Diagnostic criteria of anterior segment swept-source optical coherence tomography to detect gonioscopic angle closure.

AIMS: To compare the diagnostic performance of 360° anterior segment optical coherence tomography assessment by applying normative percentile cut-offs versus iris trabecular contact (ITC) for detecting gonioscopic angle closure. METHODS: In this multicentre study, 394 healthy individuals were included in the normative dataset to derive the age-specific and angle location-specific normative percentiles of angle open distance (AOD500) and trabecular iris space area (TISA500) which were measured every 10° for 360°. 119 healthy participants and 170 patients with angle closure by gonioscopy were included in the test dataset to investigate the diagnostic performance of three sets of criteria for detection of gonioscopic angle closure: (1) the 10th and (2) the 5th percentiles of AOD500/TISA500, and (3) ITC (ie, AOD500/TISA500=0 mm/mm2). The number of angle locations with angle closure defined by each set of the criteria for each eye was used to generate the receiver operating characteristic (ROC) curve for the discrimination between gonioscopic angle closure and open angle. RESULTS: Of the three sets of diagnostic criteria examined, the area under the ROC curve was greatest for the 10th percentile of AOD500 (0.933), whereas the ITC criterion AOD500=0 mm showed the smallest area under the ROC (0.852) and the difference was statistically significant with or without adjusting for age and axial length (p<0.001). The criterion ≥90° of AOD500 below the 10th percentile attained the best sensitivity 87.6% and specificity 84.9% combination for detecting gonioscopic angle closure. CONCLUSIONS: Applying the normative percentiles of angle measurements yielded a higher diagnostic performance than ITC for detecting angle closure on gonioscopy.

Effects of Deep Optic Nerve Head Structures on Bruch's Membrane Opening- Minimum Rim Width and Peripapillary Retinal Nerve Fiber Layer.

PURPOSE: To explore the effects of deep optic nerve head (ONH) structures on Bruch's membrane opening (BMO)-minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in healthy eyes. DESIGN: Prospective cross-sectional study. METHODS: Two hundred five healthy eyes of 141 subjects (mean ± standard deviation of age and axial length (AXL): 46.9 ± 10.0 years and 24.79 ± 1.15 mm) were enrolled. Best fit multivariable linear mixed models identified factors associated with BMO-MRW and pRNFLT. Explanatory variables included age, gender, AXL, BMO and anterior scleral canal opening (ASCO) area and ovality, magnitude of BMO and ASCO shift, peripapillary choroidal thickness, lamina cribrosa (LC) parameters, prelaminar thickness, and peripapillary scleral (PPS) angle. RESULTS: Thinner BMO-MRW was associated with older age, smaller ASCO/BMO offset magnitude, larger BMO area, thinner prelaminar thickness, deeper LC, and thinner pRNFLT (P = .011, <.001, .004, <.001, <.001, <.001 respectively). Thinner pRNFLT was associated with shorter AXL, smaller ASCO area, a more posteriorly bowed PPS, shallower LC and thinner BMO-MRW. (P = .030, .002, .035, .012, <.001 respectively) CONCLUSIONS: BMO-MRW and pRNFLT were influenced by several deep ONH structures such as BMO and ASCO position shift, BMO or ASCO area, prelaminar thickness, PPS bowing and LC depth in addition to patient characteristics such as age and AXL. The degree and/or direction of associations varied between deep ONH structures and BMO-MRW or pRNFLT. Despite both BMO-MRW and pRNFLT being surrogate parameters for RGC loss, a complex relationship with ONH deep-layer morphology was indicated.

Crystalline lens nuclear age prediction as a new biomarker of nucleus degeneration.

BACKGROUND: The crystalline lens is a transparent structure of the eye to focus light on the retina. It becomes muddy, hard and dense with increasing age, which makes the crystalline lens gradually lose its function. We aim to develop a nuclear age predictor to reflect the degeneration of the crystalline lens nucleus. METHODS: First we trained and internally validated the nuclear age predictor with a deep-learning algorithm, using 12 904 anterior segment optical coherence tomography (AS-OCT) images from four diverse Asian and American cohorts: Zhongshan Ophthalmic Center with Machine0 (ZOM0), Tomey Corporation (TOMEY), University of California San Francisco and the Chinese University of Hong Kong. External testing was done on three independent datasets: Tokyo University (TU), ZOM1 and Shenzhen People's Hospital (SPH). We also demonstrate the possibility of detecting nuclear cataracts (NCs) from the nuclear age gap. FINDINGS: In the internal validation dataset, the nuclear age could be predicted with a mean absolute error (MAE) of 2.570 years (95% CI 1.886 to 2.863). Across the three external testing datasets, the algorithm achieved MAEs of 4.261 years (95% CI 3.391 to 5.094) in TU, 3.920 years (95% CI 3.332 to 4.637) in ZOM1-NonCata and 4.380 years (95% CI 3.730 to 5.061) in SPH-NonCata. The MAEs for NC eyes were 8.490 years (95% CI 7.219 to 9.766) in ZOM1-NC and 9.998 years (95% CI 5.673 to 14.642) in SPH-NC. The nuclear age gap outperformed both ophthalmologists in detecting NCs, with areas under the receiver operating characteristic curves of 0.853 years (95% CI 0.787 to 0.917) in ZOM1 and 0.909 years (95% CI 0.828 to 0.978) in SPH. INTERPRETATION: The nuclear age predictor shows good performance, validating the feasibility of using AS-OCT images as an effective screening tool for nucleus degeneration. Our work also demonstrates the potential use of the nuclear age gap to detect NCs.

Association of Bergmeister Papilla and Deep Optic Nerve Head Structures With Prelaminar Schisis of Normal and Glaucomatous Eyes.

PURPOSE: To investigate factors associated with the severity of prelaminar schisis (PLS) in heathy subjects and glaucoma patients. DESIGN: Prospective cross-sectional study. METHODS: A total of 217 eyes of 217 subjects (110 normal eyes and 107 open angle glaucoma eyes) were studied. Frequency and severity of PLS were compared between normal and glaucomatous eyes. Multivariate logistic models were used to assess factors associated with the severity of PLS. Factors considered were age, axial length, glaucomatous damage indices, Bruch membrane opening (BMO) and anterior scleral canal opening parameters, tractional forces (posterior vitreous staging and presence of Bergmeister papilla), circumpapillary choroidal thickness, lamina cribrosa (LC) parameters, and peripapillary scleral (PPS) angle. RESULTS: The frequency of PLS was 70.9% in normal eyes and 72.0% in glaucomatous eyes. There was no difference in frequency and severity between the groups. The presence of Bergmeister papilla was the strongest predictor of a more severe PLS in both normal and glaucomatous eyes (odds ratio [OR] + 9.78, 12.5; both P < .001). A larger PPS angle in normal eyes (OR = 1.19; P = .003) and a larger BMO area and a deeper LC depth in glaucomatous eyes (OR = 1.08, 1.05; both P = .038) were associated with severity of PLS. CONCLUSIONS: The severity of PLS was strongly associated with the presence of Bergmeister papilla, suggesting a traction-related phenomenon. Correlation of PLS severity with larger BMO area and deeper LC depth, which are optic nerve head structures associated with glaucoma, suggested its possible relationship with glaucomatous damage.

Retinal Nerve Fiber Layer Optical Texture Analysis: Detecting Axonal Fiber Bundle Defects in Patients with Ocular Hypertension.

PURPOSE: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) to investigate the prevalence, patterns, and risk factors of RNFL defects in patients with ocular hypertension (OHT) who showed normal optic disc and RNFL configuration in clinical examination, normal RNFL thickness on OCT analysis, and normal visual field (VF) results. DESIGN: Cross-sectional study. PARTICIPANTS: Six hundred eyes of 306 patients with OHT. METHODS: All participants underwent clinical examination of the optic disc and RNFL, OCT RNFL imaging, and 24-2 standard automated perimetry. To detect RNFL defects, ROTA was applied. The risk score for glaucoma development was calculated according to the Ocular Hypertension Treatment Study and European Glaucoma Prevention Study (OHTS-EGPS) risk prediction model. Risk factors associated with RNFL defects were analyzed using multilevel logistic regression analysis. MAIN OUTCOME MEASURES: Prevalence of RNFL defects. RESULTS: The average intraocular pressure (IOP) measured from 3 separate visits within 6 months was 24.9 ± 1.8 mmHg for the eye with higher IOP and 23.7 ± 1.7 mmHg for the eye with lower IOP; the respective central corneal thicknesses were 568.7 ± 30.8 µm and 568.8 ± 31.2 µm. Of 306 patients with OHT, 10.8% (33 patients, 37 eyes) demonstrated RNFL defects in ROTA in at least 1 eye. Of the 37 eyes with RNFL defects, the superior arcuate bundle was the most frequently involved (62.2%), followed by the superior papillomacular bundle (27.0%) and the inferior papillomacular bundle (21.6%). Papillofoveal bundle defects were observed in 10.8% of eyes. The smallest RNFL defect spanned 0.0° along Bruch's membrane opening margin, whereas the widest RNFL defect extended over 29.3°. Age (years) (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.03-1.13), VF pattern standard deviation (decibels [dB]) (OR, 1.82; 95% CI, 1.01-3.29), cup volume (mm3) (OR, 1.24; 95% CI, 1.01-1.53), and the OHTS-EPGS risk score (OR, 1.04; 95% CI, 1.01-1.07) were associated with RNFL defects. CONCLUSIONS: A considerable proportion of patients with OHT who showed no signs of optic disc and RNFL thickness abnormalities on clinical and OCT examination exhibited RNFL defects on ROTA. Axonal fiber bundle defects on ROTA may represent the earliest discernible sign of glaucoma in the glaucoma continuum. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Deep Optic Nerve Head Structures Associated With Increasing Axial Length in Healthy Myopic Eyes of Moderate Axial Length.

PURPOSE: To elucidate which swept-source optical coherence tomography (OCT)-derived optic nerve head (ONH) parameters are associated with longer axial length (AXL) in healthy myopic eyes. DESIGN: Prospective cross-sectional observational study. METHODS: Two hundred eleven healthy eyes of 140 participants (96 emmetropic-mild myopic [AXL: 22.2-24.5 mm], 83 moderately myopic [24.5-26.0 mm], and 32 highly myopic [26.0-27.4 mm] eyes) were enrolled. Bruch membrane opening (BMO), anterior scleral canal opening (ASCO) area and ovality, minimum rim width, parameters defining misalignment between the BMO and ASCO planes, OCT-defined region of perineural canal retinal epithelium atrophy and externally oblique choroidal border tissue, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), circumpapillary choroidal thickness (cpChT), lamina cribrosa parameters, and peripapillary scleral (PPS) angle were calculated from BMO-centered radial scans reconstructed from 3D raster scans. Multivariate linear mixed models were used to elucidate ONH parameters that are independently associated with AXL. RESULTS: Longer AXL was associated with a greater misalignment between ASCO and BMO planes, larger region of externally oblique choroidal border tissue, thinner cpChT, larger PPS angle, larger ASCO area, and thicker cpRNFLT (all P < .040 after Bonferroni's correction for number of included explanatory variables). CONCLUSIONS: A greater misalignment between BMO and ASCO planes, thinner choroid, a more posteriorly bowed PPS, an enlargement of ASCO, and thicker cpRNFLT were each associated with longer AXL. An enhanced understanding of these AXL-associated configurations should provide essential information to improve our ability to detect glaucoma-induced ONH morphology in myopic eyes.

Assessment of Iris Trabecular Contact in Eyes with Gonioscopic Angle-Closure.

PURPOSE: To investigate the extent of iris trabecular contact (ITC) measured by anterior segment OCT (AS-OCT) and its association with primary angle-closure (PAC) and PAC glaucoma (PACG) in eyes with gonioscopic angle-closure and to determine the diagnostic performance of ITC for detection of gonioscopic angle-closure. DESIGN: Multicenter, prospective study. PARTICIPANTS: A total of 119 healthy participants with gonioscopic open-angle and 170 patients with gonioscopic angle-closure (94 with PAC suspect and 76 with PAC/PACG) were included. METHODS: One eye of each subject was randomly selected for AS-OCT imaging. Angle-opening distance (AOD500) and trabecular iris space area (TISA500) were measured every 10° for 360°. Two criteria of ITC500 were examined: (1) AOD500 = 0 mm and (2) TISA500 = 0 mm2. The association between the extent of ITC500 and PAC/PACG in eyes with gonioscopic angle-closure was analyzed with logistic regression analysis. MAIN OUTCOME MEASURES: Sensitivity and specificity of ITC500 for detection of gonioscopic angle-closure; odds ratio (OR) of PAC/PACG. RESULTS: The sensitivity of ITC500 ≥ 10° for detection of gonioscopic angle-closure ranged from 82.4% (AOD500 = 0 mm) to 84.7% (TISA500 = 0 mm2), and the specificity was 85.7% (for both AOD500 = 0 mm and TISA500 = 0 mm2). The extent of ITC500 determined by AS-OCT, not cumulative gonioscopy score (i.e., the sum of the modified Shaffer grades over 4 quadrants), was associated with the odds of PAC/PACG in eyes with gonioscopic angle-closure; the odds of PAC/PACG increased by 5% for every 10° increase in ITC500 (OR, 1.051, 95% confidence interval [CI], 1.022-1.080 for AOD500 = 0 mm; OR, 1.049, 95% CI, 1.022-1.078 for TISA500 = 0 mm2). Axial length and anterior chamber depth were not associated with PAC/PACG in eyes with gonioscopic angle-closure (P ≥ 0.574). CONCLUSIONS: A greater extent of ITC measured by AS-OCT, not angle-closure determined by gonioscopy, was associated with a greater odds of PAC/PACG in eyes with gonioscopic angle-closure.

Reproducibility of deep learning based scleral spur localisation and anterior chamber angle measurements from anterior segment optical coherence tomography images.

AIMS: To apply a deep learning model for automatic localisation of the scleral spur (SS) in anterior segment optical coherence tomography (AS-OCT) images and compare the reproducibility of anterior chamber angle (ACA) width between deep learning located SS (DLLSS) and manually plotted SS (MPSS). METHODS: In this multicentre, cross-sectional study, a test dataset comprising 5166 AS-OCT images from 287 eyes (116 healthy eyes with open angles and 171 eyes with primary angle-closure disease (PACD)) of 287 subjects were recruited from four ophthalmology clinics. Each eye was imaged twice by a swept-source AS-OCT (CASIA2, Tomey, Nagoya, Japan) in the same visit and one eye of each patient was randomly selected for measurements of ACA. The agreement between DLLSS and MPSS was assessed using the Euclidean distance (ED). The angle opening distance (AOD) of 750 µm (AOD750) and trabecular-iris space area (TISA) of 750 µm (TISA750) were calculated using the CASIA2 embedded software. The repeatability of ACA width was measured. RESULTS: The mean age was 60.8±12.3 years (range: 30-85 years) for the normal group and 63.4±10.6 years (range: 40-91 years) for the PACD group. The mean difference in ED for SS localisation between DLLSS and MPSS was 66.50±20.54 µm and 84.78±28.33 µm for the normal group and the PACD group, respectively. The span of 95% limits of agreement between DLLSS and MPSS was 0.064 mm for AOD750 and 0.034 mm2 for TISA750. The respective repeatability coefficients of AOD750 and TISA750 were 0.049 mm and 0.026 mm2 for DLLSS, and 0.058 mm and 0.030 mm2 for MPSS. CONCLUSION: DLLSS achieved comparable repeatability compared with MPSS for measurement of ACA.

Diagnostic assessment of glaucoma and non-glaucomatous optic neuropathies via optical texture analysis of the retinal nerve fibre layer.

The clinical diagnostic evaluation of optic neuropathies relies on the analysis of the thickness of the retinal nerve fibre layer (RNFL) by optical coherence tomography (OCT). However, false positives and false negatives in the detection of RNFL abnormalities are common. Here we show that an algorithm integrating measurements of RNFL thickness and reflectance from standard wide-field OCT scans can be used to uncover the trajectories and optical texture of individual axonal fibre bundles in the retina and to discern distinctive patterns of loss of axonal fibre bundles in glaucoma, compressive optic neuropathy, optic neuritis and non-arteritic anterior ischaemic optic neuropathy. Such optical texture analysis can detect focal RNFL defects in early optic neuropathy, as well as residual axonal fibre bundles in end-stage optic neuropathy that were indiscernible by conventional OCT analysis and by red-free RNFL photography. In a diagnostic-performance study, optical texture analysis of the RNFL outperformed conventional OCT in the detection of glaucoma, as defined by visual-field testing or red-free photography. Our findings show that optical texture analysis of the RNFL for the detection of optic neuropathies is highly sensitive and specific.

Nicotinamide riboside as a neuroprotective therapy for glaucoma: study protocol for a randomized, double-blind, placebo-control trial.

BACKGROUND: Whereas lowering the intraocular pressure (IOP) can slow optic nerve degeneration in glaucoma, many patients with glaucoma continue to develop progressive loss in vision despite a significant reduction in IOP. No treatment has been shown to be effective for neuroprotection in glaucoma. We set out to conduct a randomized controlled trial to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide precursor, is effective to slow optic nerve degeneration in patients with primary open-angle glaucoma (POAG). We hypothesize that patients treated with NR have a slower rate of progressive retinal nerve fiber layer (RNFL) thinning compared with those treated with placebo. METHODS: This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study including 125 patients with POAG. Patients will be randomized to receive 300 mg NR or placebo for 24 months. Clinical examination, optical coherence tomography imaging of the RNFL, and visual field (VF) test will be performed at the baseline, 1 month, 4 months, and then at 2-month intervals until 24 months. The primary outcome measure is the rate of RNFL thinning measured over 24 months. The secondary outcome measures include (1) time to VF progression, (2) time to progressive RNFL/ganglion cell inner plexiform layer (GCIPL) thinning, and (3) the rate of change of VF sensitivity over 24 months (to investigate neuroprotection) and 1 month (to investigate neuroenhancement). The rates of RNFL thinning and VF sensitivity decline between treatment groups will be compared with linear mixed modeling. Survival analysis will be performed to compare the differences in time from baseline to VF progression and time from baseline to progressive RNFL/GCIPL thinning between treatment groups using Cox proportional hazards models. DISCUSSION: Outcome measures in glaucoma neuroprotection trials have been centered on the detection of VF progression, which may take years to develop and confirm. In addition to addressing whether NR has a neuroprotective/neuroenhancement effect in glaucoma patients, this study will demonstrate the feasibility of studying neuroprotection in a relatively short trial period (24 months) by comparing the rates of progressive RNFL thinning, a more reproducible and objective outcome measure compared with VF endpoints, between treatment groups. TRIAL REGISTRATION: Chinese Clinical Trial Registry 1900021998.

Willingness to pay for cataract surgery in baiyin district, northwestern China.

PURPOSE: To investigate willingness to pay for cataract surgery, and its associations, in Northwestern China. METHODS: Four hundred thirty-eight persons aged 50 years and above, diagnosed with cataract indicated for surgery, identified in an outreach screening program were included. Subjects were offered a willingness-to-pay interview for the maximal amount that the subjects would be willing to pay for a cataract surgery. Age, gender, literacy, education level, occupation, and annual household income were recorded. RESULTS: Among 328 (74.9%) subjects who completed the interview, 197 (60.1%) participants were willing to pay something for the cataract surgery (mean, 902.9 ± 856.7 renminbi[RMB], [US$ 145 ± 137]; median, 500RMB, US$ 78). Individuals with presenting visual acuity (PVA) in the worse eye ≤6/60 (OR: 2.1, 95% CI: 1.3-3.2) and a high annual household incomes (OR: 2.0, 95% CI: 0.9-4.6) were likely to be willing to pay for the surgery, as revealed in the regression models. Willingness to pay any amount for cataract surgery was more likely among literate persons (OR: 1.5, 95% CI: 1.0-2.4) and persons with non-agricultural occupation (OR: 1.8, 95% CI: 1.0-3.2). CONCLUSIONS: The amount that subjects were willing to pay is significantly less than the current cost of cataract surgery (5000 RMB, US$320) in the area. Providing low-cost cataract surgery to patients in a financially sustainable manner is important to increase uptake of cataract surgery among rural residents in Northwest China.

Efficacy and safety of selective laser trabeculoplasty and pattern scanning laser trabeculoplasty: a randomised clinical trial.

AIMS: To compare the intraocular pressure (IOP) lowering effect and safety profile between pattern scanning laser trabeculoplasty (PSLT) and selective laser trabeculoplasty (SLT) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) over a 12-month follow-up. METHODS: 132 patients with POAG or OHT were consecutively enrolled and randomised (1:1) to receive PSLT (n=65) or SLT (n=67) in a single centre. IOP was measured before and then on 1 day, 1 week, 1, 3, 6, 9 and 12 months after PSLT/SLT. The primary outcome measure was the proportion of patients with ≥20% IOP reduction at 12 months without IOP-lowering medications (complete success). RESULTS: The mean baseline IOP was 21.2±4.1 mm Hg for eyes randomised to PSLT and 21.3±4.7 mm Hg for eyes randomised to SLT (p=0.898). At 12 months, the IOP was 18.3±3.1 and 17.8±3.4 mm Hg, respectively (p=0.402). IOP measurements were comparable between the groups over 12 months (overall mean difference 0.4 mm Hg, 95% CI: -0.5 to 1.3 mm Hg). 15.4% of PSLT-treated and 25.4% of SLT-treated patients achieved treatment success (difference: 10.0%, 95% CI: -3.6 to 23.6) (p=0.155), respectively. A higher baseline IOP and a greater percentage of IOP reduction at day 1 were associated with a greater percentage of IOP reduction at 12 months (p<0.001). There were no significant differences in visual field mean deviation, average retinal nerve fibre layer thickness, corneal endothelial cell count and visual acuity between the treatment groups at the baseline and 12-month follow-up (p≥0.062). CONCLUSIONS: PSLT was not superior to SLT in terms of safety and IOP-lowering efficacy in patients with POAG or OHT. TRIAL REGISTRATION NUMBER: The clinical trial was registered in the Centre for Research and Biostatistics Clinical Trials Registry, the Chinese University of Hong Kong (Identifier CUHK_CCT00407). The full trial protocol can be accessed from the authors on request.

Anterior chamber angle imaging with swept-source optical coherence tomography: comparison between CASIAII and ANTERION.

This study compared the test-retest variabilities and measurement agreement of anterior chamber angle (ACA) dimensions measured by two anterior segment swept-source optical coherence tomography (SS-OCT)-the ANTERION (Heidelberg Engineering, Heidelberg, Germany) and CASIAII (Tomey, Nagoya, Japan). Thirty-eight subjects, 18 patients with primary angle closure and 20 healthy participants with open angles, were included. The mean age was 54.7 ± 15.8 years (range: 26-75 years). One eye of each subject was randomly selected for anterior segment imaging by ANTERION and CASIAII, using the same scan pattern (6 evenly spaced radial scans across the anterior segment for three times) in the same visit. The between- and within-instrument agreement and repeatability coefficients of angle open distance (AOD500), trabecular-iris space area (TISA500), lens vault (LV), scleral spur-scleral spur distance (SSD), anterior chamber depth (ACD), and pupil diameter (PD) were measured. The anterior and posterior boundaries of the cornea, iris, and lens were automatically segmented by the SS-OCT instruments; the scleral spur was manually located by a single masked observer. There were significant differences between ANTERION and CASIAII measurements; the SSD, PD, and ACD were smaller whereas AOD500 and TISA500 were greater in ANTERION compared with CASIAII (P < 0.001). Anterior segment measurements obtained from the two SS-OCT instruments showed strong associations (R2 ranged between 0.866 and 0.998) although the between-instrument agreement was poor; the spans of 95% limits of between-instrument agreement were ≥ 1.5-folds than the within-instrument agreement for either instrument. Whereas both SS-OCT instruments showed low test-retest measurement variabilities, the repeatability coefficients of AOD500, TISA500, ACD, and PD were slightly smaller for CASIAII than ANTERION (P ≤ 0.012).

MicroRNA-19a-PTEN Axis Is Involved in the Developmental Decline of Axon Regenerative Capacity in Retinal Ganglion Cells.

Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remain elusive. In this study, we show that microRNAs are differentially expressed during RGC development and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of phosphatase and tensin homolog (PTEN), a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and it increases axon extension in RGCs isolated from aged human donors. This study uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and it demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity in optic neuropathies.

Adaptive optics two-photon microscopy enables near-diffraction-limited and functional retinal imaging in vivo.

In vivo fundus imaging offers non-invasive access to neuron structures and biochemical processes in the retina. However, optical aberrations of the eye degrade the imaging resolution and prevent visualization of subcellular retinal structures. We developed an adaptive optics two-photon excitation fluorescence microscopy (AO-TPEFM) system to correct ocular aberrations based on a nonlinear fluorescent guide star and achieved subcellular resolution for in vivo fluorescence imaging of the mouse retina. With accurate wavefront sensing and rapid aberration correction, AO-TPEFM permits structural and functional imaging of the mouse retina with submicron resolution. Specifically, simultaneous functional calcium imaging of neuronal somas and dendrites was demonstrated. Moreover, the time-lapse morphological alteration and dynamics of microglia were characterized in a mouse model of retinal disorder. In addition, precise laser axotomy was achieved, and degeneration of retinal nerve fibres was studied. This high-resolution AO-TPEFM is a promising tool for non-invasive retinal imaging and can facilitate the understanding of a variety of eye diseases as well as neurodegenerative disorders in the central nervous system.

Wide-field Trend-based Progression Analysis of Combined Retinal Nerve Fiber Layer and Ganglion Cell Inner Plexiform Layer Thickness: A New Paradigm to Improve Glaucoma Progression Detection.

OBJECTIVE: Evaluation of glaucoma progression with OCT has been centered on the analysis of progressive retinal nerve fiber layer (RNFL) thinning over the parapapillary region and/or progressive ganglion cell inner plexiform layer (GCIPL) thinning over the macula. We investigated (1) whether combining the RNFL and GCIPL as a single layer (i.e., RNFL-GCIPL) for wide-field progression analysis outperforms wide-field progression analysis of the RNFL or the GCIPL, and (2) whether eyes with progressive RNFL-GCIPL thinning are at risk of visual field (VF) progression. DESIGN: Prospective, longitudinal study. PARTICIPANTS: A total of 440 eyes from 236 glaucoma patients; 98 eyes from 49 healthy individuals. METHODS: OCT RNFL/GCIPL/RNFL-GCIPL thickness and VF measurements were obtained at ∼4-month intervals for ≥3 years. Progressive changes of the RNFL/GCIPL/RNFL-GCIPL thicknesses were analyzed over a wide field (12×9 mm2) covering the parapapillary region and the macula with trend-based progression analysis (TPA) controlled at a false discovery rate of 5%. VF progression was determined by the Early Manifest Glaucoma Trial criteria. MAIN OUTCOME MEASURES: Proportions of eyes with progressive RNFL/GCIPL/RNFL-GCIPL thinning; hazard ratios (HRs) for development of VF progression. RESULTS: More eyes showed progressive RNFL-GCIPL thinning (127 eyes; 28.9%, 95% confidence interval [CI]: 23.9%-33.8%) than progressive RNFL thinning (74 eyes; 16.8%, 95% CI: 13.1%-20.6%) and progressive GCIPL thinning (26 eyes; 5.9%, 95% CI: 3.7%-8.1%) in the glaucoma group over the study follow-up. Progressive RNFL-GCIPL thinning was almost always detected before or simultaneously with progressive RNFL thinning or progressive GCIPL thinning. The specificity of TPA (estimated from the healthy group) for detection of progressive RNFL-GCIPL thinning, progressive RNFL thinning, and progressive GCIPL thinning was 83.7% (95% CI: 74.9%-92.4%), 94.9% (95% CI: 90.6%-99.2%), and 96.9% (95% CI: 93.5%-100.0%), respectively. Eyes with progressive RNFL-GCIPL thinning had a higher risk to develop possible (HR: 2.4, 95% CI: 1.2-5.0) or likely (HR: 4.6, 95% CI: 1.5-14.0) VF progression, with adjustment of covariates, compared with eyes without progressive RNFL-GCIPL thinning. CONCLUSIONS: Progression analysis of RNFL-GCIPL thickness reveals a significant portion of progressing eyes that neither progression analysis of RNFL thickness nor GCIPL thickness would identify. Wide-field progression analysis of RNFL-GCIPL thickness is effective to inform the risk of VF progression in glaucoma patients.

Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury.

Retinal ganglion cell (RGC) degeneration, leading to irreversible blindness in chronic optic neuropathies, commonly begins with dendritic shrinkage followed by axon degeneration. Although limited axon regeneration in the optic nerve is possible with a genetic deletion of PTEN/SOCS3 after optic nerve injury, the roles of PTEN/SOCS3 on dendritic preservation and regeneration remain unclear. This study investigated the effect of PTEN/SOCS3 genetic deletion on the structural integrity of RGC dendrites and axons in the retina following optic nerve crush. Using time-lapse, in vivo confocal scanning laser ophthalmoscopy to serially image dendritic and axonal arborizations of RGCs over six months after injury, RGC dendrites and axons were only preserved in Thy-1-YFP/PTEN-/- and Thy-1-YFP/PTEN-/-SOCS3-/- mice, and axons in the retina regenerated at a rate of 21.1 µm/day and 15.5 µm/day, respectively. By contrast, dendritic complexity significantly decreased in Thy-1-YFP-SOCS3-/- and control mice at a rate of 7.0 %/day and 7.1 %/day, respectively, and no axon regeneration in the retina was observed. RGC survival probability was higher in Thy-1-YFP/PTEN-/- and Thy-1-YFP/PTEN-/-SOCS3-/- mice compared with Thy-1-YFP-SOCS3-/- and control mice. The differential responses between the transgenic mice demonstrate that although a genetic deletion of PTEN, SOCS3, or PTEN/SOCS3 allows partial axon regeneration in the optic nerve after optic nerve crush, a deletion of PTEN, but not SOCS3, ameliorates RGC dendritic shrinkage. This shows that the signaling pathways involved in promoting axon regeneration do not equally contribute to the preservation of dendrites, which is crucial to the translational application of neuroregenerative therapies for visual restoration.

Diagnostic criteria for detection of retinal nerve fibre layer thickness and neuroretinal rim width abnormalities in glaucoma.

BACKGROUND/AIMS: Although measurements of the Bruch's membrane opening minimum rim width (BMO-MRW) and retinal nerve fibre layer thickness (RNFLT) with optical coherence tomography (OCT) have been widely adopted in the diagnostic evaluation of glaucoma, there is no consensus on the diagnostic criteria to define BMO-MRW and RNFLT abnormalities. This study investigated the sensitivities and specificities of different diagnostic criteria based on the OCT classification reports for detection of glaucoma. METHODS: 340 eyes of 137 patients with glaucoma and 87 healthy individuals, all with axial length ≤26mm, had global and sectoral BMO-MRW and RNFLT measured with Spectralis OCT (Heidelberg Engineering). Six diagnostic criteria were examined: global measurement below the fifth or the first percentile; ≥1 sector measurement below the fifth or the first percentile; superotemporal and/or inferotemporal measurement below the fifth or the first percentile. The sensitivities and specificities of BMO-MRW/RNFLT assessment for detection of glaucoma (eyes with visual field (VF) defects) were compared. RESULTS: Among the six criteria examined, superotemporal and/or inferotemporal measurement below the fifth percentile showed the highest sensitivities and specificities for glaucoma detection. Abnormal superotemporal and/or inferotemporal RNFLT attained a higher sensitivity than abnormal superotemporal and/or inferotemporal BMO-MRW to detect mild glaucoma (mean VF MD: -3.32±1.59 dB) (97.9% and 88.4%, respectively, p=0.006), and glaucoma (mean VF MD: -9.36±8.31 dB) (98.4% and 93.6%, respectively, p=0.006), at the same specificity (96.1%). CONCLUSIONS: Superotemporal and/or inferotemporal RNFLT/MRW below the fifth percentile yield the best diagnostic performance for glaucoma detection with RNFLT attains higher sensitivities than MRW at the same specificity in eyes without high myopia.

Coding Region Mutation Screening in Optineurin in Chinese Normal-Tension Glaucoma Patients.

PURPOSE: To study the roles of sequence alterations in the optineurin (OPTN) gene-coding region in normal-tension glaucoma (NTG) among Chinese patients. METHODS: Genomic DNA was extracted from 190 NTG patients and 201 control subjects. The thirteen exons of OPTN were amplified by polymerase chain reaction and analyzed by direct sequencing. Detected sequence changes were compared between NTG patients and control subjects. RESULTS: Seven sequence changes in OPTN were identified in both NTG patients and control subjects. Among them, c.464G>A (T34 T), c.509C>T (T49T), c.806G>A (V148V), and c.959T>C (P199P) were synonymous codon changes, whilst c.655T>A (M98K), c.1996G>A (R545Q), and c.1582T>C (I407T) were missense changes. Two previously reported heterozygous mutations, c.458G>A (E50K) in exon 4 and c.691_692insAG in exon 6, were not found in this study. Out of these seven OPTN sequence variants, c.464G>A (T34T) was significantly associated with NTG in both the allelic and genotypic association analyses (allelic association: p = 0.0001, OR = 2.20, 95% CI: 1.46-3.31; genotypic association: p = 0.0001), whereas the association of other variants with NTG did not reach statistical significance (p > 0.05). Variants c.1582 T>C (I407T) and c.806G>A (V148V) were identified in one and two NTG patients, respectively, but not in the control subjects. CONCLUSIONS: This study confirmed the association of the OPTN T34T variant with NTG, suggesting that OPTN is a susceptibility gene for NTG in Chinese. Moreover, a variant with amino acid change (I407T) was identified in NTG but not in controls. Further studies are warranted to assess whether this variant is a causative mutation for NTG.