthalmology.

[50]  I. Constable,et al.  Predilection of the macular region to high incidence of choroidal neovascularization after intense laser photocoagulation in the monkey. , 2003, Archives of ophthalmology.

[51]  M. Killingsworth,et al.  Macrophages related to Bruch's membrane in age-related macular degeneration , 1990, Eye.

[52]  H. Yamashita,et al.  Scanning electron microscopic observation of Bruch's membrane with the osmium tetroxide treatment. , 1989, The British journal of ophthalmology.

[53]  M. Killingsworth,et al.  Evolution of geographic atrophy of the retinal pigment epithelium , 1988, Eye.

[54]  M. Kamei,et al.  TIMP-3 Accumulation in Bruch’s Membrane and Drusen in Eyes From Normal and Age-Related Macular Degeneration Donors , 1997 .

[55]  C. Martyn,et al.  Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension , 1997, The Lancet.

[56]  L. Nanney,et al.  Transforming growth factor-β stimulates wound healing and modulates extracellular matrix gene expression in pig skin. I, Excisional wound model , 1990 .

[57]  R. Guymer,et al.  Changes in Bruch’s membrane and related structures with age , 1999, Progress in Retinal and Eye Research.

[58]  P T de Jong,et al.  An international classification and grading system for age-related maculopathy and age-related macular degeneration , 1995 .

[59]  P. Penfold,et al.  Senile macular degeneration. The involvement of giant cells in atrophy of the retinal pigment epithelium. , 1986, Investigative ophthalmology & visual science.

[60]  L. Wu,et al.  Cellular expression of tropoelastin mRNA splice variants. , 1992, Matrix.

[61]  C. Grindle,et al.  Ageing changes in Bruch's membrane and their functional implications. , 1978, Transactions of the ophthalmological societies of the United Kingdom.

[62]  N. Bressler,et al.  Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration. 1994. , 2005, Retina.

[63]  J. Marshall,et al.  Age-related variation in the hydraulic conductivity of Bruch's membrane. , 1995, Investigative ophthalmology & visual science.

[64]  H. Grossniklaus,et al.  Histologic and morphometric analysis of the choroid, Bruch's membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. , 1999, Survey of ophthalmology.

[65]  S. Wray,et al.  Menkes' kinky hair disease: a light and electron microscopic study of the eye. , 1976, Investigative ophthalmology.

[66]  D. Quaglino,et al.  Ultrastructural studies on dermis from prolidase deficient subjects. , 1991, Journal of submicroscopic cytology and pathology.

[67]  S. Russell,et al.  Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration. , 2000, American journal of ophthalmology.

[68]  P. D. de Jong,et al.  Morphologic changes in age‐related maculopathy , 1997, Microscopy research and technique.

[69]  M. Ellersieck,et al.  Age-related changes in the ultrastructure of Bruch's membrane. , 1985, American journal of ophthalmology.

[70]  J. Powell,et al.  Maternal and postnatal vitamin D ingestion influences rat aortic structure, function and elastin content. , 2002, Cardiovascular research.

[71]  J. Davidson,et al.  Cutis Laxa and Premature Aging Syndromes , 2003 .

[72]  C. Curcio,et al.  Basal linear deposit and large drusen are specific for early age-related maculopathy. , 1999, Archives of ophthalmology.

[73]  S. Russell,et al.  Drusen associated with aging and age‐related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[74]  D. Burgess,et al.  Subfoveal and juxtafoveal subretinal neovascularization in the presumed ocular histoplasmosis syndrome. Visual prognosis. , 1984, Ophthalmology.

[75]  P. Penfold,et al.  An ultrastructural study of the role of leucocytes and fibroblasts in the breakdown of Bruch's membrane. , 1984, Australian journal of ophthalmology.