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      Experimental Glaucoma Causes Optic Nerve Head Neural Rim Tissue Compression: A Potentially Important Mechanism of Axon Injury

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          Abstract

          Purpose

          We tested the hypothesis that experimental glaucoma (EG) results in greater thinning of the optic nerve head (ONH) neural rim tissue than the peripapillary retinal nerve fiber layer (RNFL) tissue.

          Methods

          Longitudinal spectral-domain optical coherence tomography (SDOCT) imaging of the ONH and peripapillary RNFL was performed every other week under manometric IOP control (10 mm Hg) in 51 nonhuman primates (NHP) during baseline and after induction of unilateral EG. The ONH parameter minimum rim area (MRA) was derived from 80 radial B-scans centered on the ONH; RNFL cross-sectional area (RNFLA) from a peripapillary circular B-scan with 12° diameter.

          Results

          In control eyes, MRA was 1.00 ± 0.19 mm 2 at baseline and 1.00 ± 0.19 mm 2 at the final session ( P = 0.77), while RNFLA was 0.95 ± 0.09 and 0.95 ± 0.10 mm 2, respectively ( P = 0.96). In EG eyes, MRA decreased from 1.00 ± 0.19 mm 2 at baseline to 0.63 ± 0.21 mm 2 at the final session ( P < 0.0001), while RNFLA decreased from 0.95 ± 0.09 to 0.74 ± 0.19 mm 2, respectively ( P < 0.0001). Thus, MRA decreased by 36.4 ± 20.6% in EG eyes, significantly more than the decrease in RNFLA (21.7 ± 19.4%, P < 0.0001). Other significant changes in EG eyes included increased Bruch's membrane opening (BMO) nonplanarity ( P < 0.05), decreased BMO aspect ratio ( P < 0.0001), and decreased MRA angle ( P < 0.001). Bruch's membrane opening area did not change from baseline in either control or EG eyes ( P = 0.27, P = 0.15, respectively).

          Conclusions

          Optic nerve head neural rim tissue thinning exceeded peripapillary RNFL thinning in NHP EG. These results support the hypothesis that axon bundles are compressed transversely within the ONH rim along with glaucomatous deformation of connective tissues.

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          Most cited references61

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          Transcellular degradation of axonal mitochondria.

          It is generally accepted that healthy cells degrade their own mitochondria. Here, we report that retinal ganglion cell axons of WT mice shed mitochondria at the optic nerve head (ONH), and that these mitochondria are internalized and degraded by adjacent astrocytes. EM demonstrates that mitochondria are shed through formation of large protrusions that originate from otherwise healthy axons. A virally introduced tandem fluorophore protein reporter of acidified mitochondria reveals that acidified axonal mitochondria originating from the retinal ganglion cell are associated with lysosomes within columns of astrocytes in the ONH. According to this reporter, a greater proportion of retinal ganglion cell mitochondria are degraded at the ONH than in the ganglion cell soma. Consistently, analyses of degrading DNA reveal extensive mtDNA degradation within the optic nerve astrocytes, some of which comes from retinal ganglion cell axons. Together, these results demonstrate that surprisingly large proportions of retinal ganglion cell axonal mitochondria are normally degraded by the astrocytes of the ONH. This transcellular degradation of mitochondria, or transmitophagy, likely occurs elsewhere in the CNS, because structurally similar accumulations of degrading mitochondria are also found along neurites in superficial layers of the cerebral cortex. Thus, the general assumption that neurons or other cells necessarily degrade their own mitochondria should be reconsidered.
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            Optical coherence tomography angiography of optic disc perfusion in glaucoma.

            To compare optic disc perfusion between normal subjects and subjects with glaucoma using optical coherence tomography (OCT) angiography and to detect optic disc perfusion changes in glaucoma.
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              Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage.

              We examined the histologic structure of the optic nerve head in 15 eyes of nine persons with a known glaucoma history. All had been seeing eyes, varying from normal visual acuity and visual field to advanced glaucoma damage. The site of damage to nerve fibers is the scleral lamina cribrosa, where there is local blockage of axonal transport. Early cup size increase prior to definite field loss results from loss of nerve fibers, not from damage to astrocytic glial cells of the nerve head. No selective damage to nerve head capillaries is seen in mildly damaged specimens. Scanning electron microscopic analysis suggests that the structure of the lamina cribrosa is an important determinant of the degree of susceptibility to damage by elevated intraocular pressure.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                iovs
                iovs
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                26 August 2016
                August 2016
                : 57
                : 10
                : 4403-4411
                Affiliations
                [1 ]Discoveries in Sight Research Laboratories Devers Eye Institute and Legacy Research Institute, Legacy Health, Portland, Oregon, United States
                [2 ]Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
                Author notes
                Correspondence: Brad Fortune, Discoveries in Sight Research Laboratories, Devers Eye Institute and Legacy Research Institute, 1225 NE Second Avenue, Portland, OR 97232, USA; bfortune@ 123456deverseye.org .
                Article
                iovs-57-10-28 IOVS-16-20000
                10.1167/iovs.16-20000
                5016000
                27564522
                03074d7e-2e3f-4527-b338-42421ed4cd54

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 25 May 2016
                : 19 July 2016
                Categories
                Glaucoma

                glaucoma,optical coherence tomography,retinal ganglion cell axons,optic nerve head,retinal nerve fiber layer

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