Faculty Bibliography

Purpose : Recent studies suggest that glaucoma involves trans-neuronal changes in choline metabolism in the brain's visual system. In addition, citicoline has been suggested as a potential therapeutic for neurodegenerative diseases including glaucoma, yet the underlying mechanisms remain unclear. Here, we use proton magnetic resonance spectroscopy ( H-MRS) and optokinetics to examine the effects of chronic intraocular pressure (IOP) elevation and oral citicoline treatment on brain metabolism and visual function in a novel rat model of experimental glaucoma. Methods : Twenty-three adult Long Evans rats were divided into 3 groups. In Group 1 (n=6) and Group 2 (n=7), the right eye was intracamerally injected with an optically clear crosslinking hydrogel for chronic IOP elevation; Group 2 also received daily oral citicoline dosing for 7 days prior to hydrogel injection, and every 48 hours for 14 days post-injection. The sham group (Group 3, n=7) received an intracameral injection of buffer solution only. IOP and visual acuity (VA) were measured longitudinally using a TonoLab rebound tonometer and the OptoMotry virtual reality system, respectively. H-MRS was acquired over the left and right visual cortices at 5 weeks post-injection using a 9.4T MRI scanner. Results : VA of the left, uninjured eyes remained constant over the experimental period, whereas VA of citicoline-treated right eyes appeared to deteriorate more slowly than untreated right eyes after similar levels of chronic IOP elevation (Fig 1). The left visual cortex projecting from the right, hydrogel-injected eye without citicoline treatment showed a reduced choline level compared to the contralateral right visual cortex projecting from 1 1 the left, uninjured eye. Interestingly, a higher choline level was found in the left visual cortex of citicoline-treated rats compared to untreated rats (Fig 2). No apparent metabolic change was observed in the sham group. Conclusions : Chronic IOP elevation by intracameral hydrogel injection significantly decreased visual acuity and choline-containing compounds in the visual cortex, whereas oral administration of citicoline ameliorated these effects. Our findings suggest that oral citicoline treatment may possess neuroprotective effects on the visual cortex by replenishing choline contents during glaucomatous degeneration, and H-MRS may help in monitoring such metabolic changes in the brain

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 : Recent studies have indicated reduced blood flow in not only the eye but also the brain in patients with late glaucoma (LG). In contrast, patients with early glaucoma (EG) appear to show increased ocular blood flow, but little is known about their corresponding brain changes and their specific pathology. This study utilized non-invasive functional and molecular imaging biomarkers to determine cerebral blood flow (CBF) and neurochemical changes in the visual cortex of EG and LG patients. Methods : Four EG (age=67.00+/-5.26 years; 2F), 6 LG (age=65.33+/-2.75 years; 1F), and 5 healthy controls (age=63.00+/-3.11 years; 1F) underwent pseudo-continuous arterial spin labeling (pCASL) functional MRI and MEGA-PRESS magnetic resonance spectroscopy (MRS) at rest using a 3-Tesla MRI scanner. Basal CBF was measured from pCASL in the visual and motor cortices (Figure 1a). For MRS, the level of gamma-aminobutyric acid (GABA) in the visual cortex was quantified through the LCModel software (Figure 2a), and normalized over the N-acetyl aspartate and N-acetyl aspartyl glutamic acid complex (NAA+NAAG) to account for systematic fluctuations following LCModel guidelines. Results : Basal CBF in the white matter (WM) of the visual cortex was significantly higher for EG compared to LG (p=0.021) and controls (p=0.045), whereas basal CBF in the gray matter (GM) of the visual cortex was significantly higher for EG compared to LG (p=0.042) (Figure 1b). No apparent CBF difference was found within the motor cortex across groups (p>0.05). For MRS, normalized GABA levels appeared lower in EG than in controls (p=0.021), while LG had a trending decease compared to controls (p=0.092) (Figure 2b). Within the glaucoma groups, we also found a negative association between basal CBF and normalized GABA levels in both WM (p=0.038) and GM (p=0.039) (Figures 2c-d). Conclusions : The elevated basal CBF and lower baseline GABA levels in the visual cortex of EG suggest that vascular autoregulation dysfunction and/or neurochemical adaptation may be occurring in the brain's visual system apart from the eye during the initial phases of glaucoma pathogenesis. Within glaucoma groups, the inverse correlations demonstrated between basal CBF and baseline GABA levels may also offer a quantitative framework for interrogating inhibitory GABAergic activity and hemodynamic reactivity relationships in the glaucomatous brain during disease progression

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)

To construct an optical coherence tomography (OCT) nerve fiber layer (NFL) parameter that has maximal correlation and agreement with visual field (VF) mean deviation (MD). The NFL_MD parameter in dB scale was calculated from the peripapillary NFL thickness profile nonlinear transformation and VF area-weighted averaging. From the Advanced Imaging for Glaucoma study, 245 normal, 420 pre-perimetric glaucoma (PPG), and 289 perimetric glaucoma (PG) eyes were selected. NFL_MD had significantly higher correlation (Pearson R: 0.68 vs 0.55, p < 0.001) with VF_MD than the overall NFL thickness. NFL_MD also had significantly higher sensitivity in detecting PPG (0.14 vs 0.08) and PG (0.60 vs 0.43) at the 99% specificity level. NFL_MD had better reproducibility than VF_MD (0.35 vs 0.69 dB, p < 0.001). The differences between NFL_MD and VF_MD were -0.34 ± 1.71 dB, -0.01 ± 2.08 dB and 3.54 ± 3.18 dB and 7.17 ± 2.68 dB for PPG, early PG, moderate PG, and severe PG subgroups, respectively. In summary, OCT-based NFL_MD has better correlation with VF_MD and greater diagnostic sensitivity than the average NFL thickness. It has better reproducibility than VF_MD, which may be advantageous in detecting progression. It agrees well with VF_MD in early glaucoma but underestimates damage in moderate~advanced stages.

PURPOSE/OBJECTIVE:This study examined whether short-term use of topical nonsteroidal anti-inflammatory drug (NSAID) or steroid therapy affected the efficacy of selective laser trabeculoplasty (SLT). DESIGN/METHODS:Double-masked, randomized, placebo-controlled, dual-center, multisurgeon trial. PARTICIPANTS/METHODS:Patients older than 18 years with intraocular pressure (IOP) of more than 18 mmHg for whom the clinician decided SLT was the appropriately indicated therapy were randomized to 1 of 3 groups in a ratio of 1:1:1 as follows: ketorolac 0.5%, prednisolone 1%, or saline tears. METHODS:After SLT, patients randomized into each group were instructed to use an unmarked drop 4 times daily starting the day of SLT and continuing for 4 additional days. The Kruskal-Wallis test and Wilcoxon rank-sum test were used for continuous variables when comparing 2 or 3 treatment groups, respectively. The Fisher exact test was used for categorical variables. MAIN OUTCOME MEASURES/METHODS:The primary outcome of this study was IOP at 12 weeks. Secondary outcome measures included IOP at 1 and 6 weeks, patient-reported pain, and detectable anterior chamber inflammation. RESULTS:Ninety-six eyes of 85 patients fit inclusion criteria and were enrolled between the 2 sites. The NSAID, steroid, and placebo groups were similar in baseline demographics and baseline IOP (mean, 23.3±3.9 mmHg; P = 0.57). There was no statistically significant difference in IOP decrease among groups at week 6. Both the NSAID and steroid groups showed a statistically significantly greater decrease in IOP at week 12 compared with the placebo group (mean, -6.2±3.1 mmHg, -5.2±2.7 mmHg, and -3±4.3 mmHg, respectively; P = 0.02 [analysis of variance] and P = 0.002 [t test] for NSAID vs. placebo groups; P = 0.02 for steroid vs. placebo groups). CONCLUSIONS:Significantly better IOP reduction at 12 weeks was measured in eyes treated with steroid or NSAID drops after SLT. Short-term postoperative use of NSAID or steroid drops may improve IOP reduction after SLT. Longer-term follow-up studies are indicated.

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.

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.