Lamina Cribrosa Microarchitecture in Monkey Early Experimental Glaucoma: Global Change

Abstract

PurposeThe purpose of this study was to characterize experimental glaucoma (EG) versus control eye differences in lamina cribrosa (LC), beam diameter (BD), pore diameter (PD), connective tissue volume fraction (CTVF), connective tissue volume (CTV), and LC volume (LV) in monkey early EG.MethodsOptic nerve heads (ONHs) of 14 unilateral EG and 6 bilateral normal (BN) monkeys underwent three-dimensional reconstruction and LC beam segmentation. Each beam and pore voxel was assigned a diameter based on the largest sphere that contained it before transformation to a common cylinder with inner, middle, and outer layers. Full-thickness and layer averages for BD, PD, CTVF, CTV, and LV were calculated for each ONH. Beam diameter and PD distributions for each ONH were fit to a gamma distribution and summarized by scale and shape parameters. Experimental glaucoma and depth effects were assessed for each parameter by linear mixed-effects (LME) modeling. Animal-specific EG versus control eye differences that exceeded the maximum intereye difference among the six BN animals were considered significant.ResultsOverall EG eye mean PD was 12.8% larger (28.2 ± 5.6 vs. 25.0 ± 3.3 μm), CTV was 26.5% larger (100.06 ± 47.98 vs. 79.12 ± 28.35 × 106 μm3), and LV was 40% larger (229.29 ± 98.19 vs. 163.63 ± 39.87 × 106 μm3) than control eyes (P ≤ 0.05, LME). Experimental glaucoma effects were significantly different by layer for PD (P = 0.0097) and CTVF (P < 0.0001). Pore diameter expanded consistently across all PDs. Experimental glaucoma eye-specific parameter change was variable in magnitude and direction.ConclusionsPore diameter, CTV, and LV increase in monkey early EG; however, EG eye-specific change is variable and includes both increases and decreases in BD and CTVF.

The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications

“…Our method for 3D HMRN, delineation (Figure 13) and parameterization (Figures 14–15) of the monkey ONH has been described within a series of previous reports (Burgoyne et al, 2004; Downs et al, 2007; Lockwood et al, 2015; Pazos et al, 2016; Reynaud et al, 2016; Yang et al, 2007a; Yang et al, 2009a; Yang et al, 2007b; Yang et al, 2011b) and is summarized in detail in a recent book chapter (Yang et al, Accepted for publication Nov 2016 Forthcoming 2017). After, sacrifice and 3D reconstruction of a 6 mm trephine that contains the ONH and pp-sclera, 40 radial digital section images (4.5° degrees apart) of the reconstruction are manually delineated (Figure 13) and global values for 19 standard 3D HMRN parameters (Figures 14–15) are quantified as previously described (Downs et al, 2007; Yang et al, 2007a; Yang et al, 2009a; Yang et al, 2007b; Yang et al, 2011b).…”

“…Our method for quantifying laminar microarchitecture (LMA) has been described in previous publications (Grau et al, 2006); (Lockwood et al, 2015; Reynaud et al, 2016) and is schematically depicted in Figure 20. Each step of the method is briefly outlined in the sections that follow and is illustrated in Figures 21–24.…”

“…A gamma distribution function (Carolynne, 2014), is used to fit the frequency data of the BD and PD voxels in each eye to generate distribution parameters which were used to compare overall EG versus Control eye distribution differences. A detailed description of the overall (experiment-wide) and animal-specific (comparison of the EG to the Control eye within each individual animal) is contained within our previous paper (Reynaud et al, 2016). …”

“…We will soon report (Burgoyne et al, 2015), the FoBMO sub-sectoral character of EG eye LMA parameter change in the 14 early EG animals of Section 3.3, above (manuscript in preparation) (Reynaud et al, 2016). These analyses will form the foundation for future studies (outlined below) in which Control eye LMA data and/or sub-sectoral IOP-related stress and strain (from FE models) (Roberts et al, 2009) will be used to predict the FoBMO location of greatest EG eye LMA change (Burgoyne et al, 2015), post-laser OCT change (Yang et al, 2015b), and/or retrolaminar optic nerve axon loss (Reynaud et al, 2012).…”

Lamina cribrosa in glaucoma

“…Focal laminar defects have recently been associated with disk hemorrhages [51–53] and RNFL defects [54] in glaucoma patients, which suggests that focal damage or remodeling of the LC trabeculae may underlie many of the focal RNFL defects and resulting visual field scotomas in glaucoma. Global changes in the laminar microarchitecture have also been reported in recent NHP studies, including LC pore enlargement and increased laminar region volume and laminar connective tissue volume in glaucoma eyes compared to their fellow control eyes [55]. Hence, while focal defects are detectable clinically in human glaucoma, postmortem studies of NHP glaucoma eyes using high resolution 3D reconstructions of the LC reveal widespread remodeling of the laminar trabeculae as well.…”