Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

PURPOSE: Our previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC. METHODS: The 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians' discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term. RESULTS: The median follow-up was 60 months (range, 48-68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 µm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC. CONCLUSION: No complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.

VOLUME-RENDERED ANGIOGRAPHIC AND STRUCTURAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To evaluate multimodal imaging including volume-rendered angiographic and structural optical coherence tomography of macular telangiectasia Type 2 (MacTel2) for right-angle vein complexes, macular cavitations, and signs of deeper retinal vascular invasion. METHODS: Retrospective review of imaging performed in a community-based retinal referral center. The eyes were scanned using optical coherence tomography using split-spectrum amplitude-decorrelation techniques to derive flow information. These data were extracted and used to create volume-rendered images of the retinal vasculature with integrated structural information derived from the component optical coherence tomographic images. RESULTS: There were 24 eyes of 16 patients who had a mean age of 61.8 years. Right-angle veins seemed in association with vascular proliferation external to the deep vascular plexus. The origin of a right-angle vein was surrounded by a stellate arrangement of radiating retinal vessels apparently caused by contraction of surrounding tissue in the temporal macula. Cavitations were found in the fovea and varied in size and configuration from one examination to the next. Many smaller cavitations, called microcavitations, were seen in the surrounding macula. Vascular invasion occurred into the subretinal space. CONCLUSION: There are contractile features of the tissue in the temporal macula and the number, size, and temporal variations in the cavitations have not been in not mentioned in previous published descriptions of MacTel2. Vascular invasion of deeper layers occurred in the temporal macula through the outer nuclear layer. Volume-rendered angiographic and structural optical coherence tomography offers unprecedented ability to examine the vascular interrelationships their associations with cavitations in the macula.

Fecal Lipid Excretion after Consumption of a Black Tea Polyphenol Containing Beverage-Randomized, Placebo-Controlled, Double-Blind, Crossover Study.

Obesity is a serious medical condition worldwide. Inhibition of lipid absorption is very important in preventing obesity. In a previous study, we found that postprandial elevation of triacylglycerol was suppressed by the intake of black tea polyphenol (BTP). We also reported that BTP caused lipid excretion into feces in an animal study. The present study is a clinical trial that examined lipid excretion. In this randomized, placebo-controlled, double-blind, crossover study, in the first test period participants were asked to drink either a beverage containing 55 mg BTP or a control beverage without BTP 3 times a day for 10 d. After an 11-d interval, for the second test period, they then drank the alternate test beverage 3 times a day for 10 d. During the test periods, the participants were asked to eat meals standardized according to calorie and fat content. Stool samples were obtained during the last 3 d of each test period for fecal lipid measurements. Total lipid excretion increased from 5.51±1.73 to 6.87±1.91 g/3 d after BTP intake in comparison with intake of the control beverage. These results indicated that BTP increased lipid excretion.

Volume-Rendering Optical Coherence Tomography Angiography of Macular Telangiectasia Type 2.

PURPOSE: To evaluate the vascular structure of eyes with macular telangiectasia type 2 (MacTel2) using volume-rendered optical coherence tomography angiography (OCTA). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 14 consecutive patients (20 eyes) with MacTel2 who had a signal strength score ≥55 and could maintain fixation during the scan process. METHODS: The eyes were scanned using optical coherence tomography with split-spectrum amplitude decorrelation techniques to derive flow information. Data were extracted and used to create volume-rendered images of the retinal vasculature that could be rotated about 3 different axes for evaluation. MAIN OUTCOME MEASURES: Descriptive appraisal of the vascular abnormalities associated with MacTel2. RESULTS: Vessels posterior to the outer boundary of the deep retinal plexus were secondary to retinal thinning, vascular invasion, or a combination of both. These vessels had the same shape and distribution as the late staining seen during conventional fluorescein angiography. Lateral contraction in the temporal macula in 5 eyes created an appearance of vessels radiating from a central locus, which was the site of a right angle vein. Loss of macular tissue as part of the disease process led to a central amalgamation of the inner vascular plexus and the deep vascular plexus, which appeared to be in a state of decline. Subretinal neovascularization originated from the retinal circulation but involved not only the subretinal space but also could infiltrate the remaining, thinned, retina. CONCLUSIONS: Volume rendering of OCTA information preserves the 3-dimensional relationships among retinal vascular layers and provides opportunities to visualize retinal vascular abnormalities in unprecedented detail. The retinal vascular leakage and invasion in MacTel2 may arise as a consequence of loss of control with depletion of Müller cells and exposure of the remaining retinal vessels to the more hypoxic environment near the inner segments of the photoreceptors.

MULTIMODAL IMAGING FINDINGS AND MULTIMODAL VISION TESTING IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the interactions among multimodal imaging findings and multimodal vision testing in neovascular age-related macular degeneration. METHODS: Patients enrolled in a prospective study of neovascular age-related macular degeneration with at least 3 previous intravitreal anti-vascular endothelial growth factor injections. Each patient underwent multimodal fundus imaging including spectral domain optical coherence tomography and fundus autofluorescence, and multimodal vision testing, including visual acuity, contrast sensitivity, reading speed, and microperimetry. RESULTS: There were 73 eyes of 49 consecutive patients enrolled. Generalized estimating equations' modelling showed that the significant independent predictors of visual acuity were the area of confluent hypoautofluorescence and involvement of the foveal center with either granular or confluent hypoautofluorescence (P < 0.001). Contrast sensitivity was negatively correlated with the area of confluent hypoautofluorescence (P < 0.001), involvement of the foveal center with granular hypoautofluorescence (P = 0.017), and subfoveal choroidal thickness (P = 0.042). The only significant predictor of reading speed was the size of confluent hypoautofluorescence (P < 0.001). The size of the defect in the ellipsoid zone (P < 0.001) and the presence of intraretinal fluid (P = 0.045) were correlated with microperimetry score. CONCLUSION: Confluent absence of autofluorescence was a highly significant predictor of vision testing and serves as an easy parameter to obtain in patients with neovascular age-related macular degeneration.

Colocalization error between the scanning laser ophthalmoscope infrared reflectance and optical coherence tomography images of the heidelberg spectralis.

PURPOSE: To examine the colocalization error between the infrared reflectance (IR) scanning laser ophthalmoscope (SLO) and spectral domain optical coherence tomography (SD-OCT) images of the Heidelberg Spectralis. METHODS: The IR and corresponding horizontal raster SD-OCT images were compared in 10 healthy volunteers examined with 3 Heidelberg Spectralis + OCT instruments. The center points of retinal vessels selected by random uniform sampling in scanning laser ophthalmoscope-IR images were compared with colocalizing points in corresponding SD-OCT images by two masked readers. The error of colocalization was measured in the SD-OCT image. The point positions were recorded using Cartesian coordinates measured in microns. The error of colocalization was evaluated using a fixed-effects generalized least squares regression model with location and instrument as predictor variables. RESULTS: A total of 1,617 points in the IR and SD-OCT images were analyzed, and the mean error of colocalization was 42.2 ± 32.4 µm. The Heidelberg Spectralis instrument used was not a significant predictor of colocalization error (P = 0.15). The colocalization errors were negatively correlated with x-coordinate position (P < 0.001). CONCLUSION: There is a mean colocalization error between the IR and SD-OCT images produced by the Heidelberg Spectralis that is on the scale of many features being evaluated in the fundus. The variability in these measurements means the confidence interval for the exact colocalization is much larger. Because of the magnitude and variability of the error, the colocalization feature of the Heidelberg Spectralis should be used as a rough guide, not an absolute determinant.

MULTIMODAL VISUAL FUNCTION TESTING IN EYES WITH NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the interactions among drusen type and multimodal vision testing in eyes with nonexudative age-related macular degeneration. METHODS: Fifty-one eyes of 39 patients with nonexudative age-related macular degeneration underwent fundus imaging including spectral domain optical coherence tomography, color fundus photograph, and autofluorescence imaging, each of which was graded by 2 masked readers. Multimodal vision testing included visual acuity using the Early Treatment Diabetic Retinopathy Study protocol refraction, contrast sensitivity, and microperimetry. RESULTS: Generalized estimating equation modeling showed that the significant predictors of contrast sensitivity was the presence of pseudodrusen (P = 0.012) and refractive error (P = 0.028). The presence of pseudodrusen inversely correlated with contrast sensitivity. The significant predictors of parafoveal microperimetry score were area of confluent hypoautofluorescence (P = 0.026) and the presence of pseudodrusen (P = 0.027). Both of them showed an inverse correlation with microperimetry score. The only significant predictor of macular microperimetry score was the presence of pseudodrusen (P = 0.004), which showed an inverse correlation with microperimetry score. CONCLUSION: The analysis of predictors of the visual function highlights the importance of pseudodrusen. Pseudodrusen are not only the risk factor of late age-related macular degeneration but also affect visual function. Recognition of this problem is important for low-vision rehabilitation and therapeutic strategies for late age-related macular degeneration.

REFRACTILE DRUSEN: Clinical Imaging and Candidate Histology.

PURPOSE: To evaluate eyes with refractile drusen using clinical imaging and to identify candidate histologic correlates of refractile drusen. METHODS: Refractile drusen were defined as drusenoid material containing small refractile spherules. Retrospective analysis of color, autofluorescence, and spectral domain optical coherence tomography images of eyes with refractile drusen was performed to characterize the morphology and topography of these lesions. Macular sections from donor eyes were processed with a von Kossa stain for calcium phosphate and viewed by light microscopy. Punches of retinal pigment epithelium-choroid from donors with geographic atrophy were prepared for transmission electron microscopy. RESULTS: Fundus findings of 14 eyes of 10 patients with age-related macular degeneration (age, 82.9 ± 5.6 years) were evaluated. A generalized loss of autofluorescence signal over refractile drusen appeared to spread over a larger area than each druse, for drusen located centrally. By color fundus photography, refractile drusen showed corresponding depigmentation around drusen that were located in the center of the macula. Optical coherence tomography imaging of refractile drusen showed hyperreflective dots. In the histologic specimens, drusen contained many small spherules rich in calcium phosphate. Ultrastructural examination of the spherules showed complex assemblies consisting of concentric shells containing thin layers of calcium. CONCLUSION: Refractile drusen appear to be a stage of drusen regression marked by loss of retinal pigment epithelium, thus contributing to the development of geographic atrophy. Calcium-containing spherules appear to account for the glistening appearance.

Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.

Characteristics of central serous chorioretinopathy complicated by focal choroidal excavation.

PURPOSE: To investigate the characteristics of central serous chorioretinopathy complicated by focal choroidal excavation (FCE) using fundus angiography and optical coherence tomography (OCT). METHODS: A retrospective single-institution study. We reviewed the charts of 7 eyes of 7 patients (5 men, 2 women; mean age, 56.9 ± 9.8 years) with central serous chorioretinopathy complicated by FCE using fundus angiography and OCT. RESULTS: In six of the seven eyes, the points of leakage were at the edge of FCE on OCT. All FCE lesions were hypofluorescent from early to late phase on indocyanine green angiography. All eyes had late-phase hyperfluorescence on indocyanine green angiography secondary to choroidal vascular hyperpermeability around the FCE lesion. Five fellow eyes also had choroidal vascular hyperpermeability. The mean subfoveal choroidal thicknesses by swept source high-penetration OCT were 377 µm and 333 µm in the fellow eyes, a difference that did not reach significance (P = 0.21). CONCLUSION: Fundus angiography and OCT showed that choroidal circulatory disruption and atrophic retinal pigment epithelium at the FCE lesion might be related to central serous chorioretinopathy complicated by FCE.

Changes in fundus autofluorescence in polypoidal choroidal vasculopathy during 3 years of follow-up.

PURPOSE: To investigate changes in fundus autofluorescence (FAF) during 3 years of follow-up in patients with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective study. METHODS: We retrospectively reviewed the charts of 48 eyes of 47 patients (35 men, 12 women; mean age, 69.9 ± 7.1 years) with treatment-naïve PCV for whom FAF and indocyanine green angiography (ICGA) images were available at baseline and at 3 years ± 3 months follow-up examination. The main outcome measures were the FAF changes during 3 years of follow-up, and the correlation between them and polypoidal lesions and branching vascular networks on ICGA. RESULTS: The FAF of the polypoidal lesions showed three patterns at baseline and changes during 3 years of follow-up: confluent hypoautofluorescence surrounded by a hyperautofluorescent ring (86.1% → 51.4%), confluent hypoautofluorescence without a ring (8.3% → 43.0%), and no marked changes (5.6% → 5.6%). The FAF in 96.2% of resolved polypoidal lesions persisted on images with abnormal FAF during the 3 years of follow-up. The granular hypoautofluorescence at the branching vascular networks at baseline became partially confluent hypoautofluorescence in 41 eyes (85.4%). The mean area with confluent hypoautofluorescence that corresponded to the branching vascular network lesions increased significantly (P < 0.001) from 1.75 mm(2) to 5.10 mm(2) after 3 years of follow-up. CONCLUSION: The FAF changes in PCV during the 3 years of follow-up can indicate that FAF imaging is a useful and clinically beneficial tool for noninvasively evaluating the PCV lesions and disorders of the upper retinal pigment epithelium.

Comparison of macular pigment in three types of macular telangiectasia.

PURPOSE: To compare macular pigment in three types of macular telangiectasia (MacTel). METHODS: Twenty-six eyes of 16 patients (mean age, 62 years) with MacTel were examined. The macular pigment optical density (MPOD) was obtained by autofluorescence spectrometry using two wavelengths (488 nm, 514 nm). The density of the central macular pigment within 0.5 degree around the foveal center (MPODc) was measured from a MPOD map. RESULTS: Eight eyes of seven patients were classified as type 1, 16 eyes of eight patients as type 2, and two eyes of one patient as type 3. The macular pigment signal was seen in the area of fluorescein leakage in type 1 and the occlusive area in type 3; the macular pigment signal decreased in the area of fluorescein leakage in type 2. The mean MPODc (± standard deviation) was 0.40 ± 0.16 density unit (DU) (range, 0.17-0.57) in type 1; -0.08 ± 0.15 DU (range, -0.29-0.25) in type 2; and 0.32 ± 0.08 DU (range, 0.26-0.37) in type 3. Significant differences were seen between types 1 and 2 (P < 0.001) and types 2 and 3 (P = 0.007). There was no significant difference between types 1 and 3 (P = 0.765). In 30 age-matched normal eyes, the MPODc was 0.58 ± 0.11 DU (range, 0.38-0.79). There were significant differences between normal eyes and each MacTel subtype (type 1, P = 0.007; type 2, P < 0.001; type 3, P = 0.043). CONCLUSIONS: The macular pigment values and distributions, including leakage or occlusion, differed in each MacTel type compared with fluorescein angiography findings. The capillary occlusion in type 3 is not associated with reduced MPOD.

Usefulness of indocyanine green angiography to depict the distant retinal vascular anomalies associated with branch retinal vein occlusion causing serous macular detachment.

PURPOSE: To report the usefulness of indocyanine green angiography (ICGA) to depict the retinal vascular anomalies associated with distant branch retinal vein occlusion resulting in serous retinal detachment at the macula. METHODS: This was a retrospective, case series of 6 patients (6 eyes) with serous retinal detachments. Fluorescein angiography and ICGA showed that those 6 eyes had a distant branch retinal vein occlusion. The characteristics in ophthalmic examinations such as fundus appearance, fluorescein angiography, ICGA, optical coherence tomography, and clinical courses were evaluated. RESULTS: In addition to serous retinal detachments, five eyes exhibited hard exudates around the macula. Fluorescein angiography and ICGA clearly showed the vessel occlusion; however, no apparent abnormalities appeared in the macular area in any of the eyes. In four eyes, early-phase ICGA depicted the retinal vascular anomalies within the area of venous occlusion and those were seen as hyperfluorescent patches on late-phase ICGA. In two eyes, punctate hyperfluorescent spots were seen in the area of venous occlusion on late-phase ICGA. Optical coherence tomography depicted a serous retinal detachment at the macula and retinal swelling in the outer nuclear layer from the macula to the hyperfluorescent abnormalities on ICGA. The macular serous retinal detachments were resolved within 3 months after laser photocoagulation was applied to the hyperfluorescent areas on ICGA. CONCLUSION: Leakage from subsequent vascular anomalies after branch retinal vein occlusion can cause submacular fluid. Indocyanine green angiography is useful for detecting the causative vascular regions of the fluid.

Definitive engagement of cytotoxic CD8 T cells in C protein-induced myositis, a murine model of polymyositis.

OBJECTIVE: To substantiate a pathogenic role of cytotoxic CD8 T cells in the development of a murine polymyositis model, C protein-induced myositis (CIM). METHODS: Beta(2)-microglobulin-null mutant, perforin-null mutant, and wild-type (WT) C57BL/6 mice were immunized with skeletal muscle C protein fragments to provoke CIM. Regional lymph node CD8 or CD4 T cells stimulated with C protein-pulsed dendritic cells were transferred adoptively to naive mice. Inflammation and damage of the muscle tissues were evaluated histologically. RESULTS: The incidence of myositis development was significantly lower in ß2-microglobulin-null and perforin-null mutant mice compared with WT mice. Inflammation was less severe in mutant mice, and the incidence of muscle injury was reduced significantly. Adoptive transfer of lymph node T cells from mice with CIM induced myositis in naive recipient mice. The CD8 T cell-induced muscle injuries were significantly more severe than the CD4 T cell-induced muscle injuries. CONCLUSION: Perforin-mediated cytotoxicity by CD8 T cells is definitively responsible for muscle injury in CIM.

Safety threshold of intravitreal activated protein-C.

PURPOSE: Although activated protein C (APC) is effective in preventing the death of retinal neurons in ischemic retinopathy, it is not known at what concentrations it becomes retinotoxic. The purpose of this study was to determine the concentrations of intravitreal APC that are safe and those that are toxic for the retina, using rabbit eyes. METHODS: The left eyes of 12 rabbits received an intravitreal injection of 1.5 to 150 µg of APC in 0.1 ml of saline. The fellow eyes were treated with an intravitreal injection of the same amount of saline. Slit-lamp examination, fundus examination, fluorescein angiography (FA), and electroretinograms (ERGs) were performed before and at different times after the injection. The eyes were enucleated at 6 months after the injection and examined histologically. RESULTS: The clinical and histological differences between the control eyes and the eyes that had APC injections up to 15 µg were not significant. Localized retinal edema was observed in two of three eyes with 150 µg of APC immediately after the injection. In these two eyes, chorioretinal atrophy was observed in the area of the retinal edema at 6 months, which corresponded with a hyperfluorescent area in the FA images and focal retinal degeneration histologically. No significant changes were detected in the full-field ERGs in the eyes treated even with 150 µg of APC throughout the observation period. CONCLUSION: Our results show that an intravitreal injection of APC at a dose ≤15 µg is safe, but 150 µg of APC can be toxic to the retina.

[Prognosis for branch retinal vein occlusion].

PURPOSE: To evaluate the visual outcomes of various kinds of treatment for branch retinal vein occlusion (BRVO). METHODS: The medical records of 222 BRVO eyes without any previous treatment were reviewed. One-year visual acuity (VA) and 1-year visual gains (VG) were analyzed for each treatment. RESULTS: The one-year VA correlated with the initial VA and 1-year VG negatively correlated with the initial VA. The initial and 1-year VA of the observation group (17.6%) were 0.6 and 0.8, respectively. No difference in the 1-year VA was found among the various treatments and the average 1-year VG was 1.1 lines. The one-year VA of the single treatment group (36.0%) was 0.62 on average, without any difference between the various treatments, while only the PPV group had better 1-year VG (4.4 lines). The multiple treatment group (46.4%)showed worse initial VA (0.33), 1-year VA (0.39) and 1-year VG (0.7 line). CONCLUSIONS: Patients with better initial VA can be observed without any treatment. As a whole, the 1-year VG is about one line and some significant visual improvement can be expected regardless of the treatments. The PPV group showed larger visual gain for eyes with worse initial visual acuity. Approximately half of the patients could not achieve any improvement by a single treatment and had a poor visual prognosis.

Bubble cascade may form not only in stout beers.

In a glass of stout beer, a very large number of small dispersed bubbles form a texture motion of a bubble swarm moving downwards. Such a cascading motion is caused by a gravity-driven hydrodynamic instability and depends on the interbubble distance. To estimate these two corresponding indicators, an experimentally measured velocity profile is required and, thus, is obtained a posteriori. However, it is unknown why the bubble cascade is observed only in stout beer with nitrogen, such as Guinness beer. To address this question via a priori estimation, here, we develop a mathematical continuum model of film flow in bubbly liquid, uncovering the essential dynamics among many physical processes occurring simultaneously in a glass. To validate the proposed model, we perform a numerical simulation of the distribution of massless Lagrangian particles in an inclined container. We investigate the effects of particle concentration, inclination angle, particle diameter, and container size on the cascading film flow. The results reveal that the motion and waviness of clear-fluid film can be successfully estimated a priori to experiments or simulations. Moreover, it is found that the continuum behavior of particles in the film flow is analogous to the continuum description of rarefied gas dynamics. These findings explain how the cascading bubbles in a pint glass of stout beer satisfy the continuum assumption and suggest a general condition for the onset of the cascade, for instance, a 200-l drum for carbonated water.

Activated Protein C for Ischemic Central Retinal Vein Occlusion: One-Year Results.

Intravitreally administered activated protein C in 10 eyes with ischemic central retinal vein occlusion significantly improved macular edema; in 5 eyes, the reperfusion of the retinal nonperfused areas exceeded 50% of baseline.

Scavenger receptors for oxidized lipoprotein in age-related macular degeneration.

PURPOSE: The accumulation of macrophages is known to be involved in the pathogenesis of age-related macular degeneration (AMD), but the reasons why macrophages accumulate in AMD lesions have not been determined. Because the histopathology of AMD has some factors common with those of atherosclerosis, the authors hypothesized that macrophages accumulate to take up oxidized lipoproteins in the eyes of patients with AMD, as has been demonstrated in atherosclerosis. METHODS: Immunohistochemistry was performed on 10 surgically excised choroidal neovascular (CNV) membranes from eyes with AMD. An antibody against oxidized lipoprotein and antibodies against the scavenger receptors SR-PSOX and LOX-1 were used. Antibodies against cytokeratin, CD68, and von Willebrand factor were used to identify retinal pigment epithelium (RPE), macrophages, and vascular endothelial cells, respectively. RT-PCR was performed to detect the mRNAs of the scavenger receptors in the CNV membranes. RESULTS: Oxidized lipoproteins were immunohistochemically detected in the CNV membranes. Intense immunostaining was observed at the surface of the CNV membranes with the SR-PSOX antibody, whereas LOX-1 immunostaining was weak. Cells expressing scavenger receptors were found to be predominantly macrophages with a minority of RPE. Both SR-PSOX and LOX-1 mRNAs were detected in CNV membranes. CONCLUSIONS: Oxidized lipoproteins are present in AMD lesions. Macrophages and RPE in the CNV membranes express cell surface scavenger receptors for oxidized lipoproteins. These findings suggest that macrophages may accumulate to take up oxidized lipoproteins in AMD and that the control of oxidative stress and macrophage responses may therefore be potential treatments for AMD.

Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration.

PURPOSE: There is good evidence that oxidative stress is involved in the pathogenesis of age-related macular degeneration (AMD). Because AMD has risk factors and histopathology similar to with atherosclerosis, we hypothesized that oxidized phospholipids, which contribute to the pathogenesis of atherosclerosis, would accumulate in the eyes of AMD patients. To test this hypothesis, we investigated whether oxidized phospholipids were present in normal eyes and whether the level changed with increasing age. We then, we determined whether the levels of oxidized phospholipids were higher in eyes with AMD. METHODS: Twenty normal human donor eyes and six eyes with AMD were studied. Immunohistochemistry was performed on a tissue strip from the macular region using an antibody against oxidized phosphatidylcholine. Western blot analysis was also performed on proteins extracted from the posterior retina of donor eyes. The immunoreactivity of the specimens and the bands were quantified with NIH image software. RESULTS: Immunohistochemistry showed oxidized phosphatidylcholine was present in the photoreceptors and retinal pigment epithelium of the normal human macular area, and their levels increased with age. Eyes with AMD showed more intense immunoreactivity for oxidized phospholipids than age-matched normal eyes. CONCLUSIONS: These findings suggest that oxidative stress is involved in the pathogenesis of AMD possibly by oxidizing phospholipids in the photoreceptors as demonstrated in the arterial intima of patients with atherosclerosis. It is likely that controlling oxidation of phospholipids may be a potential treatment for AMD.