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Raw data for the paper "Differentiation of white matter histopathology using b-tensor encoding and machine learning" by Ricardo Rios-Carrillo, Alonso Ramírez-Manzanares, Hiram Luna-Munguía, Mirelta Regalado, and Luis Concha. DOI: https://doi.org/10.1371/journal.pone.0282549

The Society of Toxicologic Pathology charged a Nervous System Sampling Working Group with devising recommended practices to routinely screen the central nervous system (CNS) and peripheral nervous system (PNS) in Good Laboratory Practice–type nonclinical general toxicity studies. Brains should be weighed and trimmed similarly for all animals in a study. Certain structures should be sampled regularly: caudate/putamen, cerebellum, cerebral cortex, choroid plexus, eye (with optic nerve), hippocampus, hypothalamus, medulla oblongata, midbrain, nerve, olfactory bulb (rodents only), pons, spinal cord, and thalamus. Brain regions may be sampled bilaterally in rodents using 6 to 7 coronal sections, and unilaterally in nonrodents with 6 to 7 coronal hemisections. Spinal cord and nerves should be examined in transverse and longitudinal (or oblique) orientations. Most Working Group members considered immersion fixation in formalin (for CNS or PNS) or a solution containing acetic acid (for eye), paraffin embedding, and initial evaluation limited to hematoxylin and eosin (H&E)-stained sections to be acceptable for routine microscopic evaluation during general toxicity studies; other neurohistological methods may be undertaken if needed to better characterize H&E findings. Initial microscopic analyses should be qualitative and done with foreknowledge of treatments and doses (i.e., “unblinded”). The pathology report should clearly communicate structures that were assessed and methodological details. Since neuropathologic assessment is only one aspect of general toxicity studies, institutions should retain flexibility in customizing their sampling, processing, analytical, and reporting procedures as long as major neural targets are evaluated systematically.

Recent observations suggest that the vasoactive peptide endothelin-1 (ET-1) may be an important contributor to the etiology of glaucoma. ET-1 administration has been shown to produce optic nerve axonal loss and apoptosis of retinal ganglion cells. Ocular ET-1 levels are elevated in aqueous humor in response to elevated intraocular pressure both in glaucoma patients and in animal models of glaucoma; however, the precise mechanisms by which ET-1 mediates glaucomatous optic neuropathy are not clear. Presently we report that ET-1-mediated apoptosis was markedly attenuated in ETB receptor-deficient rats, suggesting a key role for ETB receptors in apoptosis of retinal ganglion cells by ET-1 treatment. Using virally transformed rat retinal ganglion cells (RGC-5 cells), we found that ET-1 (100 nmol/L) treatment produced apoptotic changes in these cells that was determined by flow cytometric analyses, release of mitochondrial cytochrome c to the cytosol, and increased phosphorylation of c-Jun N-terminal kinase. Pretreatment with the ETB-receptor antagonist BQ788 (1 μmol/L) was able to significantly attenuate ET-1-mediated apoptosis in RGC-5 cells. ET-1-mediated apoptotic changes in RGC-5 cells were associated with ETB-receptor activation and were accompanied by a significant upregulation of ETB-receptor expression. These studies suggest that ocular ET-1 acts through ETB receptors to mediate apoptosis of retinal ganglion cells, a key event in glaucoma and related optic neuropathies.

Purpose To describe a new method for encoding chemical shift using asymmetric readout waveforms that enables more SNR-efficient fat/water imaging. Methods Chemical shift was encoded using asymmetric readout waveforms, rather than conventional shifted trapezoid readouts. Two asymmetric waveforms are described: a triangle and a spline. The concept was applied to a fat/water separated RARE sequence to increase sampling efficiency. The benefits were investigated through comparisons to shifted trapezoid readouts. Using asymmetric readout waveforms, the scan time was either shortened or maintained to increase SNR. A matched in-phase waveform is also described that aims to improve the SNR transfer function of the fat and water estimates. The sequence was demonstrated for cervical spine, musculoskeletal (MSK), and optic nerve applications at 3T and compared with conventional shifted readouts. Results By removing sequence dead times, scan times were shortened by 30% with maintained SNR. The shorter echo spacing also reduced T 2 blurring. Maintaining the scan times and using asymmetric readout waveforms achieved an SNR improvement in agreement with the prolonged sampling duration. Conclusions Asymmetric readout waveforms offer an additional degree of freedom in pulse sequence designs where chemical shift encoding is desired. This can be used to significantly shorten scan times or to increase SNR with maintained scan time.

Optic nerve crush in mouse model is widely used for investigating the course following retinal ganglion cell (RGCs) injury. Manual cell counting from β-III tubulin stained microscopic images has been routinely performed to monitor RGCs after an optic nerve crush injury, but is time-consuming and prone to observer variability. This paper describes an automatic technique for RGC identification. We developed and validated (i) a sensitive cell candidate segmentation scheme and (ii) a classifier that removed false positives while retaining true positives. Two major contributions were made in cell candidate segmentation. First, a homomorphic filter was designed to adjust for the inhomogeneous illumination caused by uneven penetration of β-III tubulin antibody. Second, the optimal segmentation parameters for cell detection are highly image-specific. To address this issue, we introduced an offline-online parameter tuning approach. Offline tuning optimized model parameters based on training images and online tuning further optimized the parameters at the testing stage without needing access to the ground truth. In the cell identification stage, 31 geometric, statistical and textural features were extracted from each segmented cell candidate, which was subsequently classified as true or false positives by support vector machine. The homomorphic filter and the online parameter tuning approach together increased cell recall by 28%. The entire pipeline attained a recall, precision and coefficient of determination (r(2)) of 85.3%, 97.1% and 0.994. The availability of the proposed pipeline will allow efficient, accurate and reproducible RGC quantification required for assessing the death/survival of RGCs in disease models.

As the mammalian central nervous system matures, its regenerative ability decreases, leading to incomplete or non‐recovery from the neurodegenerative diseases and central nervous system insults that we are increasingly facing in our aging world population. Current neuroregenerative research is largely directed toward identifying the molecular and cellular players that underlie central nervous system repair, yet it repeatedly ignores the aging context in which many of these diseases appear. Using an optic nerve crush model in a novel biogerontology model, that is, the short‐living African turquoise killifish, the impact of aging on injury‐induced optic nerve repair was investigated. This work reveals an age‐related decline in axonal regeneration in female killifish, with different phases of the repair process being affected depending on the age. Interestingly, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of this impairment. Overall, we introduce the killifish visual system and its age‐dependent regenerative ability as a model to identify new targets for neurorepair in non‐regenerating individuals, thereby also considering the effects of aging on neurorepair., In contrast to findings in zebrafish, this study reveals a striking age‐related decline in optic nerve regeneration in the short‐living killifish, with different phases of the repair process being affected depending on the age. Interestingly, while resembling zebrafish at young age, the regenerative ability is more mammalian‐like at old age. As in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of impaired nerve regeneration.

The optic nerve (ON) is a recently recognized tractional load on the eye during larger horizontal eye rotations. In order to understand the mechanical behavior of the eye during adduction, it is necessary to characterize material properties of the sclera, ON, and in particular its sheath. We performed tensile loading of specimens taken from fresh postmortem human eyes to characterize the range of variation in their biomechanical properties and determine the effect of preconditioning. We fitted reduced polynomial hyperelastic models to represent the nonlinear tensile behavior of the anterior, equatorial, posterior, and peripapillary sclera, as well as the ON and its sheath. For comparison, we analyzed tangent moduli in low and high strain regions to represent stiffness. Scleral stiffness generally decreased from anterior to posterior ocular regions. The ON had the lowest tangent modulus, but was surrounded by a much stiffer sheath. The low-strain hyperelastic behaviors of adjacent anatomical regions of the ON, ON sheath, and posterior sclera were similar as appropriate to avoid discontinuities at their boundaries. Regional stiffnesses within individual eyes were moderately correlated, implying that mechanical properties in one region of an eye do not reliably reflect properties of another region of that eye, and that potentially pathological combinations could occur in an eye if regional properties are discrepant. Preconditioning modestly stiffened ocular tissues, except peripapillary sclera that softened. The nonlinear mechanical behavior of posterior ocular tissues permits their stresses to match closely at low strains, although progressively increasing strain causes particularly great stress in the peripapillary region.

Retinal ganglion cell axons are heavily myelinated (98%) and myelin damage in the optic nerve (ON) severely affects vision. Understanding the molecular mechanism of oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes will be essential for developing new therapeutic approaches for ON demyelinating diseases. To this end, we developed a new method for isolation and culture of ON-derived oligodendrocyte lineage cells and used it to study OPC differentiation. A critical aspect of cellular differentiation is macroautophagy/autophagy, a catabolic process that allows for cell remodeling by degradation of excess or damaged cellular molecules and organelles. Knockdown of ATG9A and BECN1 (pro-autophagic proteins involved in the early stages of autophagosome formation) led to a significant reduction in proliferation and survival of OPCs. We also found that autophagy flux (a measure of autophagic degradation activity) is significantly increased during progression of oligodendrocyte differentiation. Additionally, we demonstrate a significant change in mitochondrial dynamics during oligodendrocyte differentiation, which is associated with a significant increase in programmed mitophagy (selective autophagic clearance of mitochondria). This process is mediated by the mitophagy receptor BNIP3L (BCL2/adenovirus E1B interacting protein 3-like). BNIP3L-mediated mitophagy plays a crucial role in the regulation of mitochondrial network formation, mitochondrial function and the viability of newly differentiated oligodendrocytes. Our studies provide novel evidence that proper mitochondrial dynamics is required for establishment of functional mitochondria in mature oligodendrocytes. These findings are significant because targeting BNIP3L-mediated programmed mitophagy may provide a novel therapeutic approach for stimulating myelin repair in ON demyelinating diseases. Abbreviations: A2B5: a surface antigen of oligodendrocytes precursor cells, A2B5 clone 105; ACTB: actin, beta; APC: an antibody to label mature oligodendrocytes, anti-adenomatous polyposis coli clone CC1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9A: autophagy related 9A; AU: arbitrary units; BafA1: bafilomycin A1; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CASP3: caspase 3; CNP: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; Ctl: control; COX8: cytochrome c oxidase subunit; CSPG4/NG2: chondroitin sulfate proteoglycan 4; DAPI: 4′6-diamino-2-phenylindole; DNM1L: dynamin 1-like; EGFP: enhanced green fluorescent protein; FACS: fluorescence-activated cell sorting; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary growth factor; GFP: green fluorescent protein; HsESC: human embryonic stem cell; IEM: immunoelectron microscopy; LAMP1: lysosomal-associated membrane protein 1; LC3B: microtubule-associated protein 1 light chain 3; MBP: myelin basic protein; MFN2: mitofusin 2; Mito-Keima: mitochondria-targeted monomeric keima-red; Mito-GFP: mitochondria-green fluorescent protein; Mito-RFP: mitochondria-red fluorescent protein; MitoSOX: red mitochondrial superoxide probe; MKI67: antigen identified by monoclonal antibody Ki 67; MMP: mitochondrial membrane potential; O4: oligodendrocyte marker O4; OLIG2: oligodendrocyte transcription factor 2; ON: optic nerve; OPA1: OPA1, mitochondrial dynamin like GTPase; OPC: oligodendrocyte progenitor cell; PDL: poly-D-lysine; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; RGC: retinal ganglion cell; ROS: reactive oxygen species; RT-PCR: real time polymerase chain reaction; SEM: standard error of the mean; SOD2: superoxide dismutase 2, mitochondrial; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine methyl ester; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin, beta; TUBB3: tubulin, beta 3 class III.

Objectives: To develop an MRI-based radiomics model to predict postlaminar optic nerve invasion (PLONI) in retinoblastoma (RB) and compare its predictive performance with subjective radiologists’ assessment. Methods: We retrospectively enrolled 124 patients with pathologically proven RB (90 in training set and 34 in validation set) who had MRI scans before surgery. A radiomics model for predicting PLONI was developed by extracting quantitative imaging features from axial T2W images and contrast-enhanced T1W images in the training set. The Kruskal–Wallis test, least absolute shrinkage and selection operator regression, and recursive feature elimination were used for feature selection, where upon a radiomics model was built with a logistic regression (LR) classifier. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the accuracy were assessed to evaluate the predictive performance in the training and validation set. The performance of the radiomics model was compared to radiologists’ assessment by DeLong test. Results: The AUC of the radiomics model for the prediction of PLONI was 0.928 in the training set and 0.841 in the validation set. Radiomics model produced better sensitivity than radiologists’ assessment (81.1% vs 43.2% in training set, 82.4vs 52.9% in validation set). In all 124 patients, the AUC of the radiomics model was 0.897, while that of radiologists’ assessment was 0.674 (p < 0.001, DeLong test). Conclusion: MRI-based radiomics model to predict PLONI in RB patients was shown to be superior to visual assessment with improved sensitivity and AUC, and may serve as a potential tool to guide personalized treatment.

The optic nerve is morphologically classified as a peripheral nerve, but histologically it shares characteristics with the central nerves. Diseases that affect vision and the optic nerve are many and varied: optic neuritis, demyelination (multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and myelin oligo-dendrocyte glycoprotein antibody-related disorders), drugs, collagen disease, vasculitis, infection, trauma, vascular abnormalities, tumours, and non-tumoural masses. In this review, we summarise the magnetic resonance imaging findings for various pathological conditions that cause deterioration in visual acuity.

Oxidative stress contributes to degeneration of retinal ganglion cells and their axons in glaucoma, a leading cause of irreversible blindness worldwide, through sensitivity to intraocular pressure (IOP). Here, we investigated early elevations in reactive oxygen species (ROS) and a role for the NRF2-KEAP1-ARE endogenous antioxidant response pathway using microbead occlusion to elevate IOP in mice. ROS levels peaked in the retina at 1- and 2-wks following IOP elevation and remained elevated out to 5-wks. Phosphorylation of NRF2 and antioxidant gene transcription and protein levels increased concomitantly at 2-wks after IOP elevation, along with phosphorylation of PI3K and AKT. Inhibiting PI3K or AKT signaling prevented NRF2 phosphorylation and reduced transcription of antioxidant-regulated genes. Ocular hypertensive mice lacking Nrf2 had elevated ROS and a diminished increase in antioxidant gene expression. They also exhibited earlier axon degeneration and loss of visual function. In conclusion, the NRF2-KEAP1-ARE pathway is endogenously activated early in ocular hypertension due to phosphorylation of NRF2 by the PI3K/AKT pathway and serves to slow the onset of axon degeneration and vision loss in glaucoma. These data suggest that exogenous activation of this pathway might further slow glaucomatous neurodegeneration., Graphical abstract Image 1, Highlights • Detection of increased ROS weeks prior to glaucomatous pathology. • Increased Nrf2 phosphorylation and antioxidant proteins soon after IOP elevation. • Nrf2−/− mice have a significantly muted endogenous antioxidant response. • Nrf2−/− mice have earlier onset of axon loss after IOP elevation.

Background Due to the axial elongation–associated changes in the optic nerve and retina in high myopia, traditional methods like optic disc evaluation and visual field are not able to correctly differentiate glaucomatous lesions. It has been clinically challenging to detect glaucoma in highly myopic eyes. Objective This study aimed to develop a neural network to adjust for the dependence of the peripapillary retinal nerve fiber layer (RNFL) thickness (RNFLT) profile on age, gender, and ocular biometric parameters and to evaluate the network’s performance for glaucoma diagnosis, especially in high myopia. Methods RNFLT with 768 points on the circumferential 3.4-mm scan was measured using spectral-domain optical coherence tomography. A fully connected network and a radial basis function network were trained for vertical (scaling) and horizontal (shift) transformation of the RNFLT profile with adjustment for age, axial length (AL), disc-fovea angle, and distance in a test group of 2223 nonglaucomatous eyes. The performance of RNFLT compensation was evaluated in an independent group of 254 glaucoma patients and 254 nonglaucomatous participants. Results By applying the RNFL compensation algorithm, the area under the receiver operating characteristic curve for detecting glaucoma increased from 0.70 to 0.84, from 0.75 to 0.89, from 0.77 to 0.89, and from 0.78 to 0.87 for eyes in the highest 10% percentile subgroup of the AL distribution (mean 26.0, SD 0.9 mm), highest 20% percentile subgroup of the AL distribution (mean 25.3, SD 1.0 mm), highest 30% percentile subgroup of the AL distribution (mean 24.9, SD 1.0 mm), and any AL (mean 23.5, SD 1.2 mm), respectively, in comparison with unadjusted RNFLT. The difference between uncompensated and compensated RNFLT values increased with longer axial length, with enlargement of 19.8%, 18.9%, 16.2%, and 11.3% in the highest 10% percentile subgroup, highest 20% percentile subgroup, highest 30% percentile subgroup, and all eyes, respectively. Conclusions In a population-based study sample, an algorithm-based adjustment for age, gender, and ocular biometric parameters improved the diagnostic precision of the RNFLT profile for glaucoma detection particularly in myopic and highly myopic eyes.

The optic nerve represents one of the simplest regions of the CNS and has been useful in developing an understanding of glial development and myelination. While the visual system is frequently affected in demyelinating conditions, utilizing the optic nerve to model demyelination/remyelination studies has been difficult due to its accessibility, relatively small size, and dense nature that makes direct injections challenging. Taking advantage of the lack of oligodendrocytes and myelination in the mouse retina, we have developed a model in which the induction of apoptosis in mature oligodendrocytes allows for the selective, non-invasive generation of demyelinating lesions in optic nerve. Delivery of an inducer of oligodendrocyte apoptosis by intravitreous injection minimizes trauma to the optic nerve and allows for the assessment of oligodendrocyte death in the absence of injury related factors. Here we show that following induction of apoptosis, oligodendrocytes are lost within 3 days. The loss of oligodendrocytes is associated with limited microglial and astrocyte response, is patchy along the nerve, and results in localized myelin loss. Unlike in other regions of the murine CNS, where local demyelination stimulates activation of local oligodendrocyte precursors and remyelination, optic nerve demyelination induced by oligodendrocyte apoptosis fails to recover and results in persistent areas of myelin loss. Over time these chronic lesions change cellular composition and ultimately become devoid of GFAP+ astrocytes and OPCs. Why the optic nerve lesions fail to repair may reflect the lack of early immune responsiveness and provide a novel model of chronic demyelination.

Giant cell arteritis is the most common systemic vasculitis. It selectively affects large- and medium-sized arteries. Arterial wall inflammation leads to luminal occlusion and tissue ischemia, which cause the clinical manifestations of this vasculitis. Susceptible sites include the vascular bed of the cranial nerves and scalp including the temporal arteries, optic nerve, masseter muscles, and the posterior circulation of the central nervous system. Involvement can extend to the aorta and its primary and secondary branches, including the subclavian and axillary arteries, which leads to upper-extremity ischemia. The article presents a review of epidemiology, clinical presentation and especially ultrasound diagnostics of giant cell arteritis.

Fireflies (Coleoptera: Lampyridae) have distinct visual systems at different stages of development. Larvae have stemmata and adults have compound eyes. Adults use compound eyes to mediate photic communication during courtship. Larvae do not manifest this behavior, yet they are bioluminescent. We investigated the structure of stemmata in Photuris firefly larvae to identify anatomical substrates (i.e., rhabdomeres) conferring visual function. Stemmata were located bilaterally on the antero-lateral surfaces of the head. Beneath the ~ 130 µm diameter lens, we identified a pigmented eye-cup. At its widest point, the eye-cup was ~ 150 µm in diameter. The optic nerve exited the eye-cup opposite the lens. Two distinct regions, asymmetric in size and devoid of pigmentation, were characterized in stemmata cross-sections. We refer to these regions as lobes. Each lobe contained a rhabdom of a radial network of rhabdomeres. Pairs of rhabdomeres formed interdigitating microvilli contributed from neighboring photoreceptor cell bodies. The optic nerve contained 88 axons separable into two populations based on size. The number of axons in the optic nerve together with distinct rhabdoms suggests these structures were formed from ‘fusion stemmata.’ This structural specialization provides an anatomical substrate for future studies of visually mediated behaviors in Photuris larvae. Electronic supplementary material The online version of this article (10.1007/s00359-018-01312-2) contains supplementary material, which is available to authorized users.

Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAPGFAP-CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAPGFAP-CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAPGFAP-CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAPGFAP-CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

Glaucoma is the second leading cause of blindness worldwide and is characterized by the death of retinal ganglion cells (RGCs), the cells that send vision information to the brain. Their axons exit the eye at the optic nerve head (ONH), the main site of damage in glaucoma. The importance of biomechanics in glaucoma is indicated by the fact that elevated intraocular pressure (IOP) is a causative risk factor for the disease. However, exactly how biomechanical insult leads to RGC death is not understood. Although rat models are widely used to study glaucoma, their ONH biomechanics have not been characterized in depth. Therefore, we aimed to do so through finite element (FE) modeling. Utilizing our previously described method, we constructed and analyzed ONH models with individual-specific geometry in which the sclera was modeled as a matrix reinforced with collagen fibers. We developed eight sets of scleral material parameters based on results from our previous inverse FE study and used them to simulate the effects of elevated IOP in eight model variants of each of seven rat ONHs. Within the optic nerve, highest strains were seen inferiorly, a pattern that was consistent across model geometries and model variants. In addition, changing the collagen fiber direction to be circumferential within the peripapillary sclera resulted in more pronounced decreases in strain than changing scleral stiffness. The results from this study can be used to interpret data from rat glaucoma studies to learn more about how biomechanics affects RGC pathogenesis in glaucoma.

Background Accurate diagnosis in patients presenting with lesions at various locations within the visual pathway is challenging. This study investigated functional and structural changes secondary to such lesions to identify patterns useful to guide early and effective management. Methods Over 10,000 records from patients referred for optic nerve head assessment were reviewed and 31 patients with a final diagnosis of likely neuropathic lesions posterior to the eye were included in the current study. Fundus photographs, optic coherence tomography images and visual field tests were evaluated for changes with respect to retinal nerve fibre layer topography and prediction of structure-function paradigms. Emerging clinical patterns were examined for their consistency with the likely anatomical origin of the underlying insult in the presence of varying diagnoses. Results Data from patients with lesions along the visual system allowed identification of retinal nerve fibre layer asymmetry correlated with visual field defects and ganglion cell analysis. Bilateral discordance in retinal nerve fibre loss easily discernible from an altered pattern of the temporal-superior-nasal-inferior-temporal curve was characteristic for post-chiasmal lesions. These sometimes-subtle changes supported diagnosis in cases with multiple aetiologies or with ambiguous visual field analysis and/or ganglion cell loss. Conclusion Intricate knowledge of the retinal architecture and projections allows coherent predictions of functional and structural deficits following various lesions affecting the visual pathway. The integration of adjunct imaging and retinal nerve fibre layer thinning will assist clinicians to guide clinical investigations toward a likely diagnosis in the light of significant individual variations. The case series presented in this study aids in differential diagnosis of retrograde optic neuropathies by using retinal nerve fibre layer asymmetric patterns as an important clinical marker.

Introduction: Monitoring and diagnosing glaucoma until 2017 included funduscopy, IOP measurements, gonioscopy, pachymetry, as well as visual field tests, optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A). Radial peripapillary capillaries (RPC) can be observed by fluorescein angiography, as well as histologically - superficial and deep capillary layer. Aim: To correlate density of radial peripapillary capillary network (RPC) and retinal nerve fiber layer (RNFL) thickness in eight peripapillary segments in patients with a primary open angle glaucoma (POAG) which have the disease under 10 years of duration, over 10 years of duration and in a group of healthy patients. Methods: This is a cross-sectional review which included three groups of patients: POAG patients under 10 years of disease duration, over 10 years of disease duration and control group of patients. The study is performed on the commercial optical coherence tomography angiography system (AngioVue, Avanti RTVue-XR, Optovue, CA). Sectoral RPC density values, RPC maps and RNFL thickness were analyzed in three groups of patients, data was compared and correlation between parameters was examined. Results: Mean RPC Density values in both superior segments (S1, S2) were significantly lower in patients with glaucoma over 10 years of disease duration compared to patients with glaucoma under 10 years of disease duration (p

In an ex vivo rat glaucoma model using dissected retinas, the neurosteroid allopregnanolone (AlloP) protects retinal ganglion cells (RGCs) via GABR/GABA(A) receptors. To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A(1) and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1). Administration of rapamycin or torin 2 exerted partial histological neuroprotection, while combined administration of AlloP with bafilomycin A(1) or SAR405 induced severe degeneration in a hyperbaric condition. Electron microscopic analyses showed that the addition of AlloP significantly increased autophagosomes and degenerative autophagic vacuoles in the retinal nerve fiber layer. Immunoblotting showed that the addition of AlloP or autophagic activators increased the lipidated form of LC3B (LC3B-II) and suppressed SQSTM1. Moreover, bafilomycin A(1) increased LC3B-II and SQSTM1 protein levels in the presence of AlloP without changes in corresponding mRNAs compared to AlloP-treated retinas in a hyperbaric condition. These data indicate that AlloP likely induces a protective form of autophagy in this model. In an in vivo rat model of glaucoma, we also observed neuroprotective effects of AlloP. Injection of polystyrene microbeads into the anterior chamber increased intraocular pressure about 3-fold and induced RGC apoptosis. A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms. Abbreviations: 2HBCD: 2-Hydroxypropyl)-β-cyclodextrin; 3-MA: 3-methyladenine; AlloP: allopregnanolone; AP: autophagosome; AVd: degradative autophagic vacuoles; GCL: ganglion cell layer; INL: inner nuclear layer; IOP: intraocular pressure; IPL: inner plexiform layer; LC3B-I: cytosolic form of LC3B; LCB-II: lipidated form of LC3B; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; NDS: neuronal damage score; NFL: nerve fiber layer; OH: ocular hypertension; ON: optic nerve; ONL: outer nuclear layer; OPL: outer plexiform layer; p-STR: scotopic threshold response; RGC: retinal ganglion cells; RT-PCR: real-time reverse transcription polymerase chain reaction; SQSTM1: sequestosome 1; TUNEL: TdT-mediated dUTP Nick End Labeling

Characterization of the biomechanical behavior of the optic nerve head (ONH) in response to intraocular pressure (IOP) elevation is important for understanding glaucoma susceptibility. In this study, we aimed to develop and validate a three-dimensional (3D) ultrasound elastographic technique to obtain mapping and visualization of the 3D distributive displacements and strains of the ONH and surrounding peripapillary tissue (PPT) during whole globe inflation from 15 to 30 mmHg. 3D scans of the posterior eye around the ONH were acquired through full tissue thickness with a high-frequency ultrasound system (50 MHz). A 3D cross-correlation-based speckle-tracking algorithm was used to compute tissue displacements at ∼30,000 kernels distributed within the region of interest (ROI), and the components of the strain tensors were calculated at each kernel by using least square estimation of the displacement gradients. The accuracy of displacement calculation was evaluated using simulated rigid-body translation on ultrasound radiofrequency (RF) data obtained from a porcine posterior eye. The accuracy of strain calculation was evaluated using finite element (FE) models. Three porcine eyes were tested showing that ONH deformation was heterogeneous with localized high strains. Substantial radial (i.e., through-thickness) compression was observed in the anterior ONH and out-of-plane (i.e., perpendicular to the surface of the shell) shear was shown to concentrate in the vicinity of ONH/PPT border. These preliminary results demonstrated the feasibility of this technique to achieve comprehensive 3D evaluation of the mechanical responses of the posterior eye, which may provide mechanistic insights into the regional susceptibility in glaucoma.

SUMMARY Optic nerve sheath diameter (ONSD) enlargement is detectable in traumatic brain injury patients with raised intracranial pressure (ICP). The aim was to assess its value in neurological patients suspected to have increased ICP. Patient clinical imaging data and hospitalization outcome were analyzed. Patients were divided into groups according to brain pathology and level of consciousness with Glasgow Coma Score (GCS). Poor hospitalization outcome was assessed by modified Rankin scale (mRS) >3. Data obtained by ocular sonography performed in acute setting were compared with data of 100 control subjects. Data were expressed as mean ± SD. Intergroup comparison was performed by Student’s t-test. Data of 34 patients (63+16 years) were suitable for analysis, including 8 primary intracerebral hemorrhage (PICH), 8 subarachnoid hemorrhage (SAH), 12 PICH or SAH and intraventricular hemorrhage (IVH), 4 tumors and 2 ischemic strokes. The mean ONSD was 5.86+0.69 mm in patients versus 4.38+0.41 mm in controls (p0.05). Pronounced enlargement of ONSD was observed in patients with ICH or SAH with IVH, and in patients with GCS 3).