Faculty Bibliography

Purpose : Open-angle glaucoma (OAG) is a leading cause of blindness globally, yet the relative contributions of genetic background and the environment to the development of this disease are unclear. As a first step in determining these contributions, we document posterior pole pathology and investigate the association between optic nerve head glaucomatous features, intraocular pressure (IOP), and demographic information, in an exceptionally large cohort of free-ranging rhesus macaques. Methods : We administered ophthalmologicl exams under sedation to 55 female and 54 male animals aged 0-21 years (mean age = 6.08; SD = 4.27). IOP was measured using TonoPen and TonoVet Plus tonometers and measurements adjusted using published calibration equations (McAllister et al Optom Vis Sci. 2018). Cup/Disk ratio (CDR) was calculated from clinical examination aided by optical coherence tomography (OCT; Bioptigen Envisu). Posterior pole pathology was documented using fundus imaging. Association between CDR and age, sex, and IOP was assessed using generalized linear mixed models (GLMM) and likelihood ratio tests (LRTs). Results : The mean (+/-standard deviation) IOP in the 218 eyes measured was 19.32 (+/-6.24) mmHg. Mean CDR was 0.37 (+/-0.15). We detected elevated IOP (> 22mmHg) in 78 eyes (36.62%) and CDR > 0.7 was detected in 13 eyes (5.96 %). CDR values were highly concordant in eyes of the same animal (CDR of left and right eyes within 0.2 for all animals. IOP was a significant predictor of CDR (p<0.001) in models that either included or excluded age, and animal sex. The best fitting model included only IOP as a predictor variable (AIC =-196.3). This model was significantly better than models containing age (AIC =-185.8, p = 0.004) or both age and sex (AIC =-183.4). Additional posterior pole pathology included pigmentary macular changes (8 eyes), macular scars (2 eyes), vessel tortuosity (19 eyes), and retinal hemorrhages (5 eyes). Conclusions : IOP is a significant predictor of CDR in this cohort. Age did not appear to correlate with CDR, but controlling for relatedness may further elucidate impacts of individual biology on OAG. Similarities between rhesus and human glaucomatous phenotypes and the presence of additional retinal pathology in our population may make these animals valuable in the study of other complex human disease, such as age-related macular degeneration

Purpose : In mild glaucoma, RNFL thinning and visual field (VF) loss are often localized, but structure-function modeling is impeded by variability due to individual eye anatomy. We perform high-resolution spatial correlations of RNFLT maps for each VF location to identify relevant areas and study further improvements by geometrically aligning RNFLT maps based on artery trajectories. Methods : In 419 SITA Standard 24-2 Humphrey VFs with at most mild glaucoma (mean deviation >=-3dB) with accompanying circumpapillary Cirrus HD-OCT RNFLT maps, we computed pixel-wise correlations (52 VF locations x 40401 pixels). We then performed an alignment operation, ensuring that the two major retinal arteries follow the same lines in all scans. We piecewise linearly approximated the trajectories of the arteries on 4 concentric circles around ONH (Fig. 1a), determined the necessary rotation for each pixel, and morphed the images accordingly (Fig. 1b). Results : For the pre-alignment RNFLT (correlation maps Fig. 2 top) we observed: (1) relatively high correlations (max 0.29); (2) most of the high-correlation regions are highly localized around the median trajectories of the major arteries at most VF locations, possibly due to the stacked character of the fiber bundles close to ONH, which impedes precise spatial mapping to the VF. This observation suggests general retinal vulnerability zones rather than highly VF location-specific areas as assumed by many previous structure-function models. Accordingly, morphing the RNFLT maps by aligning the eyespecific artery locations increased the maximal correlations on 25 of the 52 VF locations (Fig. 2 bottom, marked in green), particularly in nasal and inferior VF, with improvements of up to 0.1 (inferior arcuate region of VF). At many locations, aligned vulnerability areas become substantially more conspicuous (e.g. the location enlarged on the top left) and might have been missed without aligning. Conclusions : High-resolution structure-function correlations reveal retinal vulnerability zones in mild glaucoma. At many VF locations, these zones become better correlated with VF regions when RNFLT maps are aligned along the arteries. Specific attention to RNFL thinning in these zones in glaucoma suspects may improve the detection of initial VF loss glaucoma

Purpose : Oxygen concentration in retinal blood vessels (sO ) can be critical biomarkers for diabetic retinopathy and glaucoma, leading causes of blindness worldwide. We previously demonstrated sO2measurements in rodent and human retinas with spectroscopic visible-light optical coherence tomography (vis-OCT). However, reliable measurements of sO2in a clinical setting remains an open challenge due to constraints on light exposure, imaging time, patient motion, and variation in eye geometry. Spectral calibration to optimize sO2measurements under these non-ideal imaging conditions is needed. Here, we investigate, develop, and implement such calibration. Methods : We developed vis-OCT processing software to optimize sO2measurements in humans. First, we identified an optimal spectral range for spectral measurement in which sO2was most stable. Next, we developed methods to account for alterations induced by the imaging system and eye optics. Specifically, we accounted for depth-dependent variations in the measured spectrum, such as absorption contrast, spectrally-dependent roll-off, chromatic aberrations, and eye morphology. We then imaged the retinas of 12 healthy subjects aged 22 to 60 at Northwestern Medical Hospital in Chicago, IL, and Langone Medical Center in New York, NY. All imaging was approved by the respective IRBs and strictly adhered to the Declaration of Helsinki. Light exposure in the eye was no higher than 250 muW and imaging time was no longer than 5 s. We extracted sO2from vessels larger than 50 mum in diameter using an automated version of our vis-OCT processing software. Results : We measured the sO2in 89 vessels (53 arteries and 36 veins). We found the mean sO2in arteries was 97.70 +/-4.75 % in arteries and mean sO2in veins was 53.11 +/-6.85 %. Conclusions : We developed analytical methods for depth-dependent alterations to the measured spectrum in vis-OCT retinal oximetry. Our measurements yielded spectra that are highly consistent with those reported in literature, despite variations in imaging conditions. Our results indicate a clear path forward for clinical adoption of vis-OCT

Purpose : The presence of s zone peripapillary atrophy (PPA) has been associated with glaucoma. We performed a retrospective longitudinal study to evaluate s zone PPA area as a predictor for glaucomatous structural and functional progression. Methods : Subjects with glaucoma and >4 visits were included. Subjects had Humphrey visual field (Zeiss, Dublin, CA) testing, spectral-domain OCT (Cirrus HD-OCT; Zeiss) optic nerve head (ONH) and macula scans. s zone PPA was manually delineated on the baseline en face ONH scan as the area contiguous with the optic disc with the presence of hyper-and hyporeflectivity. Mixed effects linear models accounting for intra-subject correlation, follow-up time, scan's signal strength and ethnicity, were performed to determine if baseline PPA area was associated with glaucoma severity. Subsequent models incorporating the interaction term between time and baseline PPA area were performed to determine if baseline PPA area affected the rate of change in parameters of glaucoma over time. Results : 81 eyes (56 subjects) aged 62.8+/-14.1 years with an average follow-up time 3.9+/-1.3 years were analyzed. PPA was significantly associated with mean deviation (MD), visual field index (VFI), and inferior retinal nerve fiber layer (RNFL), (p=0.033, 0.038, and 0.034, respectively), but not with average RNFL, or macular ganglion cell inner plexiform layer (GCIPL) global and sectoral measurements and ONH parameters. No significant association was detected between s zone PPA area and the rate of progression for any parameter except for VFI (p =0.035). Conclusions : Although baseline s zone PPA area is associated with some indicators of glaucoma severity, it is not a significant predictor of the rate of glaucomatous progression (except for VFI)

Purpose : Glaucoma adversely affects subjects' ability to accomplish daily activities, engage in social roles, and contributes to disability. Yet methods to evaluate glaucoma-related disability are limited. To identify daily activities and social roles associated with glaucoma, this study (1) tests the association between visual field (VF) and the Assessment of Life Habits (LIFE-H), a questionnaire developed to measure the degree of difficulty and the level(s) of assistance subjects require in order to accomplish daily activities and social roles, and (2) identifies LIFE-H items with high differential capability of person functional ability. Methods : We recruited 101 subjects aged 50 years and older diagnosed with glaucoma who underwent comprehensive ophthalmic evaluation and VF testing (Humphrey Field Analyzer, Zeiss, Dublin, CA) whom were administered the LIFE-H. Better-eye VF mean deviation (MD) was used to measure severity of visual impairment. Multivariable regression analyses determined the association between MD and 11 LIFE-H domains (totaling 37 daily activity and 38 social role items), adjusting for the covariates age, gender, race, comorbidities, and depressive symptoms. Domains not significantly associated with MD and items not applicable to 10% of subjects were excluded from further analyses, resulting in 64 qualified subjects and 40 LIFE-H items. Rasch analysis was used to determine the item hierarchical order based on the level of person ability. Results : 64 subjects of average age 66+/-10 years and better-eye MD of -5.0+/-7.4 dB qualified for the analysis. All LIFE-H domains except interpersonal relationships were significantly associated (p <= 0.05) with MD. Overall, average domain scores were high (range, 8.7+/-1.5 to 9.7+/-0.4) with the lowest scoring domains being mobility, employment, and recreation. Of the 40 LIFE-H items, 29 were daily activities and 11 were social roles. 21 items across 6 domains were detected to have high differential capability; of which 11 items were daily activities and 10 items were social roles. 11 of the 21 items were significantly associated with MD; 8 of which were social roles and 3 daily activities. Conclusions : The large impact of the social role items among the LIFE-H questionnaire highlight the psychosocial factors for subjects with glaucoma. Further evaluation of daily activities and social roles that constitute when and how glaucoma affects subjects is needed

Observational studies in glaucoma patients can provide important evidence on treatment effects, especially for combination therapies which are often used in reality. But the success relies on the reduction of selection bias through methods such as propensity score (PS) weighting. The objective of this study was to assess the effects of five glaucoma treatments (medication, laser, non-laser surgery (NLS), laser + medication, and NLS + medication) on 1-year intraocular pressure (IOP) change. Data were collected from 90 glaucoma subjects who underwent a single laser, or NLS intervention, and/or took the same medication for at least 6 months, and had IOP measures before the treatment and 12-months after. Baseline IOP was significantly different across groups (p = 0.007) and this unbalance was successfully corrected by the PS weighting (p = 0.81). All groups showed statistically significant PS-weighted IOP reductions, with the largest reduction in NLS group (-6.78 mmHg). Baseline IOP significantly interacted with treatments (p = 0.03), and at high baseline IOP medication was less effective than other treatments. Our findings showed that the 1-year IOP reduction differed across treatment groups and was dependent on baseline IOP. The use of PS-weighted methods reduced treatment selection bias at baseline and allowed valid assessment of the treatment effect in an observational study.

Glaucoma is the world's leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls.

Importance/UNASSIGNED:Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. Objective/UNASSIGNED:To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. Design, Setting, and Participants/UNASSIGNED:A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. Main Outcomes and Measures/UNASSIGNED:Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. Results/UNASSIGNED:The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4). Conclusions and Relevance/UNASSIGNED:A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Purpose : To examine the effect of co-variables commonly used in ocular structure models on ocular vessel density (VD) measurements provided by OCT angiography (OCTA) Methods : Healthy subjects with a normal comprehensive ophthalmic examination, axial length (AL) measurements, qualified visual fields (VF; Humphrey Field Analyzer; Zeiss, Dublin, CA), and optic nerve head (ONH) and macula OCT and OCTA scans (Cirrus HD-OCT 200x200 cube scans and 3x3 mm/ 6x6 mm Angioplex; Zeiss) were included. Subjects with comorbidities affecting the systemic or local micro or macro vasculature and subjects taking medications that modify vessel diameter were excluded. Peripapillary, ONH, and macular VD were calculated using the device's native software. Mixed-effects models were used accounting for age, gender, signal strength, AL, and inter- and intra-subject correlation. Results : 72 eyes (46 subjects) with a mean age of 45.1 (+/-13.9) years, mean AL of 23.82 (+/-1.03) mm, and mean signal strength of 8.32 (+/-1.04) were included in the study for ONH analysis and a subset of 33 eyes were included for macular analysis. The 3x3 and 6x6 ONH inner VD measurements decrease as age advances (-0.1 +/-0.02 mm/mm2, p=0.005; -0.07 +/-0.02 mm/mm2, p=0.0026, respectively). The central and inner measurements in the 3x3 macular scans decrease with age (-0.14 +/-0.03 mm/mm2, p=0.0006; -0.06 +/-0.01mm/mm2, p=0.0003, respectively). ONH and macula VD in both scanning sizes were not associated with AL, except for the macula 6x6 outer region (0.41 +/-0.05 mm/mm2, p=0.05). Only macular VD measurements were associated with signal strength. Conclusions : When analyzing ocular VD, the variables of age, AL, and image quality, should be considered

Purpose : To examine the effect of varying levels of intraocular (IOP) and intracranial pressure (ICP) on the reproducibility of lamina cribrosa (LC) microstructure measurements. Methods : Spectral-domain OCT scans of the optic nerve head (ONH) were obtained from adult healthy rhesus macaque monkeys while IOP and ICP were changed in a controlled environment. Gravity-based perfusion through a needle inserted into the anterior chamber controlled IOP (low, medium, high settings). Perfusion through the lateral ventricle controlled ICP (low, high settings). Scans were registered in 3D and LC microstructure measurements (beam thickness, pore diameter) were calculated from shared regions among scans acquired at each setting using a previously described segmentation algorithm. Microstructure measurement results were used to calculate the beam/pore ratio of each scan, and a 2-way ANOVA test compared the effect of different IOP and ICP settings on measurement reproducibility. Results : The results of 2 eyes were analyzed. For average beam thickness IOP had a significant effect on measurement reproducibility but ICP did not (p=0.005, p=0.66, respectively). For average pore diameter IOP also had a significant effect on measurement reproducibility but ICP did not (p=0.009, p=0.97, respectively). The effect of IOP and ICP on beam/pore ratio reproducibility was not significant (p=0.23, p=0.80, respectively). Results are summarized in Figure 1. Conclusions : Our study provides evidence that beam/pore ratio measurements are reproducible regardless of acquisition at different IOP and ICP settings. This parameter is less influenced by scanning angle and image quality than other measurements. This information supports direct comparison of beam/pore ratio measurements obtained in varying pressure settings