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Preclinical stress originates in the rat optic nerve head during development of autoimmune optic neuritis
摘要： Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Although it is the presenting symptom in many cases, the initial events are currently unknown. However, in the earliest stages of autoimmune optic neuritis in rats, pathological changes are already apparent such as microglial activation and disturbances in myelin ultrastructure of the optic nerves. αB-crystallin is a heat-shock protein induced in cells undergoing cellular stress and has been reported to be up-regulated in both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Therefore, we wished to investigate the timing and localization of its expression in autoimmune optic neuritis. Although loss of oligodendrocytes was not observed until the later disease stages accompanying immune cell infiltration and demyelination, an increase in oligodendrocyte αB-crystallin was observed during the preclinical stages. This was most pronounced within the optic nerve head and was associated with areas of IgG deposition. Since treatment of isolated oligodendrocytes with sera from myelin oligodendrocyte glycoprotein (MOG)-immunized animals induced an increase in αB-crystallin expression, as did passive transfer of sera from MOG-immunized animals to unimmunized recipients, we propose that the partially permeable blood–brain barrier of the optic nerve head may present an opportunity for blood-borne components such as anti-MOG antibodies to come into contact with oligodendrocytes as one of the earliest events in disease development.
关键词： EAE,optic nerve head,optic neuritis,oligodendrocyte,αB-crystallin,auto-antibody
更新于2025-11-21 11:08:18
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Pattern of Retinal Nerve Fiber Layer Thickness Loss in Fetal Alcohol Syndrome: A Spectral-Domain Optical Coherence Tomography Analysis
摘要： Introduction: Optic disc hypoplasia is a common feature in fetal alcohol syndrome. Thus, we aimed to evaluate the optic disc morphology changes and the peripapillary retinal nerve fiber layer thickness in these patients. Material and Methods: We performed spectral-domain optical coherence tomography in a cohort of 11 patients (22 eyes) with fetal alcohol syndrome and in an age-matched control group. We evaluated optic nerve head parameters (optic disc area and diameter, rim area, cup/disc horizontal and vertical ratios) and peripapillary retinal nerve fiber layer thickness. Results: Mean optic disc area, rim area and optic disc diameter were, respectively, in fetal alcohol syndrome patients and control subjects: 1.540 ± 0.268 and 1.748 ± 0.326 mm2; 1.205 ± 0.286 and 1.461 ± 0.314 mm2; 1.417 ± 0.124 and 1.501 ± 0.148 mm (p < 0.05). We found no significant differences between groups for cup/disc ratios. Mean retinal nerve fiber layer thickness was significantly lower in fetal alcohol syndrome patients (90.500 ± 9.344 μm) as compared to controls (111.000 ± 7.855 μm) (p < 0.0001). Analysis showed a significant decrease in retinal nerve fiber layer thickness for the superior, inferior and nasal quadrants (p < 0.005). The temporal quadrant showed no significant differences. Discussion: Optic disc area, rim area and optic disc diameters were significantly reduced in fetal alcohol syndrome patients. Although mean peripapillary retinal nerve fiber layer thickness was decreased, the temporal quadrant was spared. Conclusion: In addition to a smaller optic disc area/ diameter and rim area, we found a heterogeneous peripapillary retinal nerve fiber layer thickness loss in fetal alcohol syndrome patients with sparing of the temporal quadrant. Spectral-domain optical coherence tomography may be useful to determine the presence of fetal alcohol syndrome status.
关键词： Retina,Fetal Alcohol Spectrum Disorders,Optic Nerve Diseases,Nerve Fibers
更新于2025-09-23 15:23:52
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Characterization of Abnormal Optic Nerve Head Morphology in Albinism Using Optical Coherence Tomography
摘要： PURPOSE. To characterize abnormalities in three-dimensional optic nerve head (ONH) morphology in people with albinism (PWA) using spectral-domain optical coherence tomography (SD-OCT) and to determine whether ONH abnormalities relate to other retinal and clinical abnormalities. METHODS. Spectral-domain OCT was used to obtain three-dimensional images from 56 PWA and 60 age- and sex-matched control subjects. B-scans were corrected for nystagmus-associated motion artefacts. Disc, cup, and rim ONH dimensions and peripapillary retinal nerve fiber layer (ppRNFL) thickness were calculated using Copernicus and ImageJ software. RESULTS. Median disc areas were similar in PWA (median ? 1.65 mm2) and controls (1.71 mm2, P ? 0.128), although discs were significantly elongated horizontally in PWA (P < 0.001). In contrast, median optic cup area in PWA (0.088 mm2) was 23.7% of that in controls (0.373 mm2, P < 0.001), with 39.4% of eyes in PWA not demonstrating a measurable optic cup. This led to significantly smaller cup to disc ratios in PWA (P < 0.001). Median rim volume in PWA (0.273 mm3) was 136.6% of that in controls (0.200 mm3). The ppRNFL was significantly thinner in PWA compared with controls (P < 0.001), especially in the temporal quadrant. In PWA, ppRNFL thickness was correlated to ganglion cell thickness at the central fovea (P ? 0.007). Several ONH abnormalities, such as cup to disc ratio, were related to higher refractive errors in PWA. CONCLUSIONS. In PWA, ocular maldevelopment is not just limited to the retina but also involves the ONH. Reduced ppRNFL thickness is consistent with previous reports of reduced ganglion cell numbers in PWA. The thicker rim volumes may be a result of incomplete maturation of the ONH.
关键词： albinism,optic nerve head,optical coherence tomography
更新于2025-09-23 15:23:52
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Retinal Neuroprotection From Optic Nerve Trauma by Deletion of Arginase 2
摘要： Our previous studies have implicated expression of the mitochondrial isoform of the arginase enzyme arginase 2 (A2) in neurovascular injury during ischemic retinopathies. The aim of this study was to characterize the specific involvement of A2 in retinal injury following optic nerve crush (ONC). To accomplish this, wild-type (WT) or A2 knockout (A2?/?) mice were subjected to ONC injury. The contralateral eye served as sham control. Quantitative RT-PCR and western blot were used to evaluate mRNA and protein expression. Retinal ganglion cell (RGC) survival was assessed in retinal whole mounts. Axonal sprouting was determined by anterograde transport of Cholera Toxin B (CTB). These analyses showed increased A2 expression following ONC. Numbers of NeuN-positive neurons as well as Brn3a- and RBPMS-positive RGC were decreased in the WT retinas at 14 days after ONC as compared to the sham controls. This ONC-induced neuronal loss was diminished in the A2?/? retinas. Similarly, axonal degeneration was ameliorated by A2 deletion whereas axon sprouting was enhanced. Significant retinal thinning was also seen in WT retinas at 21 days after ONC, and this was blocked in A2?/? mice. Cell death studies showed an increase in TUNEL positive cells in the RGC layer at 5 days after ONC in the WT retinas, and this was attenuated by A2 deletion. ONC increased glial cell activation in WT retinas, and this was significantly reduced by A2 deletion. Western blotting showed a marked increase in the neurotrophin, brain derived neurotrophic factor (BDNF) and its downstream signaling in A2?/? retinas vs. WT after ONC. This was associated with increases in the axonal regeneration marker GAP-43 in A2?/? retinas. Furthermore, A2?/? retinas showed decreased NLRP3 inflammasome activation and lower interleukin (IL-) 1β/IL-18 levels as compared to WT retinas subjected to ONC. Collectively, our results show that deletion of A2 limits ONC-induced neurodegeneration and glial activation, and enhances axonal sprouting by a mechanism involving increases in BDNF and decreases in retinal inflammation. These data demonstrate that A2 plays an important role in ONC-induced retinal damage. Blockade of A2 activity may offer a therapeutic strategy for preventing vision loss induced by traumatic retinal injury.
关键词： optic nerve crush,retinal ganglion cells,retina,brain derived neurotrophic factor,neuroprotection,arginase 2
更新于2025-09-23 15:23:52
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Quantification of collagen fiber structure using second harmonic generation imaging and two-dimensional discrete Fourier transform analysis: Application to the human optic nerve head
摘要： Second Harmonic Generation (SHG) microscopy is widely used to image collagen fiber microarchitecture due to its high spatial resolution, optical sectioning capabilities and relatively non-destructive sample preparation. Quantification of SHG images requires sensitive methods to capture fiber alignment. This paper presents a 2D Discrete Fourier Transform (DFT) based method for collagen fiber structure analysis from SHG images. The method includes integrated Periodicity Plus Smooth Image Decomposition (PPSID) for correction of DFT edge discontinuity artefact, avoiding the loss of peripheral image data encountered with more commonly used windowing methods. Outputted parameters are: the collagen fiber orientation distribution, aligned collagen content and the degree of collagen fiber dispersion along the principal orientation. We demonstrate its application to determine collagen microstructure in the human optic nerve head, showing its capability to accurately capture characteristic structural features including radial fiber alignment in the innermost layers of the bounding sclera and a circumferential collagen ring in the mid-stromal tissue. Higher spatial resolution rendering of individual lamina cribrosa beams within the nerve head is also demonstrated. Validation of the method is provided in the form of correlative results from wide-angle X-ray scattering (WAXS) and application of the presented method to other fibrous tissues.
关键词： Second Harmonic Generation,edge effect artefact correction,Discrete Fourier Transform,optic nerve head,collagen fiber structure,Non-linear microscopy
更新于2025-09-23 15:23:52
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Relationship between retinal vessel diameter with both retinal nerve fibre layer thickness and optic nerve head parameters in middle‐aged Caucasians: the Northern Finland Birth Cohort Eye study
摘要： Purpose: To study the normal relationship between retinal vessel diameter (RVD) with retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters in a cohort of middle-aged Caucasians. Methods: We investigated 3070 individuals (6140 eyes). Central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured in the right eye using a semi-automated computer-assisted program. Retinal nerve fibre layer (RNFL) thickness and ONH parameters were assessed with Heidelberg retinal tomography (HRT). Results: Data from 2217 persons were analysed including RNFL, CRAE, CRVE, sex, body mass index, mean arterial pressure, diabetes status, smoking status, optic disc area, rim area, spherical refraction and intraocular pressure. A larger RVD was associated with a thicker mean global RNFL thickness especially in global and inferior segments of the retina and with larger optic discs. Each 10 lm increase in the retinal arteriolar calibre was associated with a 5.58 lm increase in mean global RNFL thickness; the corresponding value for a 10 lm increase in venular calibre was 3.79 lm (p < 0.001 for both). Retinal venular calibre displayed consistent associations with RNFL thickness in both genders (p < 0.001 for all), whereas the association of arteriolar calibre and RNFL was more prominent in men (p < 0.001). Conclusion: We found strong associations between larger RVD and thicker RNFL in all subjects. This study helps to clarify the association between RVD, RNFL thickness and ONH parameters and provides normal values for middle-aged Caucasians that will help in future studies investigating the role of vascular aetiology in systemic and eye diseases.
关键词： optic nerve head,retina,IVAN,Heidelberg retinal tomography,central retinal venular equivalent,central retinal arteriolar equivalent
更新于2025-09-23 15:23:52
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The relationship between optic nerve head deformation and visual field defects in myopic eyes with primary open-angle glaucoma
摘要： Purpose: To investigate the relationship between the morphologic features of myopic optic nerve head (ONH) and visual field (VF) defects in myopic subjects with primary open-angle glaucoma (POAG) by intraindividual comparison. Methods: Myopic POAG subjects with unilateral glaucomatous VF defect were recruited. The morphologic features of myopic ONH, including optic disc tilt, optic disc rotation, and β-zone parapapillary atrophy (PPA) were measured from color fundus photographs. The comparisons were performed between the eyes with VF defects and the contralateral eyes without VF defects. Logistic regression analysis was performed to investigate the relationship between various ocular parameters and the presence of VF defects. Results: We retrospectively included 100 eyes of 50 myopic POAG subjects. (Mean age: 50.1 ± 10.0 years). The tilt ratio was similar between the paired eyes. The degree of optic disc rotation (12.96 ± 7.21?) in eyes with VF defects were statistically greater than the contralateral eyes (6.86 ± 4.30?; P < 0.001) without VF defect. The β-zone PPA-to-disc area ratio was significantly greater in eyes with VF defects than the contralateral eyes (P = 0.024) without VF defect. In multivariate logistic regression analysis, the greater degree of optic disc rotation was significantly associated with the presence of VF defects (P < 0.001). However, tilt ratio, β-zone PPA-to-disc area ratio, refractive error, and axial length were not associated with the presence of VF defects. Conclusions: Among the morphologic features of myopic ONH, only the greater degree of the optic disc rotation was associated with the presence of VF defects in myopic subjects with POAG.
关键词： optic nerve head deformation,Myopia,POAG
更新于2025-09-23 15:23:52
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Electronic Medical Record Context Signatures Improve Diagnostic Classification using Medical Image Computing
摘要： Composite models that combine medical imaging with electronic medical records (EMR) improve predictive power when compared to traditional models that use imaging alone. The digitization of EMR provides potential access to a wealth of medical information, but presents new challenges in algorithm design and inference. Previous studies, such as PheWAS (Phenome Wide Association Study), have shown that EMR data can be used to investigate the relationship between genotypes and clinical conditions. Here, we introduce PheDAS (Phenome-Disease Association Study) to extend the statistical capabilities of the PheWAS software through a custom Python package which creates diagnostic EMR signatures to capture system-wide co-morbidities for a disease population within a given time interval. We investigate the effect of integrating these EMR signatures with radiological data to improve diagnostic classification in disease domains known to have confounding factors because of variable and complex clinical presentation. Specifically, we focus on two studies: (1) a study of four major optic nerve related conditions and (2) a study of diabetes. Addition of EMR signature vectors to radiologically-derived structural metrics improves the area under the curve (AUC) for diagnostic classification using elastic net regression, for diseases of the optic nerve. For glaucoma, the AUC improves from 0.71 to 0.83, for intrinsic optic nerve disease it increases from 0.72 to 0.91, for optic nerve edema it increases from 0.95 to 0.96, and for thyroid eye disease from 0.79 to 0.89. The EMR signatures recapitulate known comorbidities with diabetes, such as abnormal glucose but do not significantly modulate image-derived features. In summary, EMR signatures present a scalable and readily applicable approach for using EMR context to increase the statistical power of image derived features.
关键词： CT,MRI,Electronic medical records,Optic nerve
更新于2025-09-23 15:22:29
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Different Effect of Sox11 in Retinal Ganglion Cells Survival and Axon Regeneration
摘要： Purpose: The present study examines the role of Sox11 in the initial response of retinal ganglion cells (RGCs) to axon damage and in optic nerve regeneration in mouse. Methods: Markers of retinal injury were identified using the normal retina database and optic nerve crush (ONC) database on GeneNetwork2 (www.genenetwork.org). One gene, Sox11, was highly upregulated following ONC. We examined the role of this transcription factor, Sox11, following ONC and optic nerve regeneration in mice. In situ hybridization was performed using the Affymetrix 2-plex Quantigene View RNA In Situ Hybridization Tissue Assay System. Sox11 was partially knocked out by intravitreal injection of AAV2-CMV-Cre-GFP in Sox11f/f mice. Optic nerve regeneration model used Pten knockdown. Mice were perfused and the retinas and optic nerves were dissected and examined for RGC survival and axon growth. Results: Sox11 was dramatically upregulated in the retina following ONC injury. The level of Sox11 message increased by approximately eightfold 2 days after ONC. In situ hybridization demonstrated low-level Sox11 message in RGCs and cells in the inner nuclear layer in the normal retina as well as a profound increase in Sox11 message within the ganglion cells following ONC. In Sox11f/f retinas, partially knocking out Sox11 significantly increased RGC survival after ONC as compared to the AAV2-CMV-GFP control group; however, it had little effect on the ability of axon regeneration. Combinatorial downregulation of both Sox11 and Pten resulted in a significant increase in RGC survival as compared to Pten knockdown only. When Pten was knocked down there was a remarkable increase in the number and the length of regenerating axons. Partially knocking out Sox11 in combination with Pten deletion resulted in a fewer regenerating axons. Conclusion: Taken together, these data demonstrate that Sox11 is involved in the initial response of the retina to injury, playing a role in the early attempts of axon regeneration and neuronal survival. Downregulation of Sox11 aids in RGC survival following injury of optic nerve axons, while a partial knockout of Sox11 negates the axon regeneration stimulated by Pten knockdown.
关键词： optic nerve crush,AAV2,retinal ganglion cells,axon regeneration,Sox11
更新于2025-09-23 15:22:29
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Retinal Characterization of the Thy1-GCaMP3 Transgenic Mouse Line After Optic Nerve Transection
摘要： PURPOSE. GCaMP3 is a genetically encoded calcium indicator for monitoring intracellular calcium dynamics. We characterized the expression pattern and functional properties of GCaMP3 in the Thy1-GCaMP3 transgenic mouse retina. METHODS. To determine the specificity of GCaMP3 expression, Thy1-GCaMP3 (B6; CBA-Tg(Thy1-GCaMP3)6Gfng/J) retinas were processed for immunohistochemistry with anti-green fluorescent protein (anti-GFP, to enhance GCaMP3 fluorescence), anti-RBPMS (retinal ganglion cell [RGC]–specific marker), and antibodies against amacrine cell markers (ChAT, GABA, GAD67, syntaxin). Calcium imaging was used to characterize functional responses of GCaMP3-expressing (GCaMP+) cells by recording calcium transients evoked by superfusion of kainic acid (KA; 10, 50, or 100 μM). In a subset of animals, optic nerve transection (ONT) was performed 3, 5, or 7 days prior to calcium imaging. RESULTS. GFP immunoreactivity colocalized with RBPMS but not amacrine cell markers in both ONT and non-ONT (control) groups. Calcium transients evoked by KA were reduced after ONT (50 μM KA; ΔF/F0 [SD]; control: 1.00 [0.67], day 3: 0.50 [0.35], day 5: 0.31 [0.28], day 7: 0.35 [0.36]; P < 0.05 versus control). There was also a decrease in the number of GCaMP3+ cells after ONT (cells/mm2 [SD]; control: 2198 [453], day 3: 2224 [643], day 5: 1383 [375], day 7: 913 [178]; P < 0.05). Furthermore, the proportion of GCaMP3+ cells that responded to KA decreased after ONT (50 μM KA, 97%, 54%, 47%, and 58%; control, 3, 5, and 7 days, respectively). CONCLUSIONS. Following ONT, functional RGC responses are lost prior to the loss of RGC somata, suggesting that anatomical markers of RGCs may underestimate the extent of RGC dysfunction.
关键词： GCaMP3,retinal ganglion cells,Thy1-GCaMP3,calcium imaging,optic nerve transection
更新于2025-09-23 15:22:29