Faculty Bibliography

Purpose : Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that exhibits a number of neuroprotective effects on the brain and the eye. Here, we investigated the neurobehavioral effects of oral scutellarin treatment in a novel experimental model of chronic glaucoma. Methods : Ten adult C57BL/6J mice (Group 1) were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice (Group 2) received a unilateral intracameral injection of phosphate-buffered saline only. Another eight mice (Group 3) with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin from 1 week before to 2 weeks after hydrogel injection. Tonometry, optical coherence tomography, and optokinetic visuobehavioral testing were performed longitudinally to monitor the IOP, total retinal thickness, visual acuity, and contrast threshold of bilateral eyes in all three groups. Results : Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant IOP difference between scutellarin treatment and untreated groups (Figure site uses cookies. By continuing to use our website, you are agreeing to 1). With scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes (Figure 2). No significant difference in retinal thickness or optokinetic measures was found in the non-injected eyes over time or between all groups. Conclusions : Oral scutellarin treatment appeared to preserve retinal structure and visual function in experimental glaucoma induced by chronic IOP elevation. Scutellarin may be a possible candidate as a novel neurotherapeutic agent for glaucoma treatment

Purpose : Repetitive transorbital alternating current stimulation (rtACS) is an application of weak electric current near the eyes used in vision rehabilitation of optic neuropathies (ON). Conceptually rtACS entrains neuronal oscillations, augmenting neuronal function. In subjects with ON we evaluated whether rtACS influenced visual structure and function. Methods : 34 subjects with ON enrolled in a prospective trial underwent comprehensive ophthalmic evaluation, visual field (VF) 24-2 and 10-2 tests (Humphrey Field Analyzer) and OCT (Cirrus HD-OCT) retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thicknesses at baseline and follow-up (FU) visits. Subjects received rtACS 30-to 45-minutes daily for 10 days. Sham subjects (n=4) underwent the same procedures but received no current. Point-by-point analyses of VF total deviation (TD) values were conducted between rtACS and sham groups. Regression analyses determined rate of change for each TD point per eye (significant points with positive rate of change defined as improved, negative rate of change as progressed; insignificant rate of change as no change) and the association between RNFL and GCIPL between groups. Results : The number of FU visits with VF tests ranged 2 to 7, with no significant differences detected between rtACS vs sham groups' FU duration. No significant differences were detected between groups' baseline VF 24-2 and 10-2 mean deviation (MD) values (Table 1). The average numbers of improved points (VF 10-2) and progressed points (VF 24-2) were greater for rtACS while the average number of no change points was greater for sham (VF 24-2, p0.05, Table 1). Further analysis of FU duration determined a significant interaction with rtACS; number of improved points (VF 10-2) and progressed points (VF 24-2, p<0.02) were not sustained over time. No significant differences were detected in average RNFL and GCIPL thicknesses between groups. Conclusions : Preliminary analyses of the effect of rtACS in ON indicate initial improvement but not a clear benefit over time. Detection of differences between rtACS vs sham groups may be biased due to the small sham sample and range of FU duration as VF test-to-test variability is known to increase with worsening VF MD. Future analyses will assess interim effect at early vs late FU time points to evaluate the role of rtACS in vision rehabilitation

Purpose : Mutations in optineurin (OPTN) are associated with familial normal tension glaucoma and other neurodegenerative diseases. It remains unclear how OPTN loss or mutation alters visual function during aging. Here, we used transgenic mouse models and in vivo assessments to test the hypothesis that OPTN dysfunction contributes to progressive visual impairment through a toxic gain of function mechanism. Methods : Mice with C57BL/6 background were used (Fig 1): wildtype (WT; n=19), homozygous OPTN knock-out (mOPTN-KO; n=13), hemizygous mouse E50K OPTN knock-in (mE50K-het; n=8), homozygous mouse E50K OPTN knock-in (mE50K homoz; n=10), and human E50K OPTN bacterial artificial chromosome overexpression (hE50K BAC; n=6) (PMID: 31076632, 25818176). Intraocular pressure (IOP), total retinal thickness (TRT), visual acuity (VA), and contrast sensitivity (CS) were measured at 6, 12, and 18 months of age in the same mice using the TonoLab rebound tonometer, Bioptigen spectral-domain optical te uses cookies. By continuing to use our website, you are agreeing to coherence tomography imaging, and OptoMotry optokinetic virtual reality system respectively. Left and right eye data were averaged and analyzed using ANOVAs followed by posthoc tests between genotype and age groups, as well as linear regressions for VA versus contrast threshold (CT). Results : Our longitudinal study of the same mice during the aging process showed that IOP remained normal between 10-15 mmHg (Fig 2A). Small to no difference in TRT over time or compared to WT was observed (Fig 2B). mE50K-homoz, mE50K-het, and hE50K BAC mice exhibited greater age-dependent decline in VA and CT than WT or mOPTN-KO mice (Fig 2C, 2D, 2E). In contrast, mOPTN-KO mice showed preservation of VA and CT over time compared to WT. Consistently, mice with one copy of E50K OPTN (mE50K het) experienced less deterioration of VA and CT compared to mice with two copies (mE50K homoz) or mild overexpression (hE50K BAC). Conclusions : Depsite limited IOP and TRT changes between age and genotype groups, E50K OPTN was associated with differential age-dependent visual impairment (greater for CS than VA). Surprisingly, OPTN deficiency preserved visual function such that CS in knockout mice was better than WT mice. Our results suggest visual loss associated with E50K OPTN is due to a toxic gain of function mechanism, and that suppression of OPTN might constitute a therapeutic strategy for glaucomatous neurodegeneration

Purpose : Prevalence and severity of glaucoma varies between ethnicities. It has been previously shown that ocular vessel density (VD) varies among healthy subjects of different ethnicities. To further elucidate the potential role of VD in glaucoma we examined ocular VD in Caucasian, African American (AA), and Latin at similar stages of glaucoma severity. Methods : 150 glaucoma eyes of which 46 eyes (30 subjects) were Caucasian, 71 eyes (43 subjects) African American, and 33 eyes (19 subjects) Latin were included in the analysis. Comorbidities known to affect the systemic or local micro-or macro-vasculature and medications that are known to modify vessel diameter were excluded. Disease severity distribution was similar across ethnicity groups. All eyes had comprehensive ophthalmic examination, Cirrus HD-OCT (Zeiss, Dublin, CA) and OCT angiography (OCTA; Angioplex, Zeiss) qualified scans of the macula and optic nerve head regions (200x200 OCT cube scans and 3x3mm / 6x6mm OCTA scans). VD as provided by the device's native software in the inner vascular plexus was used for the analysis. Statistical analysis was performed using mixed-effects models accounting for ethnicity, age, axial length, visual field mean deviation (MD), OCT signal strength (SS), disc area and intra-subject correlation. Tukeyadjusted p-values for pairwise ethnicity comparisons were obtained.Results : No significant difference was detected in age and MD among ethnicities (Table 1). Caucasian subjects had the longest AL and thinnest RNFL, and Latin subjects had the largest disc area and cup-to-disc ratio (CDR; Table 1). No significant differences were detected among ethnicities in ONH VD in any of the scan types and regions. In the macula, Caucasians had significantly higher VD in the center of both scan sizes in comparison with both AA and Latin (Table 2). Caucasian eyes also had significantly higher VD in the full 3x3 scan in comparison with AA eyes. There were no significant differences in the rest of the macular VD measurements among the 3 groups. Conclusions : Macular VD in glaucoma subjects varies among ethnicities and might play a role in the varying disease behavior among ethnicities. Differences in foveal avascular zone size might explain our findings but further investigation is warranted

Purpose : Dampened cerebrovascular reactivity (CVR) impairs blood delivery to brain regions. Multiple studies have suggested a role of the basal forebrain (BF) in glaucoma (PMID: 31242454; ARVO 2020: 4336). However, CVR changes in BF with glaucoma severity have yet to be explored. Recently, relative CVR (rCVR) mapping was introduced using resting-state functional MRI (rsfMRI) without gas challenges. Here, we investigate rCVR changes in the visual cortex and basal forebrain with glaucoma severity. Methods : Normal (n=22), early-stage (n=18), and advanced-stage (n=19) glaucoma patients underwent anatomical MRI and rsfMRI. The optic nerve and optic chiasm volumes were measured using ImageJ. rCVR maps and regional rCVR values were generated and extracted with MriCloud online tool. Age, optical coherence tomography measurements, and Humphrey visual field perimetry were obtained from clinical records. Results are presented as mean+/-SEM. One-way ANOVA followed by post-hoc Bonferroni's multiple comparisons test, and trend analysis were applied. Results : Demographics, clinical ophthalmic assessments, and volumetric MRI assessments illustrated the characteristics of the anterior visual pathways in the normal control, earlystage glaucoma and advance-stage glaucoma groups (Fig. 1). The averaged rCVR map from normal controls is consistent with previous studies (PMID: 27888058, 32278094) (Fig. 2). Advanced-stage glaucoma patients [1.03+/-0.03 relative unit (r.u.); p<0.05] have significantly lower rCVR in the visual cortex compared to normal controls (1.20+/-0.06 r.u.; early-stage: 1.09+/-0.05 r.u.), and exhibit a decreasing trend in more severe disease. These corroborate with a previous Doppler ultrasound study (PMID: 23816432). Interestingly, rCVR in BF has an increasing trend with severity. No significant rCVR change was observed in the somatosensory cortex. Conclusions : Visual cortical rCVR decreases with glaucoma severity, while rCVR in the basal forebrain increases with severity. Our results verify visual cortical CVR reduction in glaucoma patients and further solidify that the basal forebrain plays a role in glaucoma

Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.

OBJECTIVE:Familial Dysautonomia (FD) disease, lacks a useful biomarker for clinical monitoring. In this longitudinal study we characterized the structural changes in the macula, peripapillary and the optic nerve head (ONH) regions in subjects with FD. METHODS:Data was consecutively collected from subjects attending the FD clinic between 2012 and 2019. All subjects were imaged with spectral-domain Optical Coherence Tomography (OCT). Global and sectoral measurements of mean retinal nerve fiber layer (RNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness, and ONH parameters of rim area, average cup-to-disc (C:D) ratio, and cup volume were used for the analysis. The best fit models (linear, quadratic and broken stick linear model) were used to describe the longitudinal change in each of the parameters. RESULTS:91 subjects (149 eyes) with FD of ages 5-56 years were included in the analysis. The rate of change for average RNFL and average GCIPL thicknesses were significant before reaching a plateau at the age of 26.2 for RNFL and 24.8 for GCIPL (- 0.861 µm/year (95% CI - 1.026, - 0.693) and - 0.553 µm/year (95% CI - 0.645, - 0.461), respectively). Significant linear rate of progression was noted for all ONH parameters, except for a subset of subjects (24%), with no cupping that did not show progression in any of the ONH parameters. CONCLUSIONS:The rapidly declining RNFL and GCIPL can explain the progressive visual impairment previously reported in these subjects. Among all structural parameters, ONH parameters might be most suitable for longitudinal follow-up, in eyes with a measurable cup.

Purpose/UNASSIGNED:The purpose was to establish the position of the fovea centralis to the optic nerve via en-face, near-infrared spectral domain optical coherence tomography (NIR-OCT) in healthy patients. This may shed light on physiological variability and be used for studying subtle cases of foveal ectopia in macular pathology and after retinal detachment. Methods/UNASSIGNED:SD-OCT data of 890 healthy eyes were retrospectively analyzed. Exclusion criteria included axial myopia causing tilting of the optic disc, peripapillary atrophy >1/3 the width of the disc, macular images excluding greater than half of the optic disc, and patients unable to maintain vertical head positioning. Two independent reviewers measured the horizontal and vertical distance from the fovea to the optic disc center and optic disc diameter via cross-sectional and en-face scanning laser ophthalmoloscopy OCT imaging. Results/UNASSIGNED:890 eyes were included in the study. The right and left eyes differed in the horizontal distance from the fovea to the disc center (4359 vs. 4248 µm, P < 0.001) and vertical distance from the fovea to the disc center (464 µm vs. 647, P < 0.001). This corresponded to a smaller angle between the right and left eyes (6.07° vs. 8.67°, P < 0.001). Older age was associated with a larger horizontal (P = 0.008) and vertical distance (0.025). These differences persisted after correcting for axial length in the 487 patients with axial-length data. Conclusions/UNASSIGNED:This study compares the position of the fovea centralis among individuals without macular pathology on a micron level basis. The significant variability between right and left eyes indicates that contralateral eye evaluation cannot be reliably used. Rather, true foveal ectopia requires assessments of preoperative and postoperative NIR-OCT scans. This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia. Translational Relevance/UNASSIGNED:This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia.