Important Risk Factor For Glaucoma Research Articles

Global Gene Expression Changes in Rat Retinal Ganglion Cells in Experimental Glaucoma

Intraocular pressure (IOP) is an important risk factor in glaucoma. Gene expression changes were studied in glaucomatous rat retinal ganglion cells (RGCs) to elucidate altered transcriptional pathways. RGCs were back-labeled with Fluorogold. Unilateral IOP elevation was produced by injection of hypertonic saline into the episcleral veins. Laser capture microdissection (LCM) was used to capture an equal number of RGCs from normal and glaucomatous retinal sections. RNA was extracted and amplified, labeled, and hybridized to rat genome microarrays, and data analysis was performed. After selected microarray data were confirmed by RT-qPCR and immunohistochemistry, biological pathway analyses were performed. Significant changes were found in the expression of 905 genes, with 330 genes increasing and 575 genes decreasing in glaucomatous RGCs. Multiple cellular pathways were involved. Ingenuity pathway analysis demonstrated significant changes in cardiac beta-adrenergic signaling, interferon signaling, glutamate receptor signaling, cAMP-mediated signaling, chemokine signaling, 14-3-3-mediated signaling, and G-protein-coupled receptor signaling. Gene set enrichment analysis showed that the genes involved in apoptotic pathways were enriched in glaucomatous RGCs. The prosurvival gene Stat3 was upregulated in response to elevated IOP, and immunohistochemistry confirmed that Stat3 and phosphorylated-Stat3 levels were increased in RGCs in experimental glaucoma. In addition, the expression of several prosurvival genes normally expressed in RGCs was decreased. There are extensive changes in gene expression in glaucomatous RGCs involving multiple molecular pathways, including prosurvival and prodeath genes. The alteration in the balance between prosurvival and prodeath may contribute to RGC death in glaucoma.

The Microbead Occlusion Model: A Paradigm for Induced Ocular Hypertension in Rats and Mice

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Animal models often involve techniques for IOP elevation that are surgically invasive. Here the authors describe a novel and relatively simple method for inducing a highly consistent, modest, and repeatable elevation in IOP for rats and mice. IOP was elevated unilaterally by injection of polystyrene microbeads into the anterior chamber to occlude aqueous outflow in rats (2.5-7 microL) and mice (1 microL). The fellow eye received an equivalent saline injection as internal control. The authors used tonometry to measure microbead-induced IOP elevations. Optic nerves were processed histologically to determine axon loss. For rats, a single injection of microbeads raised IOP by 21% to 34%, depending on volume, for approximately 2 weeks, though they were not tracked to full recovery. IOP in the saline-injected eye was constant. An additional injection (5 microL) extended the elevation to 8 weeks. Cumulative pressure exposure for both injections increased linearly. For mice, a single 1-microL injection of microbeads elicited a highly regular 30% elevation in IOP that persisted for more than 3 weeks, with a linear rise in cumulative pressure exposure. For both rats and mice, interanimal variability on a given day was modest, approximately 5% of the mean IOP measurement. Extended elevations (4-5 weeks) induced approximately a 20% loss of axons in both rats and mice. These data support a novel and flexible model of modest ocular hypertension with axon loss. The maximal duration of IOP elevation will be further characterized in future studies.

Measurement of intraocular pressure (IOP) in chickens using a rebound tonometer: Quantitative evaluation of variance due to position inaccuracies

Intraocular pressure (IOP), an important risk factor for glaucoma, is a continuous trait determined by a complex set of genetic and environmental factors that are largely unknown. Genetic studies in laboratory animals may facilitate the identification of genes that affect IOP. We examined the use of the rebound tonometer for measuring IOP in non-anaesthetised birds, along with the device's robustness to alignment errors. Calibration curves were obtained by measuring the IOP of cannulated chicken eyes with the rebound tonometer over a range of pressures. To simulate different types of alignment errors that might be expected with measurement of IOP in alert chickens, for some calibrations the tonometer was positioned (1) at various distances from the cornea, (2) laterally displaced from the visual axis, or (3) angled away from the visual axis. In vivo measurements were taken on three-week-old alert chickens from a layer line, a broiler line, and a layer-broiler “advanced intercross line” (AIL) designed to facilitate QTL mapping. The rebound tonometer showed excellent linearity ( R 2 = 0.95–0.99) during calibration, as well as robustness to variation in the probe-to-cornea distance over the range 3–5 mm and to lateral displacement over the range 0–2 mm. However, the tonometer appeared less robust to off-axis misalignment over the range 0–20° ( P < 0.05). Also, the slope of calibration curves sometimes differed between eyes ( P < 0.001), presumably reflecting differences in ocular structure. The IOP measured in non-anaesthetised three-week-old AIL chickens was 17.51 ± 0.13 mmHg (mean ± S.E.; N = 105 birds). IOP was significantly associated with corneal thickness ( P < 0.05) and body weight ( P < 0.001) in a regression model. Replicate measurements were necessary in order to gauge IOP accurately in individual birds; a series of seven tonometry sessions over a 12-h period during the light phase of the light/dark cycle permitted IOP to be measured with a 95% CI of ±0.7 mmHg. IOP did not differ significantly between the broiler and layer chicken lines which served as the progenitor lines for the AIL. In conclusion, the rebound tonometer permits rapid estimation of IOP in chickens and is well tolerated. The small alignment errors that are expected when taking measurements in non-anaesthetised animals are unlikely to affect accuracy. Since high IOP is a major risk factor for glaucoma, identifying QTL controlling IOP may offer future health benefits. However, our preliminary findings highlight several obstacles to mapping such QTL using the chicken advanced intercross line evaluated here.

Heritability of Intraocular Pressure in Older Female Twins

To examine the heritability of intraocular pressure (IOP) among older women not diagnosed as having glaucoma. Cross-sectional twin study. 94 monozygotic (MZ) and 96 dizygotic (DZ) female twin pairs aged 63-76 years and not diagnosed as having glaucoma. Intraocular pressure was measured using a noncontact tonometer. The contributions of genetic and environmental factors to individual differences in IOP were estimated by applying an independent pathway model to twin data. Contribution of genetic and environmental effects to the variation in IOP among MZ and DZ twins. Mean IOP of the study population was 14.1 mmHg (+/- standard deviation 3.1) with no differences observed neither between the MZ and the DZ individuals, nor between the left and the right eyes. The pair-wise correlations for IOP of the right eye were .61 in MZ and .25 in DZ and for the left eye .63 and .42. The phenotypic correlation between the left and the right eye IOP was high (r = 0.81), suggesting that they were indices of a single trait. Quantitative genetic modeling revealed that for both eyes 64% (95% confidence interval [CI], 53-71) of the variance in IOP was explained by additive genetic effects and 18% (95% CI, 11-27) by nonshared environmental factors in common. In addition, 18% (95% CI, 15-23) of the variance in IOP was explained by nonshared environmental factors specific to each eye. Additive genetic influences explained most of the individual differences in IOP among older women not diagnosed as having glaucoma. Because elevated IOP is an important risk factor for glaucoma, genetic factors underlying IOP may have a significant role in determining the risk for glaucoma, a complex progressive disease leading to death of ganglion cells.

Pharmacological Neuroprotection for Glaucoma

Glaucoma represents a group of neurodegenerative diseases characterised by structural damage to the optic nerve and slow, progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure is traditionally considered to be the most important risk factor for glaucoma, and treatment options for the disease have hitherto been limited to its reduction. However, visual field loss and RGC death continue to occur in patients with well controlled intraocular pressures and, thus, a consensus has recently emerged that additional treatment strategies are needed. One such strategy is pharmacological neuroprotection, which in the context of glaucoma, refers to the situation in which a drug is deployed to interact with neuronal or glial elements within the retina/optic nerve head and thereby facilitate the survival of RGCs. The advent of animal models of chronic glaucoma has enhanced our understanding of many of the pathological processes occurring in glaucoma and, in doing so, described logical targets for pharmacological intervention. Such targets, which have been manipulated with varying degrees of success in relevant animal paradigms include glutamate receptors, autoimmune elements, neurotrophin deprivation, nitric oxide synthesis, oxidative stress products, sodium and calcium channels, heat shock proteins and apoptotic pathways. With exciting data now emerging from many research laboratories, it is obvious that pharmacological neuroprotection for glaucoma without doubt represents an exciting development in the search for a treatment modality for this debilitating disease.

Screening for primary open-angle glaucoma in the developed world: are we there yet?

Background: In 1995, the Quebec Agency for Health Services and Technology Assessment (AETMIS) stated that a formal screening program for primary open-angle glaucoma (POAG) could not be recommended for the province of Quebec, owing to “a high degree of uncertainty and because of the high cost such a program would entail.” The purpose of this article was to evaluate the possibility of instituting a POAG screening program in light of recent advances in the diagnosis and treatment of glaucoma. Methods: We reviewed new developments that have occurred since the mid to late 1990s in the field of glaucoma. Changes that could positively influence the feasibility and organization of future glaucoma screening programs were identified. Results: New technologies, including confocal scanning laser ophthalmoscopy (HRT II), optical coherence tomography (Stratus OCT), and scanning laser polarimetry with variable corneal compensation (GDx-VCC), permit early detection of optic nerve and nerve fibre layer structural damage. Together with advanced psychophysical tests (frequency doubling perimetry and short wavelength automated perimetry) for earlier detection of functional damage, they provide an increased understanding of the diagnosis and monitoring of POAG. Elevated intraocular pressure (IOP) remains the most important risk factor for glaucoma. Clinical trials indicate that lowering IOP at different stages of the disease can arrest or decrease its rate of progression. Moreover, it is important to assess pachymetry because IOP measurements are influenced by central corneal thickness. Finally, new treatments, such as prostaglandin analogues or selective laser trabeculoplasty, are safer and may also achieve lower intraocular pressures. Interpretation: Health policy involves the investment of public resources, and cost-effectiveness analyses for POAG screening are heavily weighted by the degree of uncertainty that glaucoma screening can be effectively and reliably achieved. The many new developments and advancements outlined herein, combined with the possible increasing prevalence of POAG, necessitate the re-evaluation of screening for primary open-angle glaucoma.

Glaucoma characteristics and risk factors: results from Malmö Eye Survey

This thesis is based on data from a large glaucoma screening, comprising 32, 918 elderly citizens of Malmö and data from retrospective analysis of glaucoma patients’ charts from the Eye Department of Malmö University Hospital. The definition of glaucoma was based on reproducible visual field defects and/or glaucomatous optic nerve head damage in both groups. In study I, including screened individuals only, we found that the prevalence of glaucoma was strikingly dependent on refraction and markedly over-represented in myopic eyes, thus confirming myopia as an important risk factor for glaucoma. A new and interesting finding was that the relationship between glaucoma and myopia was stronger in eyes with low IOP, weaker in the group with intermediate pressure readings, and disappeared in eyes with higher pressures. In study II, based on screening participants, we found a significant association between the use of platelet aggregation inhibitors and optic disc hemorrhages and a nonsignificant tendency towards an overrepresentation of ODH in individuals who were taking antihypertensive medication and cholesterol-lowering agents. This could indicate an association between optic disc hemorrhages and generalized vascular disease, alternatively that individuals on platelet aggregation inhibitors are predisposed to optic disc hemorrhages, or at least prolonged or more recurrent episodes of such hemorrhages. In study III, we compared the glaucoma patients identified through screening with self-selected patients from the Eye Department of Malmö University Hospital. NTG was much more commonly found through population screening as compared to routine clinical examinations and mean IOP was significantly lower in patients identified through screening than in self-selected patients. Pseudoexfoliation and bilateral disease was, on the other hand, more common in the self-selected group. Visual field damage in the self-selected patients was significantly greater than in patients detected through population screening, but both groups had considerable mean visual field defects. Study IV compares mortality in glaucoma patients and controls from the screening as well as in the glaucoma patients diagnosed at the Eye Department. The results of this study strongly suggest that the life expectancy of glaucoma patients is the same as that of normal controls. Initiation of treatment did not appear to affect the survival curves of previously untreated patients. The full Thesis is available from: http://www.blackwell-synergy.com/links/doi/10.1111/j.1395-3907.2004.00238.x/abs

Anisometropia and degree of optic nerve damage in chronic open-angle glaucoma

PURPOSE: To address the question of whether the refractive error plays a role in the amount of optic nerve damage in glaucoma, we intraindividually compared inter-eye differences in refractive error with inter-eye differences in parameters indicating the degree of glaucomatous optic nerve damage, and we interindividually correlated refractive error with neuroretinal rim area and visual field loss. DESIGN: Comparative clinical observational study. METHODS: This comparative clinical observational study was conducted in a university eye hospital. The study included 1,444 eyes of 876 patients with primary or secondary chronic open-angle glaucoma. Patients with a highly myopic refractive error (≥ −8 diopters) were excluded, owing to differences in the anatomy of the optic nerve head. Color stereo optic disk photographs were taken and morphometrically evaluated. The main outcome measures were refractive error, neuroretinal rim area, horizontal and vertical cup/disk diameter ratios, and visual field loss. RESULTS: In an interindividual statistical analysis, area of neuroretinal rim, horizontal and vertical cup/disk diameter ratios, and mean visual field loss were not significantly ( P > .10) correlated with refractive error. In an intraindividual comparison, inter-eye differences in refractive error were not significantly ( P > .05) correlated with inter-eye differences in neuroretinal rim area and mean visual field defect. The eye with the more myopic refractive error and the contralateral eye with the less myopic refractive error did not vary significantly in neuroretinal rim area and mean visual field defect. CONCLUSIONS: For nonhighly myopic (< −8 diopters) patients with primary or secondary chronic open-angle glaucoma, the refractive error may not play a major role for the amount of glaucomatous optic neuropathy. For nonhighly myopic (< −8 diopters) patients with primary or secondary chronic open-angle glaucoma, myopia may not be an important risk factor for glaucoma.

Clinical features of pseudoexfoliation of the lens capsule: suggested management

Background: Pseudoexfoliation of the lens capsule (PEX) is found in widely varying proportions across the population of regional groups. It is strongly associated with open angle glaucoma and to a lesser extent angle closure glaucoma. This association makes PEX a very important risk factor for glaucoma, which should be sought actively in all patients over 50 years of age who seek eye care. Our ageing population may give rise to a future high caseload of PEX glaucoma, which will create challenges in diagnosis and treatment. Method: Selected literature is reviewed. It includes a description of the course of PEX and suggested optometric clinical procedures to diagnose and assess the significance of PEX. An algorithm for guidance of optometric and ophthalmological management is presented. Conclusions: PEX is a common condition in the aged. It is an easily detected strong indicator of open angle glaucoma and to a lesser extent the risk of angle closure glaucoma. The presence of PEX should alert the clinician to the need for a full glaucoma assessment.

Neuroprotection in Relation to Retinal Ischemia and Relevance to Glaucoma

Management of glaucoma is directed at the control of intraocular pressure (IOP), yet it is recognized now that increased IOP is just an important risk factor in glaucoma. Therapy that prevents the death of ganglion cells is the main goal of treatment, but an understanding of the causes of ganglion cell death and precisely how it occurs remains speculative. Present information supports the working hypothesis that ganglion cell death may result from a particular form of ischemia. Support for this view comes from the fact that not all types of retinal ischemia lead to the pathologic findings seen in glaucomatous retinas or to cupping in the optic disk area. Moreover, in animal experiments in which ischemia is caused by elevated IOP, a retinal abnormality similar to that seen in true glaucoma is produced, whereas after occlusion of the carotid arteries a different pattern of damage is found. In ischemia, glutamate is released, and this initiates the death of neurons that contain ionotropic glutamate (NMDA) receptors. Elevated glutamate levels exist in the vitreous humor of patients with glaucoma, and NMDA receptors exist on ganglion cells and a subset of amacrine cells. Experimental studies have shown that a variety of agents can be used to prevent the death of retinal neurons (particularly ganglion cells) induced by ischemia. These agents are generally those that block NMDA receptors to prevent the action of the released glutamate or substances that interfere with the subsequent cycle of events that lead to cell death. The major causes of cell death after activation of NMDA receptors are the influx of calcium into cells and the generation of free radicals. Substances that prevent this cascade of events are, therefore, often found to act as neuroprotective agents. For a substance to have a role as a neuroprotective agent in glaucoma, it would ideally be delivered topically to the eye and used repeatedly. It is, therefore, of interest that betaxolol, a β-blocker presently used to reduce IOP in humans, also has calcium channel-blocking functions. Moreover, experimental studies show that betaxolol is an efficient neuroprotective agent against retinal ischemia in animals, when injected directly into the eye or intraperitoneally.