Changes In Age-related Macular Degeneration Research Articles

Retinal Nerve Fiber Layer Thickness Changes in Age-Related Macular Degeneration Treated with Multiple Intravitreal Ranibizumab.

The objective of this study was to investigate the effect of multiple intravitreal ranibizumab (IVR) injections on the retinal nerve fiber layer (RNFL) in neovascular age-related macular degeneration (nAMD). One hundred sixty-eight eyes of 168 patients with nAMD who received an IVR at least 3 times were included in this prospective interventional case series. The RNFL thickness data on 80 healthy eyes, used as the control group, were obtained. The patients were grouped as follows: 3-10 injections (group 1, 62 eyes, 37%), 10-20 injections (group 2, 62 eyes, 37%), and ≥20 injections (group 3, 44 eyes, 26%). The RNFL thickness was measured by spectral domain optical coherence tomography. The mean baseline measurement of the RNFL thickness was 97.4 ± 6.4 μm in the control group, 96.4 ± 5.6 μm in group 1, 93.8 ± 4.6 μm in group 2, and 93.2 ± 5.3 μm in group 3. At the last follow-up, it was 95.1 ± 2.4 μm in the control group, 93.4 ± 7.3 μm in group 1, 90.5 ± 3.6 μm in group 2, and 89.2 ± 4.9 μm in group 3 (all P values >0.050). A statistically significant difference was not found between the mean total RNFL thickness of the eyes that received injections and that of the eyes in the healthy control group (P value >0.050). A statistically significant difference was not found in all the treatment groups between the intraocular pressure level taken 1 day after the administration of the injections and that recorded preintervention (all P values >0.050). Repeated IVR did not lead to a significant change in RNFL thickness in patients with nAMD.

A novel three-dimensional trilayer for studying early changes in age-related macular degeneration

Event Abstract Back to Event A novel three-dimensional trilayer for studying early changes in age-related macular degeneration Ali Shokoohmand1, 2, June E. Jeon1, Christina Theodoropoulos1, Dietmar W. Hutmacher1, 2, 3, 4 and Beatrix Feigl1, 5 1 Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation, Australia 2 QUT, Australian Prostate Cancer Research Centre – Queensland, Australia 3 Technical University of Munich (TUM), Institute for Advanced Study, Germany 4 Georgia Institute of Technology, George W Woodruff School of Mechanical Engineering, United States 5 Queensland Eye Institute, Australia Introduction: The understanding of the pathomechanisms of age-related macular degeneration (AMD) remains a challenge. Typical features of the disease such as drusen and the role of growth factors have been extensively studied[1]-[3], but it remains unclear what causes drusen formation and a growth factor imbalance. Research is directed towards animal models[4] and more recently towards stem cell based therapies which are still in their infancy[5]. Monolayer culture is a widely used alternative to animal studies, but is limited by the relative lack of sophistication when compared to the human retina, since the pathogenesis of AMD involves complex interplay between the retinal pigment epithelium (RPE), Bruch’s membrane and the choroid. It is becoming apparent that 3D culture systems are better suited for complex disease models to allow the study of cellular crosstalk within the microenvironment with advanced co-culture system[6]. Therefore, this study aimed at developing a novel humanized trilayer culture model by culturing human fetal RPE and primate choroidal cells on electrospun medical-grade polycaprolactone (PCL)-gelatin meshes to study the initial changes in AMD. Materials and Methods: Electrospun PCL-gelatin meshes were made by a custom solution electrospinning apparatus as described previously[7] (Figure 1). The overall architecture of the scaffolds, including the porosity and the surface area-to-volume ratio, was analyzed using the nano-computed tomography (nano-CT) system using a resolution of 1 µm, a voltage of 45 kVp and a current of 177 mA (n=4). The porous nature of the scaffold was an important consideration in studying the effect of co-culture and the possible crosstalk between the RPEs and the choroidal cells. The trilayer model was prepared by seeding the primate choroid endothelial cell line (RF/6A) on the bottom surface of the PCL-gelatin scaffold coated with human recombinant laminin followed by seeding human RPE cells on the top surface of the scaffold[8] (ratio 1:1; 104 cells/cm2), mimicking the retina in vivo microenvironment. Results and Discussion: Scanning electron microscopy images confirmed that PCL-gelatin electrospun scaffolds allowed excellent cell attachment and infiltration (Figure 2). Functional and morphological analysis of the human RPE cells showed that they were able to phagocytose vitronectin-coated microbeads and that they formed microvilli (Figure 2B). The quantitative analysis of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), factors critical in pathophysiological condition of AMD, indicated significant increases in production of both VEGF and PEDF in RPE/choroidal co-cultures compared to mono-cultures. Our findings indicate the functionality of the current model and provide a strong argument into the advantages of using a 3D trilayer in vitro culture model to study early changes involving the shift in the PEDF/VEGF equilibrium that occurs in AMD. Conclusion: In summary, we provide the initial evidence that a three dimensional in vitro model can be fabricated to exhibit functional characteristics typical for human RPE and choroidal cells. We believe that this novel bioengineered 3D construct can provide a platform for further studies in the pathomechanisms of AMD. This study was funded by National Health and Medical Research Council (NHMRC).

Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion.

Choroidal neovascularization is one of the major pathological changes in age-related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser-induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration.

IAP textbook of vaccines

This book is a collection of 15 chapters exploring the applications of stem cell therapy for the treatment of blinding retinal degenerative diseases. Age-related macular degeneration (ARMD) is the most important cause of vision loss in people over 55 years of age all over the world. The initial few chapters highlight the diseases where degeneration of photoreceptors leads to vision loss, followed by the potential uses of stem cells, their production and delivery while the regulatory issues in cell-based therapy are dealt with in the last chapter. The book begins with a comprehensive review of ARMD including epidemiology, clinical features, histopathology and pathogenesis supported with appropriate illustrations. This chapter also includes the latest imaging modalities (adaptive optics scanning laser ophthalmoscopy, near infrared reflectance, etc) with the objective to pick up early ARMD changes. The next chapter on general pathophysiology of retinal degeneration briefly recapitulates the phototransduction cascade and highlights how the destruction of photoreceptors appears to be the final common pathway in a number of degenerative diseases and may thus be targeted for therapeutic purposes. The third chapter introduces juvenile-onset macular degenerative disorders causing central vision loss and discusses their clinical features, inheritance pattern, basic pathology and diagnostic modalities [electroretinogram, electrooculogram, optical coherence tomography (OCT) and fundus autofluorescence] which help clinch their diagnosis. The fifth chapter familiarizes the readers with various stem cells for retinal repair. Stem cells for retinal repair may be derived from pluripotent or retinal pigment epithelium stem cells (RPESCs) which can replace damaged retina and provide trophic support. Alternatively, bone marrow or neural stem cells may also be used, but these only provide trophic support. Other than these, there are also the induced pluripotent stem cells (iPSCs) and the umbilical cord stem cells (UCSCs). This chapter ends with the mention of ongoing phase 2 trial for subretinal injection of UCSCs (www.clinicaltrials.gov No. {"type":"clinical-trial","attrs":{"text":"NCT00458575","term_id":"NCT00458575"}}NCT00458575), however, this study has been terminated. For optimal cell-based ARMD therapy a number of issues need to be addressed like cell survival in vivo, optimal stage of disease for intervention, safe and simple surgical techniques and identification of sources of cells for transplantation. The question raised in the sixth chapter is which source of RPE-like cells is better, iPSCs or human embryonic stem cells (hESCs)? The next question yet unanswered is regarding the mode of transplantation, bolus injection of dissociated RPE cells into subretinal space versus RPE monolayer transplantation. The seventh chapter introduces various ever-changing protocols for generation of RPE cells and photoreceptor (PR)-like cells from iPSCs and hESCs, for example, using stem cells for glaucoma is thought to have a neuroprotective and neuroregenerative role. Another thought is using skin biopsy to reprogramme cells to iPSCs and then differentiate them to retinal ganglion cells (RGCs) that can be used for drug screening for optimum individualized treatment. However, there is no protocol for effective RGC production. Both iPSC and ESC derived cells are immunoreactive after implantations thus need immunosuppression. The reprogramming itself leads to epigenetic effects in the resultant iPSCs rendering them immunogenic. To overcome rejection certain suggested methods are discussed in chapter nine. The tenth chapter deals with the question of RPE-like stem cell survival post-transplantation. It is known that less than one per cent of stem cells injected in the subretinal space eventually survive after 2-4 wk of transplantation due to shearing forces during injection and reflux of cells from injection site. The next chapter brings in the latest in scaffold delivery strategy. Various scaffold substrates can be used to grow RPE monolayer including natural biomaterials like amniotic membrane, lens capsule, explants of Bruch's membrane, etc. or natural polymers like extracellular matrix protein or synthetic polymers, for example, parylene, PLGA [poly(lactic-co-glycolic acid)], hydrogels, etc. The next chapter is dedicated to the use of an ingenious micromachined parylene-C device as an artificial Bruch's membrane for stem cell therapy. The chapter on gene or cell therapy talks about ex vivo gene correction followed by transplantation, which would reduce the risk of immune rejection via autologous cell therapy. However, it would also increase the mutational load of iPSCs. In the end there is mention of encapsulated cell technology for protein therapy thus delivering consistent levels of neurotrophic factors for longer periods and avoiding repeated injections. The book ends with a look into the cellular manufacturing process which ensures safety of the product that is to be administered. This book compiles the latest in stem cell research and the reader will find an introduction to all there is to know about cell therapy. Researchers as well as ophthalmologists will find reading this book an informative experience. The book can be a useful primer for beginners and also serve as a reference guide to investigators in this area as it gives a comprehensive updated review of cell-based therapy for retinal degenerative disorders in all age groups.

Combined Nonmydriatic Spectral-Domain Optical Coherence Tomography and Nonmydriatic Fundus Photography for the Detection of Age-Related Macular Degeneration Changes.

Nonmydriatic fundus photography (FP) has been a suboptimal tool for detecting age-related macular degeneration (AMD) changes. This study sought to enhance the detection of AMD changes by combining nonmydriatic FP with nonmydriatic spectral-domain optical coherence tomography (SD-OCT). The study population included 249 patients aged 65 years and older who were assessed for AMD changes using standard mydriatic biomicroscopic fundus examination. Each eye then underwent nonmydriatic FP in one session followed 1 week later with nonmydriatic FP coupled with nonmydriatic SD-OCT. Images were interpreted for detection of AMD changes, and findings were compared to the original mydriatic biomicroscopic examination. Nonmydriatic FP had 64% sensitivity, 97% specificity, and a kappa value of 0.67 in detecting AMD changes compared with the traditional mydriatic biomicroscopic examination. Combined nonmydriatic FP and nonmydriatic SD-OCT increased sensitivity to 91.5%, specificity to 98.6%, and kappa to 0.91. The addition of nonmydriatic SD-OCT to nonmydriatic FP enhances the detection of AMD changes.

Projected changes in age-related macular degeneration and driving license holders in Finland.

PurposeThe aim of the study was to approximate the occurrence of all forms of age-related macular degeneration (AMD) of the retina among the driving license holders aged 80 or more, and to project the changes to 2030 in Finland. AMD, destroying the visual cells in the central part of the retina, is a common disease of older age: one out of three individuals aged 70 or older shows early signs of AMD progressing later to relentless loss of vision. This eye disease can be detected only by an ophthalmologist. In general, little is known about the prevalence of AMD among driving license holders aged 80 or older.MethodsAt first the prevalence of individuals with either drusen or AMD in Finland among those 80 or older was approximated. Then the number of license holders in this age group was extracted from the statistics of the Finnish Transport Safety Agency and Eurostat provided us with the demographical data. The changes were projected to 2030.ResultsIn Finland, with a population of 5.35 million, the number of those aged 80 or over will increase by 175,000 by 2030. The total number of individuals with either drusen or AMD will increase from 118,000 to 193,000 by the year 2030 and an increasing proportion of them will have a driving license. The proportion of women in 2012 having a driving license in the groups 60 or younger is about 45%, while in those aged 80 or older it is only 20%.ConclusionThe number of people aged 80 years or older will increase in Finland by 2030. The number of those in this age group having a driving license will increase more rapidly as the population ages because the proportion of women with a driving license will increase in this age group. As the prevalence of drusen and AMD among women aged 80 or over is higher than among men at comparable age, this means that AMD will increase even more rapidly among drivers in this age group.

Comparison of spectral-domain and high-penetration OCT for observing morphologic changes in age-related macular degeneration and polypoidal choroidal vasculopathy

We compared the visibility of retinal and choroidal pathologies using high-penetration optical coherence tomography (HP-OCT) with a long-wavelength light source (1,050nm) and conventional spectral-domain OCT (SD-OCT) in age-related macular degeneration (AMD). One hundred and forty-six eyes were included: 63 eyes with AMD, 79 eyes with polypoidal choroidal vasculopathy (PCV), and four eyes with retinal angiomatous proliferation. The SD-OCT and HP-OCT images were compared using the grading criteria to grade the visibility of the retinal changes, the line corresponding to the retinal pigment epithelium (RPE), and the chorioscleral interface (CSI). In 132 eyes with a pigment epithelial detachment (PED), we graded the structures inside the PED, Bruch's line, and the CSI. We compared the visibility of those changes in eyes with subretinal hyperreflective changes due to a subretinal hemorrhage (SRH) (n = 17) or a hemorrhage inside the PED (HPED) (n = 12). HP-OCT provided superior visibility of the following structures compared to SD-OCT (P < 0.01): the CSI, structures inside the PED, Bruch's line inside the PED, the CSI inside the PED, SRH, type 1 CNV, polyps, and HPED. There were no significant differences between the two OCT devices in the scores for the RPE line, retinal morphology, or type 2 CNV and/or fibrin. HP-OCT visualizes morphologies beneath the RPE better than SD-OCT, and is equivalent to SD-OCT for visualizing morphologies above the RPE.

Age-related Macular Degeneration and DNA Methylation

239 ISSN 1750-1911 10.2217/EPI.13.19 © 2013 Future Medicine Ltd Epigenomics (2013) 5(3), 239–241 “The finding of epigenetic changes in age-related macular degeneration opens the door for the exploration of the role of environmental risk factors that may reduce or enhance the risk of age-related macular degeneration, allowing characterization of immune and other pathways important in this disease, identification of biomarkers and perhaps modification or enhancement of certain genes or gene pathways through pharmacoepigenetic interventions.”

Clinical characteristics of 254 cases of polypoidal choroidal vasculopathy

Objective To observe the clinical characteristics of polypoidal choroidal vasculopathy (PCV).Methods Two hundreds fifty-four PCV patients (306 eyes) were enrolled in this study.All the patients were examined for corrected visual acuity (BCVA) testing,slit-lamp microscope,indirect ophthalmoscopy,fundus photography,fluorescein angiography,indocyanine green angiography and optic coherence tomography.Results The patients included 152 males (59.8％) and 102 females (40.2％) ; the age was from 38 to 91 years,with a mean age of (65.4±8.9) years.Bilateral lesions were observed in 52 patients (20.5％) and unilateral lesions were observed in 202 patients (79.5％).BCVA varied from nonlight perception to 1.2.BCVA was lower than ＜0.1 in 167 eyes (54.6％),≥0.1 but ＜0.3 in 92 eyes(30.1％) and ≥0.3 in 47 eyes (15.4％).Vitreous hemorrhage was observed in 61 eyes (19.9％).In 202 patients with unilateral PCV lesions,drusen can be observed in the contralateral eyes of 68 patients (33.7％),exudative age-related macular degeneration changes in the contralateral eyes of 24 patients (11.9 ％),and central serous chorioretinopathy history was positive in the contralateral eyes in nine patients (4.5％).In 306 eyes,there were 43 eyes (14.1％) with high permeable choroid.PCV lesions located at macula area in 199 eyes (65.0％),under the temporal retinal vascular arcade in 49 eyes (16.0％),and peripapillary in 15 eyes (4.9％).PCV lesion formation was single in 110 eyes (35.9％),cluster in 176 eyes (57.5％),string in three eyes (1.0％),branch in four eyes (1.3％),and both single and cluster polyps in 13 eyes (4.2％).There were 125 eyes (40.8％) with sub-neuroretinal fluid,121 eyes (39.5％) with hemorrhagic pigment epithelium detachment,and 73 eyes (22.9％) with serous pigment epithelium detachment.Conclusion PCV patients have higher bilateral incidence and female prevalence,and lower rate of peripapillary lesions. Key words: Choroid diseases; Macular degeneration; Disease attributes

Transcriptome changes in age-related macular degeneration

Age-related macular degeneration (AMD) is a debilitating, common cause of visual impairment. While the last decade has seen great progress in understanding the pathophysiology of AMD, the molecular changes that occur in eyes with AMD are still poorly understood. In the current issue of Genome Medicine, Newman and colleagues present the first systematic transcriptional profile analysis of AMD-affected tissues, providing a comprehensive set of expression data for different regions (macula versus periphery), tissues (retina versus retinal pigment epithelium (RPE)/choroid), and disease state (control versus early or advanced AMD). Their findings will serve as a foundation for additional systems-level research into the pathogenesis of this blinding disease.Please see related article: http://genomemedicine.com/content/4/2/16

Transcriptome changes in age-related macular degeneration

Transcriptome changes in age-related macular degeneration

Quality of Vision Index: A New Method to Appraise Visual Function Changes in Age-Related Macular Degeneration

To explore the correlation between psychophysical measures of visual function and vision-related quality of life (QOL) in exudative age-related macular degeneration (AMD) and to obtain a new quality of vision index expressed as corrected visual acuity (cVA) that is scaled like visual acuity (VA), but that incorporates the weighted contribution of VA, contrast sensitivity (CS), and reading ability. Visual acuity, CS, and reading ability were measured in 293 patients with AMD in this multicenter prospective study. Vision-related QOL was quantified by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The validity of the questionnaire was assessed using Rasch analysis. The relationship between psychophysical tests and NEI-VFQ-25 scores was investigated. A cVA index was developed integrating Rasch-scaled NEI-VFQ-25 score with VA, CS, and reading ability as a tool to be used for evaluating vision-related QOL on the same scale as VA. A total of 27.5% of the variability of VFQ score was found to be explained by VA alone in patients with AMD. The proportion of Rasch-scaled QOL estimate variance explained by cVA was 33.2% as compared to 27.5% explained by VA and 24.5% by CS, which was a statistically significant improvement in both cases (p=0.015 and p<0.001, respectively). The correlation of reading ability with vision-related QOL was largely mediated by VA and CS and therefore it was not retained in the vision index. Visual acuity is poorly correlated with vision-related QOL in patients with AMD. Even though the new cVA index is a new method which better correlates with vision-related QOL, the major components of the individual perception of vision remain unexplained by common psychometric tests.

Loss of chromatic sensitivity in AMD and diabetes: a comparative study

Abnormalities in rod and cone photoreceptor morphology have been reported in normal aging retinas in the absence of known pathology and have been taken as an indicator of susceptibility to retinal disease. Some loss of visual performance may therefore precede retinal structural changes that can be detected reliably using conventional fundus imaging techniques. Red/green (RG) and yellow/blue (YB) colour discrimination thresholds are sensitive measures of normal retinal function and poor YB discrimination is often taken as an indicator of retinal disease, though it is generally acknowledged that RG loss is also present in most cases of acquired deficiency. Although structural changes in age-related macular degeneration (AMD) and diabetes share some similarities, significant differences remain and this may result in different patterns of RG and YB loss. The aim of this study was to quantify and compare the severity of RG and YB loss of chromatic sensitivity in patients with AMD and diabetes. Patients with varying severity of AMD and diabetes and normal subjects of similar age were recruited for the study. RG and YB colour detection thresholds were measured in the two groups of patients and the control group, using the Colour Assessment and Diagnosis (CAD) test. Each AMD subject investigated showed significant, but unequal loss of YB and RG chromatic sensitivity, with YB discrimination showing the greatest loss. Diabetic subjects also exhibited reduced chromatic sensitivity, but with almost equal and highly correlated RG and YB thresholds (R(2) = 0.99). The severity of colour vision loss measured with the CAD test also correlates well with a clinical classification index of disease progression in AMD, and with the level of hyperglycaemic control in diabetes. These findings suggest that accurate measurements of RG and YB colour thresholds can provide a sensitive measure of functional change in diseases of the retina with patterns of loss that differ significantly in AMD and diabetes.

Relationship between RPE and Choriocapillaris in Age-Related Macular Degeneration

The purpose of this study was to examine the relationships between choriocapillaris (CC) and retinal pigment epithelial changes in age-related macular degeneration (AMD). Morphologic changes in the retinal pigment epithelium (RPE)/choriocapillaris complex were quantified in dry and wet forms of AMD, and the results were compared with those in aged control eyes without maculopathy. Postmortem choroids from three aged control subjects, five subjects with geographic atrophy (GA), and three subjects with wet AMD were analyzed using a semiquantitative computer-assisted morphometric technique developed to measure the percentages of retinal pigment epithelial and CC areas in choroidal wholemounts incubated for alkaline phosphatase activity. The tissues were subsequently embedded in methacrylate and were sectioned so that structural changes could be examined. There was a linear relationship between the loss of RPE and CC in GA. A 50% reduction in vascular area was found in regions of complete retinal pigment epithelial atrophy. Extreme constriction of remaining viable capillaries was found in areas devoid of RPE. Adjacent to active choroidal neovascularization (CNV) in wet AMD, CC dropout was evident in the absence of retinal pigment epithelial atrophy, resulting in a 50% decrease in vascular area. Lumenal diameters of the remaining capillaries in wet AMD eyes were similar to those in control eyes. The primary insult in GA appears to be at the level of the RPE, and there is an intimate relationship between retinal pigment epithelial atrophy and secondary CC degeneration. CC degeneration occurs in the presence of viable RPE in wet AMD. The RPE in regions of vascular dropout are presumably hypoxic, which may result in an increase in VEGF production by the RPE and stimulation of CNV.

Characterization of Outer Retinal Morphology with High-Speed, Ultrahigh-Resolution Optical Coherence Tomography

To visualize, quantitatively assess, and interpret outer retinal morphology by using high-speed, ultrahigh-resolution (UHR) OCT. Retinal imaging was performed in the ophthalmic clinic in a cross-section of 43 normal subjects with a 3.5-microm, axial-resolution, high-speed, UHR OCT prototype instrument, using a radial scan pattern (24 images, 1500 axial scans). Outer retinal layers were automatically segmented and measured. High-definition imaging was performed with a 2.8-microm axial-resolution, high-speed, UHR OCT research prototype instrument, to visualize the finer features in the outer retina. Quantitative maps of outer retinal layers showed clear differences between the cone-dominated fovea and the rod-dominated parafovea and perifovea, indicating that photoreceptor morphology can explain the appearance of the outer retina in high-speed, UHR OCT images. Finer, scattering bands were visualized in the outer retina using high-definition imaging and were interpreted by comparison to known anatomy. High-speed UHR OCT enables quantification of scattering layers in the outer retina. An interpretation of these features is presented and supported by quantitative measurements in normal subjects and comparison with known anatomy. The thick scattering region of the outer retina previously attributed to the retinal pigment epithelium (RPE) is shown to consist of distinct scattering bands corresponding to the photoreceptor outer segment tips, RPE, and Bruch's membrane. These results may advance understanding of the outer retinal appearance in OCT images. The normative measurements may also aid in future investigations of outer retinal changes in age-related macular degeneration and other diseases.