Intravitreal Neuroglobin Mitigates Primate Experimental Glaucomatous Structural Damage in Association with Reduced Optic Nerve Microglial and Complement 3-Astrocyte Activation.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans.

Determinants of lamina cribrosa depth in healthy Asian eyes: the Singapore Epidemiology Eye Study.

AIM: To investigate the determinants of lamina cribrosa depth (LCD) in healthy eyes of Chinese and Indian Singaporean adults. METHODS: The optic nerve head (ONH) of the right eye of 1396 subjects (628 Chinese and 768 Indian subjects) was imaged with optical coherence tomography (OCT, Spectralis, Heidelberg, Germany). LCD was defined as the distance from the Bruch's membrane opening (LCD-BMO) or the peripapillary sclera (LCD-PPS) reference plane to the laminar surface. A linear regression model was used to evaluate the relationship between the LCD and its determinants. RESULTS: Both LCDs were significantly different between the two races (LCD-BMO: 421.95 (95% CI 365.32 to 491.79) µm in Chinese vs 430.39 (367.46-509.81) µm in Indians, p=0.021; and LCD-PPS: 353.34 (300.98-421.45) µm in Chinese vs 376.76 (313.39-459.78) µm in Indians, p<0.001). In the multivariable regression analysis, the LCD-PPS of the whole cohort was independently associated with females (ß=-31.93, p<0.001), Indians subjects (ß=21.39, p=0.004) (Chinese as the reference), axial length (Axl) (ß=-6.68, p=0.032), retinal nerve fibre layer thickness (RNFL) (ß=0.71, p=0.019), choroidal thickness (ChT) (ß=0.41, p<0.001), vertical cup disc ratio (VCDR) (ß=24.42, p<0.001) and disc size (ß=-60.75, p=0.001). For every 1 year older in age, the LCD-PPS was deeper on average by 1.95 µm in Chinese subjects (p=0.01) but there was no association in Indians subjects (p=0.851). CONCLUSIONS: The LCD was influenced by age, gender, race, Axl, RNFL, ChT, VCDR and disc size. This normative LCD database may facilitate a more accurate assessment of ONH cupping using OCT in Asian populations.

Longitudinal assessment of optic nerve head changes using optical coherence tomography in a primate microbead model of ocular hypertension.

In humans, the longitudinal characterisation of early optic nerve head (ONH) damage in ocular hypertension (OHT) is difficult as patients with glaucoma usually have structural ONH damage at the time of diagnosis. Previous studies assessed glaucomatous ONH cupping by measuring the anterior lamina cribrosa depth (LCD) and minimal rim width (MRW) using optical coherence tomography (OCT). In this study, we induced OHT by repeated intracameral microbead injections in 16 cynomolgus primates (10 unilateral; 6 bilateral) and assessed the structural changes of the ONH longitudinally to observe early changes. Elevated intraocular pressure (IOP) in OHT eyes was maintained for 7 months and serial OCT measurements were performed during this period. The mean IOP was significantly elevated in OHT eyes when compared to baseline and compared to the control eyes. Thinner MRW and deeper LCD values from baseline were observed in OHT eyes with the greatest changes seen between month 1 and month 2 of OHT. Both the mean and maximum IOP values were significant predictors of MRW and LCD changes, although the maximum IOP was a slightly better predictor. We believe that this model could be useful to study IOP-induced early ONH structural damage which is important for understanding glaucoma pathogenesis.

Changes in the Anterior Lamina Cribrosa Morphology with Glaucoma Severity.

This study was designed to evaluate if primary open angle glaucoma (POAG) and its severity are associated with the shape of the lamina cribrosa (LC) as measured by a global shape index (LC-GSI), or other indices of LC curvature or depth. Optical coherence tomography (OCT) scans of the optic nerve head (OHN) were obtained from subjects with POAG (n = 99) and non-glaucomatous controls (n = 76). ONH structures were delineated, the anterior LC morphology reconstructed in 3D, and the LC-GSI calculated (more negative values denote greater posterior concavity). Anterior LC depth and 2D-curvature were also measured. Severity of glaucoma was defined by the extent of visual field loss, based on the Hodapp-Parrish-Anderson grading. Linear regression analyses compared LC characteristics between controls, mild-moderate, and advanced POAG groups. After adjusting for age, gender, ethnicity, intraocular pressure, axial length and corneal curvature, the LC-GSI was most negative in the advanced POAG group (mean [standard error] = -0.34 [0.05]), followed by the mild-moderate POAG group (-0.31 [0.02]) and then controls (-0.23 [0.02], PTrend = 0.01). There was also a significant trend of increasing LC depth and greater LC horizontal curvature with increasing severity of glaucoma (PTrend = 0.04 and 0.02, respectively). Therefore, with more severe glaucoma, the LC-GSI was increasingly more negative, and the anterior LC depth and curvature greater. These observations collectively correspond to greater cupping of the ONH at the level of the LC. As the LC-GSI describes the 3D anterior LC morphology, its potential usage may be complementary to existing ONH parameters measured on OCT.