Faculty Bibliography

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 : 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 : 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

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 : 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 purpose of the present study was to quantify test-retest reproducibili-ty of measurements of stiffness of the human trabecular meshwork (HTM) by atomic force microscopy (AFM).
Method(s): Eleven 40 mum radial limbal cryostat sections from a fresh human donor rim were mounted on charged slides and rehydrated at room temperature. Stiffness at four TM locations (anterior to posterior along Schlemm's canal) was measured by AFM. At each location, a 6 x 6 grid was sampled. Indentation points were evenly distributed over a 20 mum x 20 mum area, with a rate of one load/unload cycle per second. Measurements were then repeated for calculation of test-retest variability.
Result(s): The test-retest coefficients of variation for the four measurement locations (anterior to posterior) were 24.39, 25.28, 12.74, and 14.26%, respectively, with a notable drop in the two posterior locations compared to the anterior. The test-retest coefficient for the sections was 19.17%. For the entire eye, the test-retest coefficient of variation for the measurement of the TM stiffness was 17.13%. Young's moduli consistently decreased from anterior to posterior location.
Conclusion(s): Wide regional variation suggests that single value does little to fully describe the complex array of TM stiffness levels within the eye, and future studies of TM stiffness assessed by AFM should include multiple tissue samples from each eye, with documentation of the anterior-posterior location of each measurement.
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Purpose/UNASSIGNED:The purpose of this study was to develop a machine learning model to forecast future circumpapillary retinal nerve fiber layer (cpRNFL) thickness in eyes of healthy, glaucoma suspect, and glaucoma participants from multimodal temporal data. Design/UNASSIGNED:Retrospective analysis of a longitudinal clinical cohort. Participants/UNASSIGNED:Longitudinal clinical cohort of healthy, glaucoma suspect, and glaucoma participants. Methods/UNASSIGNED:(LTBE). Main Outcome Measures/UNASSIGNED:The mean absolute difference and Pearson's correlation coefficient between the true and forecasted values of the cpRNFL in the healthy, glaucoma suspect, and glaucoma patients. Results/UNASSIGNED:< 0.01) for the 3 groups, respectively. Conclusions/UNASSIGNED:The performance of the proposed forecasting model for cpRNFL is consistent across glaucoma suspect and glaucoma patients, which implies the robustness of the developed model against the disease state. These forecasted values may be useful to personalize patient care by determining the most appropriate intervisit schedule for timely interventions.

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