Faculty Bibliography

Purpose : Glaucoma affects task performance, a measure of ability in the context of performing daily tasks. Task factors affected by glaucoma are not well characterized for practical ophthalmic application. This study identifies domains of task performance associated with structure-function measures in order to characterize task factors relevant in the context of glaucoma. Methods : We recruited adults aged 50 years and older with glaucoma, with no other ocular comorbidities, who underwent ophthalmic evaluation. Eleven domains of task performance were analyzed (Table) using the standardized Assessment of Life Habits questionnaire to measure 1) ability to perform tasks (accomplishment, scale 0-10) and 2) satisfaction with task performance (satisfaction, scale 1-5). Better eye visual field mean deviation (MD) and OCT retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) average thickness were analyzed. Multivariable regression analyses determined the association between task performance and MD, RNFL, and GCIPL, adjusting for age, race, glaucoma and depressive symptoms. Depressive symptoms were in the models due to their known association with vision loss. Results : 77 subjects of average age 68 +/- 9.2 years and baseline MD of -3.7 +/- 6.3 dB, RNFL of 76.1 +/- 13.3 mum and GCIPL of 69.8 +/- 10.7 mum were enrolled. Overall task performance scores were high (accomplishment 9.3 +/- 0.6, satisfaction 4.5 +/- 0.5). For accomplishment, MD, RNFL, and GCIPL were significant indicators for overall task performance scores (p < 0.001) and for >=6 domains (p <= 0.028, Table). For satisfaction, RNFL was a significant indicator for overall task performance scores (p = 0.037). Unlike accomplishment, satisfaction was less associated with structure-function (3 domains across measures). Depressive symptoms were significantly associated with task performance (p <= 0.05) in all domains except communication. Conclusions : Task performance affected by glaucoma is underrecognized in ophthalmic practice. Awareness of task performance accomplishment (ability) may be relevant in glaucoma more so than patients' satisfaction. Satisfaction is a measure of patients' perception and their reports often overestimate actual ability. Therefore, measuring accomplishment and its association with structure-function measures may guide future evaluation of those tasks most affected by glaucoma in order to enable timely treatment for task performance limitations

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.

Advances in imaging have made it increasingly common to study soft tissues without first embedding them in plastic or paraffin and without using labels or stains. The process, however, usually still involves fixation and cryosectioning, which could deform the tissues. Our goal was to quantify the morphological changes of ocular tissues caused by formalin fixation and cryosectioning. From each of 6 porcine eyes, 4 regions were obtained: cornea, equatorial and posterior sclera, and posterior pole containing the optic nerve head. Samples were imaged using visible light microscopy fresh, 1-minute and 24-hours post-fixation, and post-cryosectioning. Effects were assessed by 14 parameters representing sample size and shape. Overall, formalin fixation and sectioning caused only minimal changes to the ocular tissues, with average percentage parameter differences of 0.1%, 1%, and 1.2% between fresh and post-fixing by 1 minute, 24 hours, and post-cryosectioning, respectively. Parameter changes were not directional, and were only weakly dependent on the duration of fixation and the region of the eye. These results demonstrate that formalin fixation and cryosectioning are good choices for studying ocular tissue morphology and structure, as they do not cause the large tissue shrinkage or distortions typically associated with other, more complicated, techniques.

Glaucoma is a leading cause of blindness that leads to characteristic changes in the optic nerve head (ONH) region, such as nasalization of vessels. It is unknown whether the spatial location of this vessel shift inside the ONH occurs within the lamina cribrosa (LC) or the prelaminar tissue. The purpose of this study was to compare the location of the central retinal vessel trunk (CRVT) in the LC and prelaminar tissue in living healthy and glaucomatous eyes. We acquired 3-dimensional ONH scans from 119 eyes (40 healthy, 29 glaucoma suspect, and 50 glaucoma) using optical coherence tomography (OCT). The CRVT location was manually delineated in separate projection images of the LC and prelamina. We found that the CRVT in glaucoma suspect and glaucomatous eyes was located significantly more nasally compared to healthy eyes at the level of the prelamina. There was no detectable difference found in the location of the CRVT at the level of the LC between diagnostic groups. While the nasal location of the CRVT in the prelamina has been associated with glaucomatous axonal death, our results suggest that the CRVT in the LC is anchored in the tissue with minimal variation in glaucomatous eyes.

Purpose: Caloric restriction (CR) has been shown in animal models to increase longevity and delay the effects of aging. This study investigates the effect of CR on ocular tissues in a cohort of human subjects adopting a particular CR lifestyle (CRWay). Methods: Age matched healthy controls and CRWay members with no general or ocular co-morbidities underwent a full ophthalmic examination including visual field (VF) and optical coherence tomography (OCT) (Cirrus HD-OCT) testing. Duration of time in the CRWay, body mass index (BMI), axial length, central corneal thickness, VF mean deviation (MD) and OCT measured retinal nerve fiber layer (RNFL) thickness, cup to disc (C/D) ratio, and ganglion cell inner plexiform layer (GCIPL) thickness were analyzed. Multivariate linear regressions were used to estimate RNFL and GCIPL thicknesses using the above variables. Results: Nine CRWay subjects (18 eyes) were compared to a population of 23 age-matched controls (46 eyes). The average age of all subjects was 60.8+/-10.4 years, and the duration of time in the CRWay ranged from 2-36 years. The average BMI was 20.7+/-1.6 for the CR participants and 28.3+/-5.2 for the control group. GCIPL thickness was negatively associated with BMI for the CRWay group. Multivariate analyses showed that C/D ratio, BMI, participation in the CR lifestyle, and the interaction terms between these variables were significant in the model for predicting RNFL thickness and GCIPL thickness (all p-values<0.03). Conclusions: A chronic CR lifestyle shows a significant effect on ocular structures, deserving further investigation in a larger cohort and investigation into the mechanisms of action