Faculty Bibliography

Purpose: It has been shown that Asians have a high prevalence of normal tension glaucoma, while Caucasians and African-Americans have predominantly high tension glaucoma. This study compared the lamina cribrosa (LC) microstructure of a cohort of Korean and American eyes in order to discern microstructure differences between the cohorts that could contribute to this phenomenon.
Method(s): The optic nerve head of 53 healthy eyes (42 subjects; 38 Korean eyes and 15 American eyes, consisting of a mixture of Caucasian and African-American eyes) was scanned 3 times during the same session with Cirrus HD-OCT (Zeiss, Dublin CA). These scans were registered and averaged to increase LC visibility using a method we have previously described. The area of the ONH featuring clearly visible LC was delineated, and scans were semi-automatically analyzed within the delineated area to segment the LC microstructure in 3D. The LC measurements of beam thickness, pore diameter, and beam/pore ratio were compared using a hierarchical linear model taking ethnicity and age into account.
Result(s): Baseline characteristics were similar between the cohorts (Table 1). Mean pore diameter was on average 3.78mum bigger in Asian subjects compared to non-Asian subjects (p<0.001), and beam/pore ratio was 0.33 units smaller in Asian subjects (p<0.001). No differences were detected in beam thickness.
Conclusion(s): The in vivo microstructure of the LC varies among different ethnicities. Further research is needed to determine the cause, effect and clinical relevance of these differences. (Table presented)

Purpose : We previously described the two-dimensional continuous time hidden Markov model (2D CT-HMM) to model glaucoma progression using structural and functional measurements simultaneously. The purpose of this study was to validate the glaucoma progression prediction performance of a previously trained model on data collected from a different cohort. Methods : A 2D CT-HMM was trained using optical coherence tomography (OCT; Cirrus HD-OCT, Zeiss, Dublin, CA) mean circumpapillary retinal nerve fiber layer (cRNFL) thickness and visual field index (VFI; Humphrey Field Analyzer, Zeiss) obtained from 107 eyes of 107 subjects, including glaucoma and glaucoma suspect. Average observation period was 4.2 years (7.1 visits). Approximately 1 year of longitudinal data were collected from a separate cohort. 78 eyes of 39 subjects, glaucoma and glaucoma suspect, with an average of 2.2 +/- 0.4 visits were included. After matching the distribution of OCT and VF data on the training cohort, 19 eyes from 14 subjects were selected. The previously trained model was tested on these cases. One visit was used as an input to the model to predict the state at the next visit at least 6 months later, with 4 possible state changes (stable, OCT, VF, or OCT+VF progression). The percentage of correct prediction against the actual recorded state was reported as the prediction accuracy. Results : Baseline age of the test cohort was 58.4 +/- 13.9 years, VFI 93.6 +/- 8.3, mean cRNFL thickness 74.0 +/- 10.9mum. Figure 1 shows the trained model. The size of the circle (state) shows the number of subjects passing through the state. The grayscale of the state indicates the length of time spent there, increasing white to black. Lines indicate state changes, with the blue line being the most likely. This information is also shown in numerical form. The inset shows an example of model use. The calculated prediction accuracy of this pre-trained 2D CT-HMM on test data was 52.6%. Conclusions : Although the glaucoma progression prediction performance of the trained 2D CT-HMM was slightly lower than that previously reported, it is acceptable given the training and testing cohorts were different, and it exceeds the random chance of making a correct prediction, 25%. Furthermore, unlike conventional methods, this model requires only one visit as an input, which makes it a potentially useful tool in the clinical prediction of glaucoma progression. (Figure Presented)

Purpose : Ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thicknesses measured by OCT have been shown to be useful for glaucoma diagnosis and progression detection. The purpose of this study was to determine the disease severity threshold (tipping point) at which the longitudinal rate of change for RNFL and GCIPL thickness slows down; allowing to determine the preferred location to follow structural damage along the spectrum of the disease severity. Methods : Subjects with comprehensive ophthalmic examination and >= 5 visits with qualified visual field (VF; Humphrey Field Analyzer; Zeiss, Dublin, CA) and OCT (Cirrus HDOCT; Zeiss) optic nerve head and macular scans were enrolled. Piece-wise linear mixed effects model was used to identify the tipping points of RNFL and GCIPL vs. VF mean deviation (MD), respectively, and model with quadratic term for RNFL vs. GCIPL. To account for the difference in dynamic ranges, RNFL and GCIPL rate of change were standardized (normal distribution, mean=0 sd=1). Results : 177 eyes (125 open angle glaucoma, 45 glaucoma suspect, and 7 healthy eyes) of 114 subjects were analyzed. Subjects' mean age: 70 +/- 11 years, median VF MD: -1.78 dB ([Q1, Q3]; -5.8, -0.2), baseline average RNFL and GCIPL thicknesses: 73.2 +/- 14.9mum and 68.3 +/- 10.7mum, respectively, average follow-up time: 3.4 +/- 1 years, mean visits per subject: 5.6, with a grand total of 1,010 follow-up visits. Tipping point for RNFL occur at earlier stage of the disease and the rate of change is faster than for GCIPL (Table). However, after standardization, the slopes for RNFL and GCIPL were similar. When comparing the rate of change for RNFL and GCIPL, no tipping point was detected, but as RNFL and GCIPL decreased, the rate of change in RNFL became significantly smaller. Conclusions : Rate of RNFL thinning slows down at an earlier stage of functional damage than GCIPL. Different dynamic ranges give the impression that RNFL decreases faster, but accounting for the larger dynamic range, a similar rate of change to GCIPL is observed across the entire disease severity spectrum. Our results do not indicate whether RNFL or GCIPL is better for detecting progression except for very advanced stages of the disease where RNFL progression rate stalls

Purpose: When assessing treatment effects in observational studies, the propensity score (PS) method is commonly used to reduce the selection bias of treatments. Weighting subjects by the inverse probability of treatment using the PS mimics treatment s ran e domization e Our y c o ntin as to g apply PS t r website, you are ag ation o g glaucoma treatment c cmeepdtication with rates of structural changes in a longitudinal cohort of glaucoma subjects.
Method(s): Glaucoma subjects treated with prostaglandin, beta blockers, and/or carbonic anhydrase inhibitors (CAIs) with > 2 visits with qualified OCT (Cirrus HD-OCT; Zeiss) were included. Subjects were on medication for at least 3 months prior to each OCT visit. Multinomial PS for baseline medication selection was estimated by baseline age, visual field (VF) mean deviation (MD), intraocular pressure and ethnicity. Rates of change for OCT's average circumpapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses were calculated per eye using linear regression. Their associations with baseline RNFL, GCIPL, baseline medication, post-baseline medication and medication duration were tested using linear regression with and without PS weighting.
Result(s): 207 eyes (117 subjects) were qualified with average age of 62.2+/-12.7 years and median MD of -3.6 dB (IQR -9.0, -1.4) at baseline, and a mean follow-up of 3.2+/-1.8 years. The average duration of treatment range from 1.3+/-1.8 to 2.4+/-2.5 years for CAIs and prostaglandin, respectively. At baseline, average RNFL and GCIPL were 71.5+/-14.4 mum and 65.9+/-13.5 mum. Throughout follow-up, mean rate of change for RNFL and GCIPL were -0.30+/-2.60 mum/year and 0.27+/-7.72 mum/year. Without PS weighting, no medication effect was shown to be associated with either rate of change. With PS weighting, however, the rate of change for RNFL was significantly associated with taking CAIs (-1.26 mum/year, p=0.029) and prostaglandin (-0.98 mum/year, p=0.044) and baseline RNFL (-0.05 mum/year, p=0.017). Longer use of the medications slowed RNFL decrease, although the effects were not statistically significant. No association was detected between treatment and rate of change for GCIPL.
Conclusion(s): PS can be useful to reduce treatment selection bias and facilitate more rigorous estimation of medication effects in observational glaucoma research

The lamina cribrosa is a primary site of damage in glaucoma. While mechanical distortion is hypothesized to cause reduction of axoplasmic flow, little is known about how the pores, which contains the retinal ganglion cell axons, traverse the lamina cribrosa. We investigated lamina cribrosa pore paths in vivo to quantify differences in tortuosity of pore paths between healthy and glaucomatous eyes. We imaged 16 healthy, 23 glaucoma suspect and 48 glaucomatous eyes from 70 subjects using a swept source optical coherence tomography system. The lamina cribrosa pores were automatically segmented using a previously described segmentation algorithm. Individual pore paths were automatically tracked through the depth of the lamina cribrosa using custom software. Pore path convergence to the optic nerve center and tortuosity was quantified for each eye. We found that lamina cribrosa pore pathways traverse the lamina cribrosa closer to the optic nerve center along the depth of the lamina cribrosa regardless of disease severity or diagnostic category. In addition, pores of glaucoma eyes take a more tortuous path through the lamina cribrosa compared to those of healthy eyes, suggesting a potential mechanism for reduction of axoplasmic flow in glaucoma.

Purpose/UNASSIGNED:To introduce an experimental approach for direct comparison of the primate optic nerve head (ONH) before and after death by exsanguination. Method/UNASSIGNED:The ONHs of four eyes from three monkeys were imaged with spectral-domain optical coherence tomography (OCT) before and after exsanguination under controlled IOP. ONH structures, including the Bruch membrane (BM), BM opening, inner limiting membrane (ILM), and anterior lamina cribrosa (ALC) were delineated on 18 virtual radial sections per OCT scan. Thirteen parameters were analyzed: scleral canal at BM opening (area, planarity, and aspect ratio), ILM depth, BM depth; ALC (depth, shape index, and curvedness), and ALC visibility (globally, superior, inferior, nasal, and temporal quadrants). Results/UNASSIGNED:All four ALC quadrants had a statistically significant improvement in visibility after exsanguination (overall P < 0.001). ALC visibility increased by 35% globally and by 36%, 37%, 14%, and 4% in the superior, inferior, nasal, and temporal quadrants, respectively. ALC increased 4.1%, 1.9%, and 0.1% in curvedness, shape index, and depth, respectively. Scleral canals increased 7.2%, 25.2%, and 1.1% in area, planarity, and aspect ratio, respectively. ILM and BM depths averaged -7.5% and -55.2% decreases in depth, respectively. Most, but not all, changes were beyond the repeatability range. Conclusions/UNASSIGNED:Exsanguination allows for improved lamina characterization, especially in regions typically blocked by shadowing in OCT. The results also demonstrate changes in ONH morphology due to the loss of blood pressure. Future research will be needed to determine whether there are differences in ONH biomechanics before and after exsanguination and what those differences would imply.

Although elevated intraocular pressure (IOP) and age are major risk factors for glaucoma, their effects on glaucoma pathogenesis remain unclear. This study examined the onset and progression of glaucomatous changes to ocular anatomy and physiology, structural and physiological brain integrity, and visuomotor behavior in the DBA/2J mice via non-invasive tonometry, multi-parametric magnetic resonance imaging (MRI) and optokinetic assessments from 5 to 12 months of age. Using T2-weighted MRI, diffusion tensor MRI, and manganese-enhanced MRI, increasing IOP elevation at 9 and 12 months old coincided with anterior chamber deepening, altered fractional anisotropy and radial diffusivity of the optic nerve and optic tract, as well as reduced anterograde manganese transport along the visual pathway respectively in the DBA/2J mice. Vitreous body elongation and visuomotor function deterioration were observed until 9 months old, whereas axial diffusivity only decreased at 12 months old in diffusion tensor MRI. Under the same experimental settings, C57BL/6J mice only showed modest age-related changes. Taken together, these results indicate that the anterior and posterior visual pathways of the DBA/2J mice exhibit differential susceptibility to glaucomatous neurodegeneration observable by in vivo multi-modal examinations.

Purpose/UNASSIGNED:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods/UNASSIGNED:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results/UNASSIGNED:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions/UNASSIGNED:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Ocular imaging has been heavily incorporated into glaucoma management and provides important information that aids in the detection of disease progression. Longitudinal studies have shown that the circumpapillary retinal nerve fiber layer is an important parameter for glaucoma progression detection, whereas other studies have demonstrated that macular parameters, such as the ganglion cell inner plexiform layer and optic nerve head parameters, also are useful for progression detection. The introduction of novel technologies with faster scan speeds, wider scanning fields, higher resolution, and improved tissue penetration has enabled the precise quantification of additional key ocular structures, such as the individual retinal layers, optic nerve head, choroid, and lamina cribrosa. Furthermore, extracting functional information from scans such as blood flow rate and oxygen consumption provides new perspectives on the disease and its progression. These novel methods promise improved detection of glaucoma progression and better insight into the mechanisms of progression that will lead to better targeted treatment options to prevent visual damage and blindness.

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 x 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 x 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.European Journal of Human Genetics advance online publication, 30 August 2017; doi:10.1038/ejhg.2017.136.