Intracranial Pressure and Its Relationship to Glaucoma: Current Understanding and Future Directions

Retrospective and prospective studies looking at the role of cerebrospinal fluid pressure (CSFP)/intracranial pressure (ICP) have stimulated new theories and hypotheses regarding the underlying causal events for glaucoma. Most recently, studies supporting a low CSFP/ICP as a risk factor for glaucoma have been published. This review summarizes the current understanding of CSFP/ICP and its potential role in the pathogenicity of the disease

Intracranial Pressure and Its Relationship to Glaucoma: Current Understanding and Future Directions

Retrospective and prospective studies looking at the role of cerebrospinal fluid pressure (CSFP)/intracranial pressure (ICP) have stimulated new theories and hypotheses regarding the underlying causal events for glaucoma. Most recently, studies supporting a low CSFP/ICP as a risk factor for glaucoma have been published. This review summarizes the current understanding of CSFP/ICP and its potential role in the pathogenicity of the disease

Analysis of Cerebrospinal Fluid Pressure Estimation Using Formulae Derived From Clinical Data

Purpose: To evaluate a frequently used regression model and a new, modified regression model to estimate cerebrospinal fluid pressure (CSFP). Methods: Datasets from the Beijing iCOP study from Tongren Hospital, Beijing, China, and the Mayo Clinic, Rochester, Minnesota, were tested in this retrospective, case-control study. An often-used regression model derived from the Beijing iCOP dataset, but without radiographic data, was used to predict CSFP by using demographic and physiologic data. A regression model was created using the Mayo Clinic dataset and tested against a validation group. The Mayo Clinic-derived formula was also tested against the Beijing Eye Study population. Intraclass correlation was used to assess predicted versus actual CSFP. Results: The Beijing-derived regression equation was reported to have an intraclass correlation coefficient (ICC) of 0.71, indicating strong correlation between predicted and actual CSFP in the study population. The Beijing iCOP regression model poorly predicted CSFP in the Mayo Clinic population with an ICC of 0.14. The Mayo Clinic-derived regression model similarly did not predict CSFP in its Mayo Clinic validation group (ICC 0.28 ± 0.04) nor in the Beijing Eye Study population (ICC 0.06). Conclusions: Formulae used to predict CSFP derived from clinical data fared poorly against a large retrospective dataset. This may be related to differences in lumbar puncture technique, in the populations tested, or the timing of collection of physiologic variables in the Mayo Clinic dataset. Caution should be used when interpreting results based on formulaic derivation of CSFP

Body Mass Index Has a Linear Relationship with Cerebrospinal Fluid Pressure

To examine the relationship between body mass index (BMI) and cerebrospinal fluid pressure (CSFP), as low BMI and low CSFP have recently been described as risk factors for primary open-angle glaucoma (POAG)

Cerebrospinal Fluid Pressure Decreases with Older Age

Clinical studies implicate low cerebrospinal fluid pressure (CSFP) or a high translaminar pressure difference in the pathogenesis of primary open angle glaucoma (POAG) and normal tension glaucoma (NTG). This study was performed to examine the effect of age, sex, race and body mass index (BMI) on CSFP

Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from model animals. To assess the structure-function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometer scale. In our datasets retinal ganglion cell dendrites degenerate early in human glaucoma, with remodeling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure-function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma

Effect of trinucleotide repeat expansion on the expression of TCF4 mRNA in Fuchs' endothelial corneal dystrophy

Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings

Analysis of Circadian Rhythm Gene Expression With Reference to Diurnal Pattern of Intraocular Pressure in Mice

Citation: Dalvin LA, Fautsch MP. Analysis of circadian rhythm gene expression with reference to diurnal pattern of intraocular pressure in mice. Invest Ophthalmol Vis Sci. 2015;56:265756: -266356: . DOI:10.1167 PURPOSE. To determine the expression of circadian rhythm clock genes in the iris-ciliary body complex of mice and their association with the diurnal pattern of intraocular pressure (IOP). METHODS. Thirty wild-type C57BL/6 mice were acclimated to a 12-hour light-dark cycle. Intraocular pressure was measured with a rebound tonometer at six time points daily (circadian time [CT] 2, 6, 10, 14, 18, and 22 hours) for five consecutive days. On day 6, mice were euthanized at CT 2, 6, 10, 14, 18, and 22. Eyes were flash-frozen or fixed in 4% phosphate-buffered paraformaldehyde. Total RNA was extracted from the iris-ciliary body complex, and RNA expression of circadian rhythm genes Bmal1, Clock, Cry1, Cry2, Per1, and Per2 was assessed by quantitative real-time PCR. Fixed eyes were paraffin embedded, and immunohistochemistry was performed to localize corresponding proteins (BMAL1, CLOCK, CRY1, CRY2, PER1, and PER2). Linear regression analysis was performed to correlate gene expression with IOP. RESULTS. Intraocular pressure demonstrated a consistent circadian pattern. The clock genes Bmal1, Clock, Cry1, Cry2, Per1, and Per2 showed a circadian pattern of expression in the iris-ciliary body complex of mice. Bmal1, Clock, Cry1, Per1, and Per2 gene expression demonstrated statistically significant correlations with diurnal variations of IOP. BMAL1, CLOCK, CRY1, CRY2, PER1, and PER2 proteins were found to be expressed locally in the nonpigmented epithelium of the ciliary body. CONCLUSIONS. Expression patterns of candidate circadian rhythm genes correlates with the diurnal pattern variation of IOP in mouse eyes, indicating a possible mechanism of IOP regulation through these genes. Keywords: aqueous outflow, iris-ciliary body complex, clock genes, intraocular pressure, circadian rhythm E levated intraocular pressure (IOP) is a strong risk factor for primary open-angle glaucoma (POAG), and current standard of care focuses on the reduction in IOP as the primary modality to reduce optic nerve damage and prevent vision loss. 1 Characterization of molecular regulators of IOP would help identify novel molecules that can be used as therapeutic targets for the treatment of POAG. Intraocular pressure is the result of a balance between secretion and outflow of aqueous humor, a colorless fluid in the anterior segment of the eye. 2 Three variables are of interest in this balance: the rate of aqueous humor formation, the resistance to outflow, and the episcleral venous pressure. The rate of formation and resistance to outflow are the primary targets for current drug therapy aimed at lowering IOP. The ciliary body is responsible for aqueous humor production, primarily via active secretion from its nonpigmented epithelium. Aqueous humor secretion is known to vary in a circadian manner, decreasing by up to 50% during sleep. 8 Epinephrine may play a role in this change, but the mechanism behind decreased secretion remains poorly understood. 9 Outflow facility also decreases slightly at night. 10,11 However, the decrease in outflow does not appear to be significant enough to compensate for the decrease in aqueous secretion, and the cause of this decrease in outflow remains unknown. 10 While the decrease in aqueous humor secretion and the slight decrease in aqueous humor outflow suggest a nocturnal normality or slight decrease in IOP, multiple studies have repeatedly demonstrated a sinusoidal pattern of IOP that peaks at night when animals are maintained on a 12-hour light-dark cycle. 12-16 Interestingly, IOP is higher at night irrespective of diurnal or nocturnal habits of the animals, which suggests that IOP is regulated by light intensity and not by the level of activity. 17 This circadian pattern of IOP is abolished in the absence of a distinct light-dark cycle