Faculty Bibliography

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.

We present a technique to reduce speckle in visible-light optical coherence tomography (vis-OCT) that preserves fine structural details and is robust against sample motion. Specifically, we locally modulate B-scans orthogonally to their axis of acquisition. Such modulation enables acquisition of uncorrelated speckle patterns from similar anatomical locations, which can be averaged to reduce speckle. To verify the effectiveness of speckle reduction, we performed in-vivo retinal imaging using modulated raster and circular scans in both mice and humans. We compared speckle-reduced vis-OCT images with the images acquired with unmodulated B-scans from the same anatomical locations. We compared contrast-to-noise ratio (CNR) and equivalent number of looks (ENL) to quantify the image quality enhancement. Speckle-reduced images showed up to a 2.35-dB improvement in CNR and up to a 3.1-fold improvement in ENL with more discernable anatomical features using eight modulated A-line averages at a 25-kHz A-line rate.

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

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 : OCT Angiography (OCTA) can be used to measure retinal vessel density (VD). These scans can be of various sizes and may be centered on the optic nerve head (ONH) or macula. In this study, we examined the glaucoma discrimination performance of VD using different scanning sizes and locations and compared it with the performance of conventional structural and functional biomarkers to identify the best glaucoma discrimination scanning protocol. Methods : 79 healthy and glaucomatous eyes (50 subjects) were included in the study. Subjects with diabetes, vascular disease, or who were using medications known to affect retinal thickness were excluded. 3x3 and 6x6mm ONH and macula OCTA images were obtained using Cirrus HD-OCT Angioplex (Zeiss, Dublin, CA). Global and sectoral VD was calculated using native software on the device. Area under the receiver operating characteristics (AUC) was used to determine the discrimination ability of VD, retinal nerve fiber layer (RNFL) thickness, rim area, cup-to-disc (C/D) ratio, ganglion cell inner plexiform layer (GCIPL) thickness, and visual field mean deviation (MD). Bootstrapping was used for comparison between the AUCs. Results : Subjects with glaucoma had statistically significantly different measurements than healthy individuals for all tested parameters except for the majority of macula VD (both 3x3 and 6x6 scanning sizes; Table). VD measurements that had the best glaucoma discrimination ability were acquired from the ONH from all sectors of the 3x3 scans and in the outer and full sectors in the 6x6 scans (Table). For these ONH parameters, no significant difference was detected from the best discriminating parameter (average RNFL and rim area). All macula VD measurements had significantly worse discrimination performance. Conclusions : Among VD scanning options, the ONH scans are the most suitable for glaucoma discrimination. However, the coarse sampling in the larger scan (6x6mm) reduces this capability inside and immediately adjacent to the ONH

The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.

PURPOSE/OBJECTIVE:To investigate predictive factors associated with the rate of visual field (VF) loss in open-angle glaucoma. DESIGN/METHODS:Prospective multicenter cohort study. METHODS:Perimetric glaucoma patients of the Advanced Imaging for Glaucoma study were selected for analysis if they had 9 completed visits. Confirmed rapid significant progression (CRSP) of VF was defined as a significant (P<0.05) negative VF index (VFI) slope < -1%/year or a mean deviation (MD) slope < -0.5 dB/year, confirmed at 2 consecutive follow-up visits. Slow progression was defined as VFI slope > -0.5%/year or MD slope > -0.25 dB/year. Fourier-domain optical coherence tomography (FD-OCT) measured optic disc, peripapillary retinal nerve fiber layer (NFL), and macular ganglion cell complex (GCC) thicknesses. Logistic regression was used to identify baseline predictors for CRSP and slow progression. Linear regression was used to identify baseline predictors for the VFI and MD slope. RESULTS:Eyes (n=150) of 103 participants were included. Slow progression was observed in 80 eyes (53.3%) and CRSP in 23 eyes (15.3%). Larger NFL and GCC baseline focal loss volume (FLV), thinner central corneal thickness (CCT), and lower VFI were significant (p<0.05) baseline predictors of more rapid progression on univariate analysis. The predictor with the highest odds ratio (OR) was NFL-FLV, which was also the most significant non-VF predictor in the multivariate analysis. Eyes with NFL-FLV > 8.5% had an OR of 2.67 for CRSP and 0.42 for slow progression. Disc hemorrhage during the follow up was also important, with an OR of 2.61 for CRSP and 0.23 for slow progression for each occurrence. CONCLUSIONS:Focal loss measured by FD-OCT or VF, along with CCT, are strong baseline predictors for the rate of glaucoma progression.

Background/UNASSIGNED:The capabilities of visible-light optical coherence tomography (vis-OCT) in noninvasive anatomical and functional retinal imaging have been demonstrated by multiple groups in both rodents and healthy human subjects. Translating laboratory prototypes to an integrated clinical-environment-friendly system is required to explore the full potential of vis-OCT in disease management. Methods/UNASSIGNED:We developed and optimized a portable vis-OCT system for human retinal imaging in clinical settings. We acquired raster- and circular-scan images from both healthy and diseased human eyes. Results/UNASSIGNED:The new vis-OCT provided high-quality retinal images of both subjects without any known eye diseases and patients with various retinal diseases, including retinal occlusive disease and diabetic retinopathy (DR) over a broad range of ages. Conclusions/UNASSIGNED:A newly designed vis-OCT system is sufficiently optimized to be suited for routine patients' examinations in clinics. Vis-OCT has the potential to add new anatomical and functional imaging capabilities to ophthalmic clinical care.