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The Effect of Age on Optic Nerve Axon Counts, SDOCT Scan Quality, and Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in Rhesus Monkeys.

ABSTRACT: To evaluate the effect of age on optic nerve axon counts, spectral-domain optical coherence tomography (SDOCT) scan quality, and peripapillary retinal nerve fiber layer thickness (RNFLT) measurements in healthy monkey eyes.In total, 83 healthy rhesus monkeys were included in this study (age range: 1.2-26.7 years). Peripapillary RNFLT was measured by SDOCT. An automated algorithm was used to count 100% of the axons and measure their cross-sectional area in postmortem optic nerve tissue samples (N = 46). Simulation experiments were done to determine the effects of optical changes on measurements of RNFLT. An objective, fully-automated method was used to measure the diameter of the major blood vessel profiles within each SDOCT B-scan.Peripapillary RNFLT was negatively correlated with age in cross-sectional analysis (P < 0.01). The best-fitting linear model was RNFLT(μm) = -0.40 × age(years) + 104.5 μm (R(2) = 0.1, P < 0.01). Age had very little influence on optic nerve axon count; the result of the best-fit linear model was axon count = -1364 × Age(years) + 1,210,284 (R(2) < 0.01, P = 0.74). Older eyes lost the smallest diameter axons and/or axons had an increased diameter in the optic nerve of older animals. There was an inverse correlation between age and SDOCT scan quality (R = -0.65, P < 0.0001). Simulation experiments revealed that approximately 17% of the apparent cross-sectional rate of RNFLT loss is due to reduced scan quality associated with optical changes of the aging eye. Another 12% was due to thinning of the major blood vessels.RNFLT declines by 4 μm per decade in healthy rhesus monkey eyes. This rate is approximately three times faster than loss of optic nerve axons. Approximately one-half of this difference is explained by optical degradation of the aging eye reducing SDOCT scan quality and thinning of the major blood vessels.Current models used to predict retinal ganglion cell losses should be reconsidered.

SUBMITTER: Fortune B

PROVIDER: S-EPMC4043106 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Project description:In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve cross-section were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of ~18.5 (p genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

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The Effect of Age on Optic Nerve Axon Counts, SDOCT Scan Quality, and Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in Rhesus Monkeys.

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