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• W2942553901 abstract "Early age-related macular degeneration (AMD) is characterized by degeneration of the choriocapillaris, the vascular supply of retinal photoreceptor cells. We assessed vascular loss during disease progression in the choriocapillaris and larger vessels in the deeper choroid. Human donor maculae from controls (n = 99), early AMD (n = 35), or clinically diagnosed with geographic atrophy (GA; n = 9, collected from outside the zone of retinal pigment epithelium degeneration) were evaluated using Ulex europaeus agglutinin-I labeling to discriminate between vessels with intact endothelial cells and ghost vessels. Morphometric analyses of choriocapillaris density (cross-sectional area of capillary lumens divided by length) and of vascular lumen/stroma ratio in the outer choroid were performed. Choriocapillaris loss was observed in early AMD (Bonferroni-corrected P = 0.024) with greater loss in GA (Bonferroni-corrected P < 10−9), even in areas of intact retinal pigment epithelium. In contrast, changes in lumen/stroma ratio in the outer choroid were not found to differ between controls and AMD or GA eyes (P > 0.05), suggesting choriocapillaris changes are more prevalent in AMD than those in the outer choroid. In addition, vascular endothelial growth factor-A levels were negatively correlated with choriocapillaris vascular density. These findings support the concept that choroidal vascular degeneration, predominantly in the microvasculature, contributes to dry AMD progression. Addressing capillary loss in AMD remains an important translational target. Early age-related macular degeneration (AMD) is characterized by degeneration of the choriocapillaris, the vascular supply of retinal photoreceptor cells. We assessed vascular loss during disease progression in the choriocapillaris and larger vessels in the deeper choroid. Human donor maculae from controls (n = 99), early AMD (n = 35), or clinically diagnosed with geographic atrophy (GA; n = 9, collected from outside the zone of retinal pigment epithelium degeneration) were evaluated using Ulex europaeus agglutinin-I labeling to discriminate between vessels with intact endothelial cells and ghost vessels. Morphometric analyses of choriocapillaris density (cross-sectional area of capillary lumens divided by length) and of vascular lumen/stroma ratio in the outer choroid were performed. Choriocapillaris loss was observed in early AMD (Bonferroni-corrected P = 0.024) with greater loss in GA (Bonferroni-corrected P < 10−9), even in areas of intact retinal pigment epithelium. In contrast, changes in lumen/stroma ratio in the outer choroid were not found to differ between controls and AMD or GA eyes (P > 0.05), suggesting choriocapillaris changes are more prevalent in AMD than those in the outer choroid. In addition, vascular endothelial growth factor-A levels were negatively correlated with choriocapillaris vascular density. These findings support the concept that choroidal vascular degeneration, predominantly in the microvasculature, contributes to dry AMD progression. Addressing capillary loss in AMD remains an important translational target. The choroid is a distinctive vascular tissue that supports vision by supplying oxygen and nutrients to the outer retina and retinal pigment epithelium (RPE) while removing waste.1Nickla D.L. Wallman J. The multifunctional choroid.Prog Retin Eye Res. 2010; 29: 144-168Google Scholar, 2Chirco K.R. Sohn E.H. Stone E.M. Tucker B.A. Mullins R.F. Structural and molecular changes in the aging choroid: implications for age-related macular degeneration.Eye (Lond). 2017; 31: 10-25Google Scholar These functions are critical in light of the substantial metabolic activity of the neural retina.3Linsenmeier R.A. Braun R.D. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia.J Gen Physiol. 1992; 99: 177-197Google Scholar The choroid is a component of the peripheral circulatory system and has a high degree of blood flow, receiving >80% of the ophthalmic artery's volume.4Harris A. Atlas of Ocular Blood Flow. Butterworth Heinemann, Philadelphia, PA2003Google Scholar The choroid has other unique features, including the following: i) an extremely dense capillary network (the choriocapillaris) with vascular lumens that occupy >50% of the volume of the choriocapillaris layer in a healthy macula; ii) large-diameter capillaries that permit passage of multiple red blood cells; iii) diaphragm-bearing fenestrae, particularly on the inner (ie, facing the retina) surface; iv) a segmental pattern of supply and collection with anastomosing microvasculature; and v) a specific pattern of gene expression.5Whitmore S.S. Sohn E.H. Chirco K.R. Drack A.V. Stone E.M. Tucker B.A. Mullins R.F. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.Prog Retin Eye Res. 2014; 45: 1-29Google Scholar Although imaging the choroid in living subjects was formerly challenging, the development of the new imaging modalities, such as the enhanced depth imaging mode of spectral-domain optical coherence tomography (OCT) and OCT angiography (OCTA), has allowed the structure of the choroid to be evaluated in health and different disease states. The application of enhanced depth imaging mode of spectral-domain OCT has provided insight into the state of the choroid in several macular diseases, including central serous retinopathy,6Imamura Y. Fujiwara T. Margolis R. Spaide R.F. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy.Retina. 2009; 29: 1469-1473Google Scholar polypoidal vasculopathy,7Peiretti E. Pozzoni M.C. Fossarello M. Spaide R.F. Polypoidal choroidal vasculopathy in association with choroidal nevus.Retin Cases Brief Rep. 2009; 3: 12-14Google Scholar and high myopia.8Fujiwara T. Imamura Y. Margolis R. Slakter J.S. Spaide R.F. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes.Am J Ophthalmol. 2009; 148: 445-450Google Scholar OCTA has enabled the noninvasive and rapid elucidation of the critical role the choriocapillaris plays in several vision-threatening diseases affecting the central retina, such as age-related macular degeneration (AMD),9Choi W. Moult E.M. Waheed N.K. Adhi M. Lee B. Lu C.D. de Carlo T.E. Jayaraman V. Rosenfeld P.J. Duker J.S. Fujimoto J.G. Ultrahigh-speed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy.Ophthalmology. 2015; 122: 2532-2544Google Scholar, 10Jia Y. Bailey S.T. Hwang T.S. McClintic S.M. Gao S.S. Pennesi M.E. Flaxel C.J. Lauer A.K. Wilson D.J. Hornegger J. Fujimoto J.G. Huang D. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye.Proc Natl Acad Sci U S A. 2015; 112: E2395-E2402Google Scholar, 11Roisman L. Zhang Q. Wang R.K. Gregori G. Zhang A. Chen C.-L. Durbin M.K. An L. Stetson P.F. Robbins G. Miller A. Zheng F. Rosenfeld P.J. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration.Ophthalmology. 2016; 123: 1309-1319Google Scholar acute macular neuroretinopathy,12Lee S.Y. Cheng J.L. Gehrs K.M. Folk J.C. Sohn E.H. Russell S.R. Guo Z. Abràmoff M.D. Han I.C. Choroidal features of acute macular neuroretinopathy via optical coherence tomography angiography and correlation with serial multimodal imaging.JAMA Ophthalmol. 2017; 135: 1177-1183Google Scholar and diabetic retinopathy.13Abràmoff M.D. Fort P.E. Han I.C. Jayasundera K.T. Sohn E.H. Gardner T.W. Approach for a clinically useful comprehensive classification of vascular and neural aspects of diabetic retinal disease.Invest Ophthalmol Vis Sci. 2018; 59: 519-527Google Scholar, 14Nesper P.L. Roberts P.K. Onishi A.C. Chai H. Liu L. Jampol L.M. Fawzi A.A. Quantifying microvascular abnormalities with increasing severity of diabetic retinopathy using optical coherence tomography angiography.Invest Ophthalmol Vis Sci. 2017; 58: BIO307-BIO315Google Scholar The ability to quantify the structure of layers of the human macula using automated image analysis has made valuable contributions to our understanding of the dynamic nature of the retina and choroid in normal conditions and in response to various stimuli.15Arora K.S. Jefferys J.L. Maul E.A. Quigley H.A. Choroidal thickness change after water drinking is greater in angle closure than in open angle eyes.Invest Ophthalmol Vis Sci. 2012; 53: 6393-6402Google Scholar, 16Abràmoff M.D. Mullins R.F. Lee K. Hoffmann J.M. Sonka M. Critser D.B. Stasheff S.F. Stone E.M. Human photoreceptor outer segments shorten during light adaptation.Invest Ophthalmol Vis Sci. 2013; 54: 3721-3728Google Scholar, 17Vural A.D. Kara N. Sayin N. Pirhan D. Ersan H.B.A. Choroidal thickness changes after a single administration of coffee in healthy subjects.Retina. 2014; 34: 1223-1228Google Scholar, 18Kim D.Y. Fingler J. Zawadzki R.J. Park S.S. Morse L.S. Schwartz D.M. Fraser S.E. Werner J.S. Optical imaging of the chorioretinal vasculature in the living human eye.Proc Natl Acad Sci U S A. 2013; 27: 14354-14359Google Scholar, 19Kim D.Y. Silverman R.H. Chan R.V.P. Khanifar A.A. Rondeau M. Lloyd H. Schlegel P. Coleman D.J. Measurement of choroidal perfusion and thickness following systemic sildenafil (Viagra(®)).Acta Ophthalmol. 2013; 91: 183-188Google Scholar The choroid has recently received renewed attention in the study of AMD, a common debilitating disease that affects millions of individuals in the United States alone. Although anti–vascular endothelial growth factor (VEGF) agents have been effective at limiting the vision loss associated with advanced, exudative, choroidal neovascularization,20Martin D.F. Maguire M.G. Ying G.-S. Grunwald J.E. Fine S.L. Jaffe G.J. CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Google Scholar, 21Bakall B. Folk J.C. Boldt H.C. Sohn E.H. Stone E.M. Russell S.R. Mahajan V.B. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab.Am J Ophthalmol. 2013; 156: 15-22.e1Google Scholar, 22Tozer K. Roller A.B. Chong L.P. Sadda S. Folk J.C. Mahajan V.B. Russell S.R. Boldt H.C. Sohn E.H. Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents.Ophthalmology. 2013; 120: 2029-2034Google Scholar geographic atrophy (GA) remains a major cause of central vision loss. The central vision loss of GA is caused by the death of photoreceptor cells, RPE, and choriocapillary endothelial cells in the macular region of the retina. Before the widespread use of anti-VEGF agents, approximately 10% of the US population older than 70 years had GA, which was similar to the prevalence of exudative AMD.23Friedman D.S. O'Colmain B.J. Muñoz B. Tomany S.C. McCarty C. de Jong P.T.V.M. Nemesure B. Mitchell P. Kempen J. Eye Diseases Prevalence Research GroupPrevalence of age-related macular degeneration in the United States.Arch Ophthalmol. 2004; 122: 564-572Google Scholar However, now that exudative AMD has an effective treatment that can restore vision and prevent vision loss, the fraction of patients with irreversible blindness from GA has increased.24Grunwald J.E. Daniel E. Huang J. Ying G.-S. Maguire M.G. Toth C.A. Jaffe G.J. Fine S.L. Blodi B. Klein M.L. Martin A.A. Hagstrom S.A. Martin D.F. CATT Research GroupRisk of geographic atrophy in the comparison of age-related macular degeneration treatments trials.Ophthalmology. 2014; 121: 150-161Google Scholar Moreover, there is some evidence that GA may be exacerbated in patients receiving anti-VEGF therapy.25Grunwald J.E. Pistilli M. Daniel E. Ying G.-S. Pan W. Jaffe G.J. Toth C.A. Hagstrom S.A. Maguire M.G. Martin D.F. Comparison of age-related macular degeneration treatments trials research group: incidence and growth of geographic atrophy during 5 years of comparison of age-related macular degeneration treatments trials.Ophthalmology. 2017; 124: 97-104Google Scholar Although structural and functional changes in the choroid have classically been considered to be relatively late events in the pathogenesis of AMD (with RPE changes considered primary26Hogan M.J. Role of the retinal pigment epithelium in macular disease.Trans Am Acad Ophthalmol Otolaryngol. 1972; 76: 64-80Google Scholar), several recent reports have described cellular and molecular changes in the choroid that occur early in disease. Functional studies of choroidal filling by Pauleikhoff et al27Pauleikhoff D. Spital G. Radermacher M. Brumm G.A. Lommatzsch A. Bird A.C. A fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease.Arch Ophthalmol. 1999; 117: 1353-1358Google Scholar and of subfoveal blood flow by Grunwald et al28Grunwald J.E. Metelitsina T.I. Dupont J.C. Ying G.-S. Maguire M.G. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity.Invest Ophthalmol Vis Sci. 2005; 46: 1033-1038Google Scholar have shown slower filling and decreased choroidal volume and flow with progression of AMD and in association with abundance of drusen, early morphologic indicators of AMD.29Berenberg T.L. Metelitsina T.I. Madow B. Dai Y. Ying G.-S. Dupont J.C. Grunwald L. Brucker A.J. Grunwald J.E. The association between drusen extent and foveolar choroidal blood flow in age-related macular degeneration.Retina. 2012; 32: 25-31Google Scholar Histologically, loss of viable choriocapillaris endothelium has been noted in human donor eyes in association with drusen30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar before the gross dropout of RPE cells.5Whitmore S.S. Sohn E.H. Chirco K.R. Drack A.V. Stone E.M. Tucker B.A. Mullins R.F. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.Prog Retin Eye Res. 2014; 45: 1-29Google Scholar, 31Biesemeier A. Taubitz T. Julien S. Yoeruek E. Schraermeyer U. Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration.Neurobiol Aging. 2014; 35: 2562-2573Google Scholar Moreover, the choriocapillaris is the major site of deposition of the membrane attack complex of complement, which increases during normal aging and in AMD, suggesting a putative mechanism by which vascular injury could be linked to the AMD risk alleles of complement genes.32Mullins R.F. Schoo D.P. Sohn E.H. Flamme-Wiese M.J. Workamelahu G. Johnston R.M. Wang K. Tucker B.A. Stone E.M. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning.Am J Pathol. 2014; 184: 3142-3153Google Scholar These observations have led us and others to speculate that choriocapillaris degeneration may be a primary event in early AMD. Whether choroidal changes further contribute to the geographic atrophy of advanced dry AMD is less well understood. For example, there has been some controversy about the relationship between vascular changes and geographic atrophy, with different results obtained using different approaches.31Biesemeier A. Taubitz T. Julien S. Yoeruek E. Schraermeyer U. Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration.Neurobiol Aging. 2014; 35: 2562-2573Google Scholar McLeod et al33McLeod D.S. Grebe R. Bhutto I. Merges C. Baba T. Lutty G.A. Relationship between RPE and choriocapillaris in age-related macular degeneration.Invest Ophthalmol Vis Sci. 2009; 50: 4982-4991Google Scholar studied whole mounts of human maculae and found that, although choriocapillaris vascular loss was notable in the center of atrophy, the edges had some preserved (although attenuated) vasculature with loss of RPE. Eyes with GA show choroidal thinning.34Sohn E.H. Khanna A. Tucker B.A. Abràmoff M.D. Stone E.M. Mullins R.F. Structural and biochemical analyses of choroidal thickness in human donor eyes.Invest Ophthalmol Vis Sci. 2014; 55: 1352-1360Google Scholar, 35Adhi M. Lau M. Liang M.C. Waheed N.K. Duker J.S. Analysis of the thickness and vascular layers of the choroid in eyes with geographic atrophy using spectral-domain optical coherence tomography.Retina. 2014; 34: 306-312Google Scholar In contrast, a recent report by Yiu et al36Yiu G. Chiu S.J. Petrou P.A. Stinnett S. Sarin N. Farsiu S. Chew E.Y. Wong W.T. Toth C.A. Relationship of central choroidal thickness with age-related macular degeneration status.Am J Ophthalmol. 2015; 159: 617-626Google Scholar found that (after correcting for refraction) GA is not associated with a thinner choroid. However, the choroidal thickness was related to the size of the atrophic lesion. Moreover, recent OCTA studies suggest that there is a concentric ring of vascular loss (or impaired flow) that is larger than the zone of RPE loss.9Choi W. Moult E.M. Waheed N.K. Adhi M. Lee B. Lu C.D. de Carlo T.E. Jayaraman V. Rosenfeld P.J. Duker J.S. Fujimoto J.G. Ultrahigh-speed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy.Ophthalmology. 2015; 122: 2532-2544Google Scholar Superimposed on the possible changes in choroidal thickness in GA, the choroid undergoes thinning during normal aging at the rate of approximately 1 to 2 μm per year.37Shin J.W. Shin Y.U. Cho H.Y. Lee B.R. Measurement of choroidal thickness in normal eyes using 3D OCT-1000 spectral domain optical coherence tomography.Korean J Ophthalmol. 2012; 26: 255-259Google Scholar The biological and anatomic basis of this thinning is not well understood, although it is accompanied by changes in the levels of protease inhibitors, with increased collagen and decreased ground substance.34Sohn E.H. Khanna A. Tucker B.A. Abràmoff M.D. Stone E.M. Mullins R.F. Structural and biochemical analyses of choroidal thickness in human donor eyes.Invest Ophthalmol Vis Sci. 2014; 55: 1352-1360Google Scholar The relationship between the health of the choriocapillaris and choroidal thickness has not been exhaustively studied. Our goal was to evaluate the relationship between the choriocapillaris, deeper choroidal vasculature, and choroidal thickness in unaffected eyes, eyes with early/intermediate AMD, and eyes clinically diagnosed with geographic atrophy. Morphologic features of the choroid were determined, and the vascular density of the choriocapillaris was decreased in eyes with AMD, and especially in GA, but the ratio of vascular lumen area/choroidal stroma area deeper than the choriocapillaris was not different between GA cases, AMD cases, and controls. Furthermore, the concentration of VEGF-A protein was negatively correlated with the density of the choriocapillaris in eyes without advanced AMD. These findings support the notion that choroidal vascular changes are notable in early AMD with functional consequences on VEGF-A levels that could predispose to advanced wet AMD. Human donor eyes were selected from a large tissue collection of the Institute for Vision Research at the University of Iowa (Iowa City, IA). Eyes in this collection were obtained from the Iowa Lions Eye Bank after informed consent of the donor next of kin, and all experiments were performed in accordance with the Declaration of Helsinki. A total of 143 eyes were used, of which 35 had either a clinical diagnosis of AMD or were determined to have AMD by the histologic feature of confluent basal laminar deposit in the macula,38Sarks S.H. Sarks S.H. Ageing and degeneration in the macular region: a clinico-pathological study.Br J Ophthalmol. 1976; 60: 324-341Google Scholar as determined by one of us (R.F.M.) and 99 were unaffected controls. Eyes with a clinical diagnosis of geographic atrophy but with intact RPE in the studied sections (n = 9) were also included in the study. GA eyes sectioned through regions of RPE loss were excluded, and measurements were collected from within the macula, >500 μm from the central lesion. All samples used in the study were from donors aged 65 years and older. The average ages of donors in this study for controls, AMD, and GA were 80.0, 84.2, and 85.8 years, respectively. Eyes with choroidal neovascularization were not included in this data set, although in several cases the contralateral eyes had neovascular lesions. None of the donors examined in this study overlapped with a smaller, previous morphometric study on choriocapillaris.30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar Either whole or bisected macular punches (8 mm thick), centered on the fovea centralis, were fixed in 4% paraformaldehyde in phosphate-buffered saline for 2 hours, before cryoprotection in sucrose and embedding for cryostat sectioning, as described previously.30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar, 39Barthel L.K. Raymond P.A. Improved method for obtaining 3-microns cryosections for immunocytochemistry.J Histochem Cytochem. 1990; 38: 1383-1388Google Scholar Sections were labeled with biotin-conjugated Ulex europaeus agglutinin-I (UEA-I), which was visualized with avidin–Texas red (both from Vector Laboratories, Burlingame, CA), to detect endothelial cells of the choroid, as described previously.30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar For some experiments, anti-CD45 antibody (BD Biosciences, San Jose, CA) was used in dual labeling, as described previously.30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar One of the advantages of labeling the vasculature with UEA-I, in contrast to hematoxylin-eosin labeling, is that it allows the observer to discriminate between intact vessels lined with endothelial cells and ghost vessels, in which a vascular lumen is present but is not lined with endothelium (Figure 1). Fluorescence micrographs from each donor were collected using a 20× objective and assembled using the photomerge tool in an image processing program (Adobe Photoshop CS version 8.0; Adobe, San Jose, CA). Files were then opened in ImageJ software version 1.52 (NIH, Bethesda, MD; http://imagej.nih.gov/ij),40Abramoff M.D. Magalhães P.J. Ram S.J. Image processing with ImageJ.Biophotonics International. 2004; 11: 36-42Google Scholar and pixels were converted to micrometers. Choriocapillaris vascular density (μm2/μm length of Bruch membrane) was measured, as described previously.30Mullins R.F. Johnson M.N. Faidley E.A. Skeie J.M. Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration.Invest Ophthalmol Vis Sci. 2011; 52: 1606-1612Google Scholar For choroidal thickness, measurements were collected from Bruch membrane to the innermost margin of sclera/outer aspect of the lamina fusca, as assessed by the regular pattern of fibrillar collagen. In addition, the total choroidal area was determined using the polygon tool, and the cross-sectional vascular areas were collected from all UEA-I–surrounded choroidal vessels, as depicted in Figure 2. In all cases, the investigator making the measurements was masked to the affection status of the donor. The unitless lumen/stroma ratio was calculated as the ratio of the nonchoriocapillaris vascular lumen area/the total area. Because three measurements were collected (thickness, choriocapillaris density, and lumen/stroma ratio), a Bonferroni correction factor of 3 was applied (ie, P values were multiplied by 3). In addition, the length of capillary/length of Bruch membrane ratio was measured in randomly selected fields from the 143 maculae used in this study, as described previously,46Ramrattan R.S. van der Schaft T.L. Mooy C.M. de Bruijn W.C. Mulder P.G. de Jong P.T. Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging.Invest Ophthalmol Vis Sci. 1994; 35: 2857-2864Google Scholar except that UEA-I positivity was used to identify choriocapillaris vessels. To measure the levels of VEGF-A, trephine punches (6 mm thick), centered approximately 7 mm superonasal to the fovea, were collected from the neural retina of 14 donors and snap frozen within 8 hours of death. These juxtamacular punches were collected exactly adjacent to measured areas of choriocapillaris. None of the donors had advanced AMD (GA or CNV). Tissues were homogenized with disposable pestles (Sigma, St. Louis, MO) for 90 seconds in phosphate-buffered saline/1% Triton X-100/protease inhibitor cocktail (Roche, Basel, Switzerland) buffer. Protein concentration was determined using the Bradford assay reagents, according to the manufacturer's instructions (BioRad, Hercules, CA). VEGF-A was quantified in 20 μg of retinal protein, analyzed in duplicate, using a human VEGF-A enzyme-linked immunosorbent assay kit, according to the manufacturer's instructions (Ray Biotech, Peachtree Corners, GA). Levels of VEGF-A protein were determined by linear interpolation based on a standard curve of 8.23 to 6000 pg/mL of VEGF-A. Choriocapillaris vascular density was significantly higher in control eyes, compared with early AMD eyes (3.41 versus 2.61 μm2/μm; P = 0.009; Bonferroni-corrected P = 0.027). This difference was especially remarkable when control eyes were compared with GA eyes (1.33 μm2/μm; Bonferroni-corrected P < 10−6) (Figure 3A and Table 1). In addition, GA eyes showed significant choriocapillaris dropout compared with early AMD (Bonferroni-corrected P < 10−5) (Figure 3A). In contrast, the lumen/stroma ratio (Figure 3B) (ie, vascular cross-sectional areas of large and intermediate vessels divided by total choroidal area) did not differ significantly between controls, early AMD, and GA donors (Table 1). Example images of the choriocapillaris in age-matched control, early AMD, and GA eyes are depicted in Figure 4.Table 1Morphometric Features of the Choroid in Donor MaculaeMeasurementControl groupAMD groupGA groupPcorr for control vs AMD groupPcorr for control vs GA groupCC density, means ± SD3.40 ± 1.682.61 ± 1.51.33 ± 0.450.028<10−9Lumen/stroma ratio, means ± SD0.175 ± 0.070.164 ± 0.070.134 ± 0.0510.21Measurement data from controls, early/dry AMD, and GA donor maculae. P values are corrected for multiple measurements.AMD, age-related macular degeneration; CC, choriocapillaris; GA, geographic atrophy; Pcorr, Bonferroni-corrected P value. Open table in a new tab Figure 4Examples of unaffected control (A and E), early age-related macular degeneration (AMD; B and F), and geographic atrophy (GA; C, D, G, and H) maculae labeled with Ulex europaeus agglutinin-I (UEA-I) lectin (red) and anti-CD45 (green; A–D). Corresponding bright-field images are depicted in E through H. Note the loss of UEA-I–positive capillaries over the course of AMD progression. C and D are from the same macula as G and H, whereas C and G are outside of the central atrophic lesion depicted in D and H. Donor ages are 86, 82, and 99 years, respectively. Asterisks indicate drusen. Scale bar = 50 μm. CC, choriocapillaris; CH, outer choroid; RPE, retinal pigment epithelium.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Measurement data from controls, early/dry AMD, and GA donor maculae. P values are corrected for multiple measurements. AMD, age-related macular degeneration; CC, choriocapillaris; GA, geographic atrophy; Pcorr, Bonferroni-corrected P value. Similar results for capillary loss were obtained using the metric of capillary length/total length of Bruch membrane. This metric gave ratios in controls, early AMD, and GA maculae of 53.1%, 41.9%, and 28.2%, respectively. These values were significantly different between early AMD and controls (P < 0.001), GA and controls (P < 10−5), and GA and early AMD (P < 0.01). To determine whether choroidal thinning is related to choriocapillaris dropout, linear regression was performed using the 99 control donor maculae, in which choriocapillaris density and lumen/stroma ratios were analyzed on the basis of choroidal thickness (Figure 5). Data from these analyses show that there is only a weak relationship between choroidal thickness compared with choriocapillaris density (r2 = 0.01) and outer choroid lumen/stroma ratio (r2 = 0.04). Plots for total choroidal area versus vascular lumen area in controls, early AMD eyes, and GA eyes are depicted in Supplemental Figure S1. Relationships between choroidal thickness and vascular parameters for controls, early AMD, and GA maculae are depicted in Supplemental Figure S2. To determine whether vascular loss contributes to retinal hypoxia, the amount of VEGF-A present in the neural retina of 14 eyes was determined. Levels of VEGF-A ranged from 38.5 to 442.3 pg/mL. Regression analysis showed that vascular density was inversely related to VEGF-A levels (P = 0.015). In other words, retinas overlying atrophic choroids showed higher expression of VEGF-" @default.
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• W2942553901 title "Choriocapillaris Degeneration in Geographic Atrophy" @default.
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