-
Current Opinion in Ophthalmology Mar 2022Biomechanics is an important aspect of the complex family of diseases known as the glaucomas. Here, we review recent studies of biomechanics in glaucoma. (Review)
Review
PURPOSE OF REVIEW
Biomechanics is an important aspect of the complex family of diseases known as the glaucomas. Here, we review recent studies of biomechanics in glaucoma.
RECENT FINDINGS
Several tissues have direct and/or indirect biomechanical roles in various forms of glaucoma, including the trabecular meshwork, cornea, peripapillary sclera, optic nerve head/sheath, and iris. Multiple mechanosensory mechanisms and signaling pathways continue to be identified in both the trabecular meshwork and optic nerve head. Further, the recent literature describes a variety of approaches for investigating the role of tissue biomechanics as a risk factor for glaucoma, including pathological stiffening of the trabecular meshwork, peripapillary scleral structural changes, and remodeling of the optic nerve head. Finally, there have been advances in incorporating biomechanical information in glaucoma prognoses, including corneal biomechanical parameters and iridial mechanical properties in angle-closure glaucoma.
SUMMARY
Biomechanics remains an active aspect of glaucoma research, with activity in both basic science and clinical translation. However, the role of biomechanics in glaucoma remains incompletely understood. Therefore, further studies are indicated to identify novel therapeutic approaches that leverage biomechanics. Importantly, clinical translation of appropriate assays of tissue biomechanical properties in glaucoma is also needed.
Topics: Biomechanical Phenomena; Glaucoma; Humans; Intraocular Pressure; Optic Disk; Sclera; Trabecular Meshwork
PubMed: 34954731
DOI: 10.1097/ICU.0000000000000829 -
Progress in Retinal and Eye Research Mar 2020Glaucoma is one of the leading causes of vision impairment worldwide. In order to further understand the molecular pathobiology of this disease and to develop better... (Review)
Review
Glaucoma is one of the leading causes of vision impairment worldwide. In order to further understand the molecular pathobiology of this disease and to develop better therapies, clinically relevant animal models are necessary. In recent years, both the rat and mouse have become popular models in glaucoma research. Key reasons are: many important biological similarities shared among rodent eyes and the human eye; development of improved methods to induce glaucoma and to evaluate glaucomatous damage; availability of genetic tools in the mouse; as well as the relatively low cost of rodent studies. Commonly studied rat and mouse glaucoma models include intraocular pressure (IOP)-dependent and pressure-independent models. The pressure-dependent models address the most important risk factor of elevated IOP, whereas the pressure-independent models assess "normal tension" glaucoma and other "non-IOP" related factors associated with glaucomatous damage. The current article provides descriptions of these models, their characterizations, specific techniques to induce glaucoma, mechanisms of injury, advantages, and limitations.
Topics: Animals; Disease Models, Animal; Glaucoma; Intraocular Pressure; Optic Nerve; Retinal Ganglion Cells
PubMed: 31557521
DOI: 10.1016/j.preteyeres.2019.100799 -
Current Opinion in Neurology Feb 2021Negative findings on neuroimaging are part of the diagnostic criteria for idiopathic intracranial hypertension (IIH), a syndrome characterized by increased intracranial... (Review)
Review
PURPOSE OF REVIEW
Negative findings on neuroimaging are part of the diagnostic criteria for idiopathic intracranial hypertension (IIH), a syndrome characterized by increased intracranial pressure (ICP). Some positive neuroimaging findings are associated with increased ICP, but their role in diagnosis of IIH has not been established. We provide an overview of these findings and their relevance for diagnosis of raised intracranial pressure.
RECENT FINDINGS
MRI acquisition techniques have significantly improved in the last few decades leading to better characterization of the intracranial changes associated with IIH, including empty sella turcica, optic nerve tortuosity, distension of the optic nerve sheath, posterior globe flattening, slit-like ventricles, and venous sinus stenosis. These may be MRI biomarkers of increased ICP. Prevalence difference between people with and without increased ICP, and reversibility of these MRI findings following treatment of increased ICP inform evaluation of their diagnostic potential.
SUMMARY
MRI and magnetic resonance venography findings are important tools in the diagnosis of IIH. Empty sella turcica, optic nerve protrusion, distension of the optic nerve sheath, optic nerve tortuosity, posterior globe flattening, and transverse sinus stenosis have been found to be the most promising diagnostic markers for IIH, although absence of these findings does not rule out the diagnosis.
Topics: Biomarkers; Constriction, Pathologic; Humans; Intracranial Hypertension; Magnetic Resonance Imaging; Neuroimaging; Optic Nerve; Pseudotumor Cerebri
PubMed: 33230036
DOI: 10.1097/WCO.0000000000000885 -
Progress in Retinal and Eye Research Jul 2021The optic nerve head can morphologically be differentiated into the optic disc with the lamina cribrosa as its basis, and the parapapillary region with zones alpha... (Review)
Review
The optic nerve head can morphologically be differentiated into the optic disc with the lamina cribrosa as its basis, and the parapapillary region with zones alpha (irregular pigmentation due to irregularities of the retinal pigment epithelium (RPE) and peripheral location), beta zone (complete RPE loss while Bruch's membrane (BM) is present), gamma zone (absence of BM), and delta zone (elongated and thinned peripapillary scleral flange) within gamma zone and located at the peripapillary ring. Alpha zone is present in almost all eyes. Beta zone is associated with glaucoma and may develop due to a IOP rise-dependent parapapillary up-piling of RPE. Gamma zone may develop due to a shift of the non-enlarged BM opening (BMO) in moderate myopia, while in highly myopic eyes, the BMO enlarges and a circular gamma zone and delta zone develop. The ophthalmoscopic shape and size of the optic disc is markedly influenced by a myopic shift of BMO, usually into the temporal direction, leading to a BM overhanging into the intrapapillary compartment at the nasal disc border, a secondary lack of BM in the temporal parapapillary region (leading to gamma zone in non-highly myopic eyes), and an ocular optic nerve canal running obliquely from centrally posteriorly to nasally anteriorly. In highly myopic eyes (cut-off for high myopia at approximately -8 diopters or an axial length of 26.5 mm), the optic disc area enlarges, the lamina cribrosa thus enlarges in area and decreases in thickness, and the BMO increases, leading to a circular gamma zone and delta zone in highly myopic eyes.
Topics: Bruch Membrane; Glaucoma; Humans; Myopia; Optic Disk; Sclera; Tomography, Optical Coherence
PubMed: 33309588
DOI: 10.1016/j.preteyeres.2020.100933 -
Molecular Neurodegeneration Mar 2022Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology... (Review)
Review
Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world's leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.
Topics: Glaucoma; Humans; Neurodegenerative Diseases; Neuroprotection; Optic Nerve
PubMed: 35313950
DOI: 10.1186/s13024-022-00524-0 -
Proceedings of the National Academy of... Nov 2022Axon regeneration is an energy-demanding process that requires active mitochondrial transport. In contrast to the central nervous system (CNS), axonal mitochondrial...
Axon regeneration is an energy-demanding process that requires active mitochondrial transport. In contrast to the central nervous system (CNS), axonal mitochondrial transport in regenerating axons of the peripheral nervous system (PNS) increases within hours and sustains for weeks after injury. Yet, little is known about targeting mitochondria in nervous system repair. Here, we report the induction of sustained axon regeneration, neural activities in the superior colliculus (SC), and visual function recovery after optic nerve crush (ONC) by M1, a small molecule that promotes mitochondrial fusion and transport. We demonstrated that M1 enhanced mitochondrial dynamics in cultured neurons and accelerated in vivo axon regeneration in the PNS. Ex vivo time-lapse imaging and kymograph analysis showed that M1 greatly increased mitochondrial length, axonal mitochondrial motility, and transport velocity in peripheral axons of the sciatic nerves. Following ONC, M1 increased the number of axons regenerating through the optic chiasm into multiple subcortical areas and promoted the recovery of local field potentials in the SC after optogenetic stimulation of retinal ganglion cells, resulting in complete recovery of the pupillary light reflex, and restoration of the response to looming visual stimuli was detected. M1 increased the gene expression of mitochondrial fusion proteins and major axonal transport machinery in both the PNS and CNS neurons without inducing inflammatory responses. The knockdown of two key mitochondrial genes, or , abolished the growth-promoting effects of M1 after ONC, suggesting that maintaining a highly dynamic mitochondrial population in axons is required for successful CNS axon regeneration.
Topics: Humans; Axons; Mitochondrial Proteins; Nerve Crush; Nerve Regeneration; Optic Nerve; Optic Nerve Injuries; Retinal Ganglion Cells; Sciatic Nerve; Small Molecule Libraries
PubMed: 36306327
DOI: 10.1073/pnas.2121273119 -
Autophagy Oct 2021Retinal ganglion cell axons are heavily myelinated (98%) and myelin damage in the optic nerve (ON) severely affects vision. Understanding the molecular mechanism of...
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. 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.
Topics: Autophagy; Cell Differentiation; Mitochondria; Mitophagy; Oligodendroglia; Optic Nerve
PubMed: 33404293
DOI: 10.1080/15548627.2020.1871204 -
Nature Immunology Dec 2020Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or...
Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, glaucoma and ischemia-reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study, we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that had neuroprotective properties and drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors. This pro-regenerative neutrophil promoted repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations. Our findings could ultimately lead to the development of new immunotherapies that reverse CNS damage and restore lost neurological function across a spectrum of diseases.
Topics: Animals; Axons; Biomarkers; Cell Communication; Cell Plasticity; Cell Survival; Central Nervous System; Intercellular Signaling Peptides and Proteins; Mice; Nerve Regeneration; Neurons; Neutrophil Infiltration; Neutrophils; Optic Nerve; Receptors, Interleukin-8B; Spinal Cord; Transcriptome; Zymosan
PubMed: 33106668
DOI: 10.1038/s41590-020-00813-0 -
Proceedings of the National Academy of... Aug 2023Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light,...
Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases-for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
Topics: Humans; Transcriptome; Endothelial Cells; Optic Disk; Glaucoma; Optic Nerve; Sclera
PubMed: 37566633
DOI: 10.1073/pnas.2306153120 -
Asia-Pacific Journal of Ophthalmology...Recent advances in artificial intelligence have provided ophthalmologists with fast, accurate, and automated means for diagnosing and treating ocular conditions, paving... (Review)
Review
Recent advances in artificial intelligence have provided ophthalmologists with fast, accurate, and automated means for diagnosing and treating ocular conditions, paving the way to a modern and scalable eye care system. Compared to other ophthalmic disciplines, neuro-ophthalmology has, until recently, not benefitted from significant advances in the area of artificial intelligence. In this narrative review, we summarize and discuss recent advancements utilizing artificial intelligence for the detection of structural and functional optic nerve head abnormalities, and ocular movement disorders in neuro-ophthalmology.
Topics: Artificial Intelligence; Eye; Humans; Ophthalmologists; Ophthalmology; Optic Nerve
PubMed: 35533331
DOI: 10.1097/APO.0000000000000512