Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Zhao, Da; Wong, Vickie; Nguyen, Christine T. O.; Jobling, Andrew I; Fletcher, Erica L.; Vingrys, Algis J.

doi:10.1167/iovs.19-27113

Cited by 18 publications

(19 citation statements)

References 53 publications

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“…The results found confirmatory evidence that GCC thickness correlates positively to RGC abundance. While several studies analyzed mouse retinas with both OCT and RGC-specific immunostaining 41–44 , relatively few have tested the correlations between these measurements 5, 45 . Nishioka and colleagues studied correlations between RGC density determined by immunostaining with RBPMS and OCT-derived GCC thickness in mice with experimental autoimmune encephalomyelitis (EAE) 5 .…”

Section: Discussionmentioning

confidence: 99%

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Hedberg-Buenz

Meyer

Heide

et al. 2020

Preprint

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PurposeDespite popularity of optical coherence tomography (OCT) in glaucoma studies, it’s unclear how well OCT-derived metrics compare to traditional measures of retinal ganglion cell (RGC) abundance. Here, Diversity Outbred (J:DO) mice are used to directly compare ganglion cell complex (GCC)-thickness measured by OCT to metrics of retinal anatomy measured ex vivo with retinal wholemounts or optic nerve cross sections.MethodsJ:DO mice (n = 48) underwent OCT and fundoscopic exams, with GCC-thickness measured using automated segmentation. Following euthanasia, RGC axons were quantified from para-phenylenediamine-stained optic nerve cross sections and RGC somas from BRN3A-immunolabeled retinal wholemounts with total cellularity assessed by TO-PRO or hematoxylin nuclear staining.ResultsJ:DO tissues lacked overt disease. GCC-thickness (62.4 ± 3.7 µm), RGC abundance (3,097 ± 515 BRN3A+ nuclei/mm2; 45,533 ± 9,077 axons), and total inner retinal cell abundance (6,952 ± 810 nuclei/mm2) varied broadly. GCC-thickness correlated significantly to RGC somal density (r = 0.46) and axon number (r = 0.49), whereas total inner retinal cellularity did not. Retinal area (20.3 ± 2.4 mm2) and optic nerve (0.09 ± 0.02 mm2) cross-sectional area varied widely. Sex did not significantly influence any of these metrics. In bilateral comparisons, GCC-thickness (r = 0.89), inner retinal cellularity (r = 0.47), and RGC axon abundance (r = 0.72) all correlated significantly.ConclusionsAmongst outbred mice with widely variable phenotypes, OCT-derived measurements of GCC thickness correlate significantly to RGC abundance and axon number. The extensive phenotypic variability exhibited by J:DO mice make them a powerful resource for studies of retinal anatomy using quantitative genetics.

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Section: Discussionmentioning

confidence: 99%

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Hedberg-Buenz

Meyer

Heide

et al. 2020

Preprint

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“…The photopic negative (PhNR) and positive scotopic threshold responses are parameters of the electroretinogram (ERG) that are largely generated by RGCs in the inner retina 8‐10 . RGC function has been shown to recover after acute and chronic IOP insults even after prolonged periods of functional loss 11‐13 . Capacity for recovery is reduced with advancing age 14 and can be modified by interventions such as exercise and diet restriction 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial

Hui

Tang

Williams

et al. 2020

Clinical Exper Ophthalmology

139

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Importance: Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD + , is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown. Background: To examine the effects of nicotinamide on inner retinal function in glaucoma, in participants receiving concurrent glaucoma therapy. Design: Crossover, double-masked, randomized clinical trial. Participants recruited from two tertiary care centres. Participants: Fifty-seven participants, diagnosed and treated for glaucoma. Methods: Participants received oral placebo or nicotinamide and reviewed six-weekly. Participants commenced 6 weeks of 1.5 g/day then 6 weeks of 3.0 g/day followed by crossover without washout. Visual function measured using electroretinography and perimetry. Main outcome measures: Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio).

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“…Some clinical trials have investigated the effects of PEA on IOP: Costagliola et al 46 treated normal tension glaucoma patients with PEA 600 mg a day for 6 months, recording a significant IOP reduction (from 14.4 ± 3.2 mm Hg to 11.1 ± 4.3 mmHg, p < 0.01) at the end of the follow up; similar data have been reported for a shorter period of therapy (two months) by Gagliano 15 in open angle glaucoma and ocular hypertensive patients. We observed a reduction in IOP of more than 1 mmHg, which may seem like a small reduction: however, the Early Manifest Glaucoma Trial (EMGT) pointed out a 10% reduction in the risk of progression for every mmHg of IOP reduction 2 , so it is still clinically relevant since IOP-mediated ganglion cell dysfunction may be reversible 47 .…”

Section: Discussionmentioning

confidence: 72%

Effect of palmitoylethanolamide on inner retinal function in glaucoma: a randomized, single blind, crossover, clinical trial by pattern-electroretinogram

Rossi

Scudeller

Lumini

et al. 2020

Sci Rep

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Glaucoma is a neurodegenerative disease, our study aimed to evaluate the potential effects of Palmitoylethanolamide (PEA) supplementation on RGCs function by PERG examination, and to record effects on intraocular pressure, visual field and quality of life. It was a single centre, randomized, prospective, single blind, two treatment, two period crossover study on stable glaucoma patients on topical monotherapy comparing current topical therapy alone or additioned with PEA 600 mg one tablet a day. At baseline, at 4 and at 8 months, all patients underwent to complete ophthalmic examination, pattern electroretinogram, visual field, and quality of life evaluation. 40 patients completed the study: mean age 66.6 ± 7.6 years; 21 (52.5%) male; 35 POAG (87.5%). At baseline, most patients had an early visual field defect, the IOP was well controlled. At the end of the PEA 600 mg supplementation, a significantly higher (mean 0.56 μV, 95% CI 0.30-0.73, p < 0.001) in the P50-wave amplitude was observed; in the PEA period a significantly lower IOP (− 1.6 mmHg, 95% CI − 2 to 1.2, p < 0.001) and higher quality of life scores (+ 6.7, 95% CI 4-9.9, p < 0.001) were observed. Our study is the first to show promising effects of PEA on PERG and on quality of life in glaucoma patients. Glaucoma is a progressive and multifactorial neurodegeneration in which pro-apoptotic signals are developed towards the retinal ganglion cells (RGC) and their axons: neurodegeneration is the progressive loss of structure or function of neurons resulting from the imbalance between protective factors and harmful influences on RGCs. It is widely recognized that the high outflow resistance in the trabecular meshwork outflow pathways causes an increase in intra-ocular pressure (IOP) and that the IOP levels cause deformation of the lamina cribrosa resulting in axonal damage and consequent apoptosis of the RGCs. Therefore, currently, the only approach proven to be efficient in preserving visual function is lowering IOP in both the initial and advanced stages 1-4. Many glaucoma patients experience damage that continues despite tonometric compensation, therefore other possible treatment areas have been studied, including ocular blood flow and neuroprotection. Neuroprotection can be defined as a therapeutic approach aimed at preventing, blocking and, in some cases, reversing neuronal cell damage 5. Numerous compounds have been shown to be neuroprotective in animal models of experimental glaucoma, such as memantine 6 and brimonidine 7 : but so far, no compound has reached a level of evidence sufficient to be considered a neuroprotective agent in humans 8. Blood flow abnormalities in the optic nerve head may initiate the glaucomatous cascade leading to neuroaxonal damage 9,10 , although perfusion pressure may be relevant in glaucoma but very difficult to measure 11. Secondary trans-synaptic degeneration may also involve higher visual centers and treatment strategies to prevent

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Reversibility of Retinal Ganglion Cell Dysfunction From Chronic IOP Elevation

Cited by 18 publications

References 53 publications

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial

Effect of palmitoylethanolamide on inner retinal function in glaucoma: a randomized, single blind, crossover, clinical trial by pattern-electroretinogram

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