Search Results (28)

Glaucoma, a leading cause of irreversible blindness, is characterised by progressive optic nerve damage, with elevated intraocular pressure (IOP) and extracellular matrix (ECM) remodelling in the lamina cribrosa (LC) contributing to its pathophysiology. While current treatments focus on IOP reduction, they fail to address the underlying fibrotic changes that perpetuate neurodegeneration. The Src proto-oncogene, a non-receptor tyrosine kinase, has emerged as a key regulator of cellular processes, including fibroblast activation, ECM deposition, and metabolism, making it a promising target for glaucoma therapy. Beyond its well-established roles in cancer and fibrosis, Src influences pathways critical to trabecular meshwork function, aqueous humour outflow, and neurodegeneration. However, the complexity of Src signalling networks remains a challenge, necessitating further investigation into the role of Src in glaucoma pathogenesis. This paper explores the therapeutic potential of Src inhibition to mitigate fibrotic remodelling and elevated IOP in glaucoma, offering a novel approach to halting disease progression. Full article

Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p < 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role. Full article

Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness of the LC connective tissue. Integrins are cell surface proteins that provide the key molecular link connecting cells to the ECM and serve as bidirectional sensors transmitting signals between cells and their environment to promote cell adhesion, proliferation, and remodelling of the ECM. Here, we investigated the expression of αVβ3 integrin in glaucoma LC cell, and its effect on stiffness-induced ECM gene transcription and cellular proliferation rate in normal (NLC) and glaucoma (GLC) LC cells, by down-regulating αVβ3 integrin expression using cilengitide (a known potent αVβ3 and αVβ5 inhibitor) and β3 integrin siRNA knockdown. Methods: GLC cells were compared to age-matched controls NLC to determine differential expression levels of αVβ3 integrin, ECM genes (Col1A1, α-SMA, fibronectin, vitronectin), and proliferation rates. The effects of αVβ3 integrin blockade (with cilengitide) and silencing (with a pool of four predesigned αVβ3 integrin siRNAs) on ECM gene expression and proliferation rates were evaluated using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting in the human NLC cells cultured on soft (4 kPa) and stiff (100 kPa) substrate and in GLC cells grown on standard plastic plates. Results: αVβ3 integrin gene and protein expression were enhanced (p < 0.05) in GLC cells as compared to NLC. Both cilengitide and siRNA significantly reduced αVβ3 expression in GLC. When NLC were grown in the stiff substrate, cilengitide and siRNA also significantly reduced the increased expression in αVβ3, ECM components, and proliferation rate. Conclusions: Here, we provide evidence of cilengitide- and siRNA-mediated silencing of αVβ3 integrin expression, and inhibition of ECM synthesis in LC cells. Therefore, αVβ3 integrin may be a promising target for the development of novel anti-fibrotic therapies for treating the LC cupping of the ONH in glaucoma. Full article

Glaucoma, a leading cause of blindness, is a multifactorial condition that leads to progressive loss of retinal ganglion cells (RGCs) and vision. Therapeutic interventions based on reducing ocular hypertension are not always successful. Emerging features of glaucoma include mitochondrial dysfunction and oxidative stress. In the current study, NDI1-based gene therapy, which improves mitochondrial function and reduces reactive oxygen species, was delivered intraocularly via an adeno-associated viral vector (AAV). This AAV-NDI1 therapy protected RGCs from cell death in treated (1552.4 ± 994.0 RGCs/mm²) versus control eyes (1184.4 ± 978.4 RGCs/mm², p < 0.05) in aged DBA/2J mice, a murine model of glaucoma. The photonegative responses (PhNRs) of RGCs were also improved in treated (6.4 ± 3.3 µV) versus control eyes (5.0 ± 3.1 µV, p < 0.05) in these mice. AAV-NDI1 also provided benefits in glaucomatous human lamina cribrosa (LC) cells by significantly increasing basal and maximal oxygen consumption rates and ATP production in these cells. Similarly, NDI1 therapy significantly protected H₂O₂-insulted primary porcine LC cells from oxidative stress. This study highlights the potential utility of NDI1 therapies and the benefits of improving mitochondrial function in the treatment of glaucoma. Full article

Background/Objectives: To assess the frequency, extent, localization and potential progression of optic disc drusen (ODD) and the correlation with the angioid streak (AS) length and retinal atrophy in patients with pseudoxanthoma elasticum (PXE). Methods: This retrospective study included patient data from a dedicated PXE clinic at the Department of Ophthalmology, University of Bonn, Germany (observation period from February 2008 to July 2023). Two readers evaluated the presence, localization, and the extent of the ODD on fundus autofluorescence (FAF) imaging at baseline and the follow-up assessments. Additionally, we measured the length of the longest AS visible at baseline and follow-up and the area of atrophy at baseline, both on FAF. Results: A total of 150 eyes of 75 PXE patients (median age at baseline 51.8 years, IRQ 46.3; 57.5 years, 49 female) underwent retrospective analysis. At baseline, 23 of 75 patients exhibited ODD in a minimum of one eye, resulting in an ODD prevalence of 30.7% in our cohort of PXE patients. Among these, 14 patients showed monocular and 9 binocular ODD that were localized predominantly nasally (46.9%). During the observational period (mean 97.5 ± 44.7 months), only one patient developed de novo ODD in one eye and one other patient showed a progression in the size of the existing ODD. The group of patients with ODD had significantly longer ASs (median 7020 µm, IQR 4604; 9183, vs. AS length without ODD: median 4404 µm, IQR 3512; 5965, p < 0.001). No association with the size of the atrophy was found at baseline (p = 0.27). Conclusions: This study demonstrates a prevalence of ODD of 30.7%. ODD presence is associated with longer ASs (an indicator of the severity and extent of ocular Bruch’s membrane calcification), suggesting that ODD formation is tightly related to ectopic calcification—possibly secondary to calcification of the lamina cribrosa. Prospective studies investigating the impact of ODD (in conjunction with intraocular pressure) on visual function in PXE warrant consideration. Full article

There are scarce data regarding the rate of the occurrence of primary open-angle glaucoma (POAG) and visible lamina cribrosa pores (LCPs) in the eyes of individuals with African ancestry; the potential impact of these features on disease burden remains unknown. We recruited subjects with POAG to the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Through regression models, we evaluated the association between the presence of LCPs and various phenotypic features. In a multivariable analysis of 1187 glaucomatous eyes, LCPs were found to be more likely to be present in eyes with cup-to-disc ratios (CDR) of ≥0.9 (adjusted risk ratio (aRR) 1.11, 95%CI: 1.04–1.19, p = 0.005), eyes with cylindrical-shaped (aRR 1.22, 95%CI: 1.11–1.33) and bean pot (aRR 1.24, 95%CI: 1.13–1.36) cups versus conical cups (p < 0.0001), moderate cup depth (aRR 1.24, 95%CI: 1.06–1.46) and deep cups (aRR 1.27, 95%CI: 1.07–1.50) compared to shallow cups (p = 0.01), and the nasalization of central retinal vessels (aRR 1.33, 95%CI: 1.23–1.44), p < 0.0001). Eyes with LCPs were more likely to have a higher degree of African ancestry (q0), determined by means of SNP analysis (aRR 0.96, 95%CI: 0.93–0.99, p = 0.005 for per 0.1 increase in q0). Our large cohort of POAG cases of people with African ancestry showed that LCPs may be an important risk factor in identifying severe disease, potentially warranting closer monitoring by physicians. Full article

Detailed visualization of the cribriform plate is challenging due to its intricate structure. This study investigates how computed tomography (CT) with a novel photon counting (PC) detector enhance cribriform plate visualization compared to traditionally used energy-integrated detectors in patients. A total of 40 patients were included in a retrospective analysis, with half of them undergoing PC CT (Naeotom Alpha Siemens Healthineers, Forchheim, Germany) and the other half undergoing CT scans using an energy-integrated detector (Somatom Sensation 64, Siemens, Forchheim, Germany) in which the cribriform plate was visualized with a temporal bone protocol. Both groups of scans were evaluated for signal-to-noise ratio, radiation dose, the imaging quality of the whole scan overall, and, separately, the cribriform plate and the clarity of volume rendering reconstructions. Two independent observers conducted a qualitative analysis using a Likert scale. The results consistently demonstrated excellent imaging of the cribriform plate with the PC CT scanner, surpassing traditional technology. The visualization provided by PC CT allowed for precise anatomical assessment of the cribriform plate on multiplanar reconstructions and volume rendering imaging with reduced radiation dose (by approximately 50% per slice) and higher signal-to-noise ratio (by approximately 75%). In conclusion, photon-counting technology provides the possibility of better imaging of the cribriform plate in adult patients. This enhanced imaging could be utilized in skull base-associated pathologies, such as cerebrospinal fluid leaks, to visualize them more reliably for precise treatment. Full article

Purpose: To compare the differences between eyes with pseudoexfoliative glaucoma (PXG) when they are divided into two groups (hypertensive PXG and normotensive PXG) according to the intraocular pressure (IOP). Methods: This is a retrospective study. Data from 86 hypertensive PXG eyes and 80 normotensive PXG eyes were included. Hypertensive PXG was defined as PXG with IOP ≥ 22 mmHg, and normotensive PXG was defined as with IOP ≤ 21 mmHg). Central corneal thickness (CCT) was measured by ultrasound pachymetry. Lamina cribrosa thickness (LT) was evaluated using swept-source optical coherence tomography. Results: No significant differences were observed between hypertensive and normotensive PXG in terms of age, gender, axial length, hypertension, or diabetes. Normotensive PXG eyes had thinner CCT than hypertensive PXG eyes (p = 0.02). To compare LT, a sub-analysis was performed after matching age, VF MD and retinal nerve fiber layer thickness. The normotensive PXG group (n = 32) demonstrated significantly thinner LT compared with the hypertensive PXG group (n = 32) at similar ages and levels of glaucoma severity (p < 0.001). Conclusions: Eyes with normotensive PXG demonstrated thinner CCT and LT compared with those with hypertensive PXG, suggesting structural vulnerability to glaucoma. Full article

Background/Aims: Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry. In these patients’ eyes, a large cup-to-disc ratio (LCDR > 0.90) suggests greater retinal ganglion cell loss, though these patients often display varied visual ability. This study investigated the prevalence and risk factors associated with LCDR in African ancestry individuals with POAG and explored the differences between blind (>20/200) and not blind (≤20/200) LCDR eyes. Methods: A case–control methodology was used to investigate the demographic, optic disc, and genetic risk factors of subjects in the Primary Open-Angle African American Glaucoma Genetics Study. Risk factors were analyzed using univariable and multivariable logistic regression models with inter-eye correlation adjusted using generalized estimating equations. Results: Out of 5605 eyes with POAG, 1440 eyes (25.7%) had LCDR. In the multivariable analysis, LCDR was associated with previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.04), decreased mean deviation (OR = 1.08), increased pattern standard deviation (OR = 1.06), thinner retinal nerve fiber layer (OR = 1.05), nasalization of vessels (OR = 2.67), bayonetting of vessels (OR = 1.98), visible pores in the lamina cribrosa (OR = 1.68), and a bean-shaped cup (OR = 2.11). Of LCDR eyes, 30.1% were classified as blind (≤20/200). In the multivariable analysis, the statistically significant risk factors of blindness in LCDR eyes were previous glaucoma surgery (OR = 1.72), increased intraocular pressure (OR = 1.05), decreased mean deviation (OR = 1.04), and decreased pattern standard deviation (OR = 0.90). Conclusions: These findings underscore the importance of close monitoring of intraocular pressure and visual function in African ancestry POAG patients, particularly those with LCDR, to preserve visual function. Full article

Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells throughout the body can differentiate into fibroblast-like cells through epithelial-to-mesenchymal transition (EMT) and contribute to ECM fibrosis. This is investigated here in the context of glaucoma and PPA. Human-donor ONH sections were assessed for the presence of the RPE cell-specific marker RPE65 using immunofluorescence. We examined the EMT response of ARPE-19 cells to the following glaucoma-related stimuli: cyclic mechanical stretch, mechanical stiffness, transforming growth factor beta (TGFβ), and tumour necrosis factor alpha (TNFα). The gene expression was measured using the PCR of the epithelial tight junction marker zona occludens 1 (ZO-1) and the mesenchymal markers alpha smooth muscle actin (αSMA) and vimentin. A scratch assay was used to assess the ARPE-19 migration. Significant RPE-65 staining was demonstrated in the glaucomatous ONH. The cyclic stretching and substrate stiffness of the ARPE-19 cells caused a significant decrease in ZO-1 (p = 0.04), and an increase in αSMA (p = 0.04). The scratch assays demonstrated increased migration of ARPE19 in the presence of TNFα (p = 0.02). Furthermore, ARPE-19 cells undergo an EMT-like transition (gain of αSMA, loss of ZO-1 and increased migration) in response to glaucomatous stimuli. This suggests that during PPA, RPE cells have the potential to migrate into the ONH and differentiate into fibroblast-like cells, contributing to glaucomatous ONH cupping. Full article

Purpose: To describe anatomical peculiarities associated with axial elongation in the human myopic eye. Methods: Reviewing the results of previous histomorphometrical investigations of enucleated human globes, as well as reviewing findings obtained in population-based studies and hospital-based clinical investigations of myopic patients and non-myopic individuals. Results: Myopic axial elongation is associated with a change from a mostly spherical eye shape to a prolate ellipsoid form. It is combined with choroidal and scleral thinning, most pronounced at the posterior pole and less pronounced in the fundus midperiphery. In the fundus midperiphery, the retina and density of the retinal pigment epithelium (RPE) and photoreceptors decrease with a longer axial length, while in the macular region, retinal thickness, RPE cell density, and choriocapillaris thickness are not related to axial length. With axial elongation, a parapapillary gamma zone develops, leading to an enlargement of the optic disc-fovea distance and a decrease in angle kappa. Axial elongation is also correlated with an increase in the surface and volume of Bruch’s membrane (BM), while BM thickness remains unchanged. Axial elongation causes moderately myopic eyes to show a shift of BM opening to the foveal direction so that the horizontal disc diameter becomes shorter (with a consequent vertical ovalization of the optic disc shape), a temporal gamma zone develops, and the optic nerve exit takes an oblique course. Features of high myopia are an enlargement of the RPE opening (myopic parapapillary beta zone) and BM opening (secondary macrodisc), elongation and thinning of the lamina cribrosa, peripapillary scleral flange (parapapillary delta zone) and peripapillary choroidal border tissue, secondary BM defects in the macular region, myopic maculoschisis, macular neovascularization, and cobblestones in the fundus periphery. Conclusions: These features combined may be explained by a growth in BM in the fundus midperiphery leading to axial elongation. Full article

Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of damage in glaucoma where there is fibrosis of the connective tissue in the lamina cribrosa (LC) extracellular matrix. As a ubiquitous second messenger, calcium (Ca²⁺) can interact with various cellular proteins to regulate multiple physiological processes and contribute to a wide range of diseases, including cancer, fibrosis, and glaucoma. Our research has shown evidence of oxidative stress, mitochondrial dysfunction, an elevated expression of Ca²⁺ entry channels, Ca²⁺-dependent pumps and exchangers, and an abnormal rise in cytosolic Ca²⁺ in human glaucomatous LC fibroblast cells. We have evidence that this increase is dependent on Ca²⁺ entry channels located in the plasma membrane, and its release is from internal stores in the endoplasmic reticulum (ER), as well as from the mitochondria. Here, we summarize some of the molecular Ca²⁺-dependent mechanisms related to this abnormal Ca²⁺-signalling in human glaucoma LC cells, with a view toward identifying potential therapeutic targets for ongoing optic neuropathy. Full article

(1) Background: To compare optic nerve sheath diameter (ONSD) in normal-tension glaucoma (NTG) and healthy eyes and to investigate the association between ONSD and lamina cribrosa (LC) morphology. (2) Methods: This cross-sectional study included 69 NTG eyes and 69 healthy eyes matched for age, axial length, and intraocular pressure. The LC curvature index (LCCI) was measured from horizontal Cirrus HD-OCT B-scan images from five uniformly divided positions vertically of the optic nerve. The average LCCI was defined as the mean of the measurements at these five locations. ONSD was measured as the width of the optic nerve sheath at the site perpendicular 3 mm behind the posterior globe. LCCI and ONSD were compared in eyes with NTG and healthy eyes. The clinical factors that could affect LCCI were analyzed. (3) Results: NTG eyes had significantly smaller mean ONSD (4.55 ± 0.69 mm vs. 4.97 ± 0.58 mm, p < 0.001) and larger average LCCI (11.61 ± 1.43 vs. 7.58 ± 0.90, p < 0.001) than matched healthy control eyes. LCCI was significantly correlated with smaller ONSD, higher intraocular pressure, thinner global retinal nerve fiber thickness, and worse visual field loss in all subjects (all Ps ≤ 0.022). (4) Conclusions: NTG eyes had smaller ONSD and greater LCCI than healthy control eyes. In addition, a negative correlation was observed between ONSD and LCCI. These findings suggest that cerebrospinal fluid pressure, which ONSD indirectly predicts, may affect LC configuration. Changes in the retrolaminar compartment may play a role in glaucoma pathogenesis. Full article