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.

Dynamic analysis of dark-light changes of the anterior chamber angle with anterior segment OCT.

PURPOSE: To describe the use of anterior segment optical coherence tomography (OCT) in studying the dynamic dark-light changes of the anterior chamber angle. METHODS: Thirty-seven normal subjects with open angles on dark-room gonioscopy and 18 subjects with narrow angles were analyzed. The dynamic dark-light changes of the anterior-chamber angle were captured with real-time video recording. The angle opening distance (AOD500) and trabecular iris space area (TISA500) of the nasal angle and the pupil diameter in each of the representative serial images were measured. Linear regression analysis was performed to investigate the association between AOD500/TISA500 and pupil diameter. Demographic and biometry measurements associated with the AOD difference (AOD500((light)) - AOD500((dark))) and TISA difference (TISA500((light)) - TISA500((dark))) were analyzed with univariate and multivariate regression models. RESULTS: The AOD500/TISA500 measured in the light in the open-angle and the narrow-angle groups were 694 +/- 330 microm/0.24 +/- 0.10 mm(2) and 265 +/- 78 microm/0.10 +/- 0.03 mm(2), respectively. These values were significantly greater than the AOD500/TISA500 measured in the dark (492 +/- 265 microm/0.16 +/- 0.08 mm(2) and 119 +/- 82 microm/0.05 +/- 0.04 mm(2), respectively, all with P < 0.001). The ranges of the AOD/TISA difference were 13 to 817 microm/0.011 to 0.154 mm(2), with an average of 180 microm/0.073 mm(2). Multivariate regression analysis identified a positive correlation between anterior chamber depth and the AOD/TISA difference. Fifty eyes showed significant correlations between AOD/TISA and pupil diameter, whereas one eye showed no association. Four eyes in the narrow angle group developed appositional angle closure in the dark. CONCLUSIONS: The dynamic dark-light changes of the anterior chamber angle can be imaged and analyzed with anterior segment OCT. Although the angle width generally decreased linearly with increasing pupil diameter, the differences of the angle width measured in the dark and in the light varied substantially among individuals.

Novel approach for anterior chamber angle analysis: anterior chamber angle detection with edge measurement and identification algorithm (ACADEMIA).

OBJECTIVE: To describe a novel approach to measuring anterior chamber angle dimensions and configurations. METHODS: Sixty-nine images were selected randomly from the ultrasound biomicroscopic image database to develop the algorithm. Thirty images were selected for further analyses. The value of each pixel of the 8-bit grayscale ultrasound biomicroscopic images was quantized into 0 (black) or 1 (white), and the edge points outlining the angle were detected and fitted with straight lines. The dimensions and profiles of anterior chamber angles were then measured. RESULTS: The algorithm failed to identify the edge points correctly in 8 (11.6%) of 69 images because of strong background noise. Three basic types of angle configuration were identified based on the derived angle profiles: constant, increasing, and decreasing, which corresponded to flat, bowed forward, and bowed backward iris contours, respectively. The angle measurements demonstrated high correlation with trabecular-iris angle and angle opening distance 500 (calculated as the distance from the corneal endothelium to the anterior iris surface perpendicular to a line drawn at 500 mum from the scleral spur). The strongest association was found between the averaged angle derived from the angle profile and the angle opening distance 500 (r = 0.91). CONCLUSION: The proposed algorithm has high correlations with angle opening distance and trabecular-iris angle with the added advantages of being fully automated, reproducible, and able to capture the characteristic angle configurations. However, good-quality ultrasound biomicroscopic images with high signal-to-noise ratio are required to identify the edge points correctly.

Comparative study of retinal nerve fiber layer measurement by StratusOCT and GDx VCC, II: structure/function regression analysis in glaucoma.

PURPOSE: To evaluate the structure/function relationship between visual field sensitivity and retinal nerve fiber layer (RNFL) thickness measured by StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) and GDx VCC (Laser Diagnostic Technologies, Inc., San Diego, CA). METHODS: Eighty-nine subjects (27 who had healthy eyes, 21 who were glaucoma suspect, 41 who had glaucoma) were enrolled in this cross-sectional study. RNFL thickness was measured using the StratusOCT and the GDx VCC, and visual field (VF) was examined using the Humphrey VF analyzer. The relationship between RNFL thickness and VF sensitivity-expressed in terms of mean deviation (MD) in decibel (dB) scale, unlogged 1/lambert (L), and Advanced Glaucoma Intervention Study (AGIS) and Collaborative Initial Glaucoma Treatment Study (CIGTS) VF scores-were evaluated with linear and nonlinear regression models. Coefficient of determination (R(2)) was calculated, and regression models were compared using the Akaike information criterion and the F test. RESULTS: In plotting MD against RNFL thickness, curvilinear regression models demonstrated the best fit, whereas linear regression attained the best associations when VF sensitivity was expressed in 1/L. However, when healthy subjects were excluded from the analyses, the second-order polynomial was better than linear regression in describing the relation between 1/L and GDx VCC-measured RNFL thickness. Regression profiles between AGIS/CIGTS VF scores and RNFL thickness were best described in the linear and the first-order inverse models for GDx VCC and StratusOCT RNFL measurements, respectively. In general, StratusOCT RNFL measurements achieved higher associations with visual function in all the respective regression analyses than did GDx VCC. CONCLUSIONS: Description of structure/function relationships in glaucoma depends on the choice of perimetry scale, the type of RNFL measuring device, and the characteristics of the studied groups. The higher association with visual function in StratusOCT RNFL measurements compared with that in GDx VCC suggested optical coherence tomography might be a better approach for evaluating structure/function relationships. Curvilinear regression profiles found between StratusOCT RNFL thickness and MD/VF scores provide an explanation for those longitudinal observations, showing that VFs with higher AGIS/CIGTS VF scores or worse MD at baseline are at higher risk for deterioration. Regression analysis of the structure/function profile could provide important information in the assessment of the trend and pattern of glaucoma progression.