Browsing by Subject "Glaucoma"

Now showing 1 - 10 of 62
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    A narrative review on the association of high intraocular pressure and glaucoma in patients with retinal vein occlusion
    (AME Publishing Company, 2022) Jabbehdari, Sayena; Yazdanpanah, Ghasem; Cantor, Louis B.; Hajrasouliha, Amir Reza; Ophthalmology, School of Medicine
    Background and objective: Retinal vein occlusion (RVO) is a major cause of vision loss and elevated intraocular pressure (IOP), high ocular perfusion pressure, and glaucoma are known ophthalmic risk factors for RVO. The aim of this paper is to provide the update on the association and management of high IOP/glaucoma and RVO. Methods: A literature review was performed in PubMed and Medline until May 2022 utilizing specific keywords and cross-matched reference lists. Key content and findings: The association of RVO with high IOP/glaucoma may be attributed to retinal ganglion cell loss due to retinal ischemia in high IOP and glaucoma. As new modalities showed, decreased optic disc perfusion, reduced density of blood vessels in the optic nerve head of glaucoma patients, changes in the peripapillary microvascular parameters, and decreased retinal nerve fiber layer (RNFL) thickness of the optic nerve head of eyes with RVO suggest a common pathway between RVO and glaucoma. Literature suggests the close follow up for glaucoma development among patients with non-arteriovenous (AV) crossing (optic cup or optic nerve sited) RVO in fellow eye and management of elevated IOP among RVO cases treated with anti-vascular endothelial growth factor (VEGF) antibodies/corticosteroids and those with preexisting primary open angle glaucoma (POAG). Conclusions: Determining potential patient responses to treatment and considering therapeutic options are challenging among patients with RVO and glaucoma. However, IOP lowering managements in preventing IOP spikes in patients with preexisting glaucoma and early treatment of macular edema in eyes with RVO is recommended.
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    A Novel Technique Identifies Valve-Like Pathways Entering and Exiting Schlemm's Canal in Macaca nemestrina Primates With Similarities to Human Pathways
    (Frontiers Media, 2022-07-04) Martin, Elizabeth A.; Johnstone, Murray A.; Ophthalmology, School of Medicine
    Purpose: The aim of the study was 1) to describe a novel combination of techniques that permit immunohistochemistry imaging of Schlemm's canal inlet (SIV) and outlet (SOV) valve-like structures, 2) to identify tissue-level SIV adhesive relationships linking the trabecular meshwork (TM) to hinged collagen leaflets at the Schlemm's canal (SC) external wall, and 3) to determine whether the SIV lumen wall's adhesive vascular markers are similar to those of the SC inner wall endothelium. Materials and Methods: Anterior segments of 16 M. nemestrina primates underwent immunohistochemistry (IHC) labeling. We perfused fluorescent microspheres into 12 of the eyes. Limbal tissues were divided into quadrants, viscoelastic introduced into SC, tissues fixed, immunohistochemistry performed, radial segments cut, tissues clarified, and confocal microscopy performed. Finally, we generated ImageJ 3D projections encompassing the TM, SC, and distal pathways. Results: IHC imaging identified 3D relationships between SIV, collector channel ostia, collector channels (CC), SOV, and intrascleral channels. Imaging depth increased 176.9%, following clarification (p < 0.0001). Imaging demonstrated CD31, collagen type 1 and 4 in the walls of the SIV lumen and more distal pathways. In eight eyes, 384 segments were examined, 447 SIV identified, and 15.4% contained microspheres. Conclusion: Our technique's imaging depth permitted the identification of SIV linkage between the TM and SOV. We found comparable cell-cell adhesion molecules (CD31) and basement membrane components in the SC inner wall and SIV lumen walls. Recent OCT studies have suggested that SIV tensional relationships may control CC entrance dimensions that regulate distal resistance. Cellular adhesive properties sustain SIV tensional relationships. These SIV cell-cell and cell-basement membrane properties warrant further study because abnormalities could be a factor in the IOP elevation of glaucoma.
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    Age and sex affect TGFβ2-induced ocular hypertension in C57BL/6J mice
    (Elsevier, 2022) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Peng, Michael; Mao, Weiming; Ophthalmology, School of Medicine
    Glaucoma is a leading cause of blindness worldwide. The loss of vision in glaucoma patients is due to optic nerve damage. The most important risk factor of glaucoma is elevated intraocular pressure (IOP) which is due to glaucomatous changes in the trabecular meshwork. Animal models, especially mouse models for ocular hypertension (OHT), are important for studying glaucoma. Published studies showed that 2.5X107 PFU adenoviral vectors expressing the biologically active form of human TGFβ2 elevate IOP in female C57BL/6J mice when they are intravitreally delivered. In this study, we found that 2.5X107 PFU adenoviral TGFβ2 vector did not elevate IOP in 3- or 5-month old male C57BL/6J mice. In contrast, 5X107 PFU of the same viral vectors elevated IOP in both 3- and 5-month old male C57BL/6J mice. Also, 5-month old mice showed earlier OHT and higher IOP compared to 3-month old mice. In summary, our data showed that age and sex play roles in adenoviral vector-mediated TGFβ2-induced OHT in C57BL/6J mice.
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    Analyses of the development and function of stem cell derived cells in neurodegenerative diseases
    (2022-12) Lavekar, Sailee Sham; Meyer, Jason; Canfield, Scott; Belecky-Adams, Teri; Mastracci, Teresa; Perrin, Benjamin
    Human pluripotent stem cells (hPSCs) are an attractive tool for the study of different neurodegenerative diseases due to their potential to form any cell type of the body. Due to their versatility and self-renewal capacity, they have different applications such as disease modeling, high throughput drug screening and transplantation. Different animal models have helped answer broader questions related to the physiological functioning of various pathways and the phenotypic effects of a particular neurodegenerative disease. However, due to the lack of success recapitulating some targets identified from animal models into successful clinical trials, there is a need for a direct translational disease model. Since their advent, hPSCs have helped understand various disease effectors and underlying mechanisms using genetic engineering techniques, omics studies and reductionist approaches for the recognition of candidate molecules or pathways required to answer questions related to neurodevelopment, neurodegeneration and neuroregeneration. Due to the simplified approach that iPSC models can provide, some in vitro approaches are being developed using microphysiological systems (MPS) that could answer complex physiological questions. MPS encompass all the different in vitro systems that could help better mimic certain physiological systems that tend to not be mimicked by in vivo models. In this dissertation, efforts have been directed to disease model as well as to understand the intrinsic as well as extrinsic cues using two different MPS. First, we have used hPSCs with Alzheimer’s disease (AD)-related mutations to differentiate into retinal organoids and identify AD related phenotypes for future studies to identify retinal AD biomarkers. Using 5 month old retinal organoids from AD cell lines as well as controls, we could identify retinal AD phenotypes such as an increase in Aβ42:Aβ40 ratio along with increase in pTau:Tau. Nanostring analyses also helped in identification of potential target genes that are modulated in retinal AD that were related to synaptic dysfunction. Thus, using retinal organoids for the identification of retinal AD phenotypes could help delve deeper into the identification of future potential biomarkers in the retina of AD patients, with the potential to serve as a means for early identification and intervention for patients. The next MPS we used to serve to explore non-cell autonomous effects associated with glaucoma to explore the neurovascular unit. Previous studies have demonstrated the degeneration of RGCs in glaucoma due to a point mutation OPTN(E50K) that leads to the degeneration of RGCs both at morphological and functional levels. Thus, using the previous studies as a basis, we wanted to further unravel the impact of this mutation using the different cell types of the neurovascular unit such as endothelial cells, astrocytes and RGCs. Interestingly, we observed the barrier properties being impacted by the mutation present in both RGCs and astrocytes demonstrated through TEER, permeability and transcellular transport changes. We also identified a potential factor TGFβ2 that was observed to be overproduced by the OPTN E50K astrocytes to demonstrate similar effects with the exogenous addition of TGFβ2 on the barrier. Furthermore, the inhibition of TGFβ2 helped rescue some of the barrier dysfunction phenotypes. Thus, TGFβ2 inhibition can be used as a potential candidate that can be used to further study its impact in in vivo models and how that can be used in translational applications. Thus, MPS systems have a lot of applications that can help answer different physiologically relevant questions that are hard to approach using in vivo models and the further development of these systems to accentuate the aspects of neural development and how it goes awry in different neurodegenerative diseases.
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    Aqueous outflow regulation – 21st century concepts
    (Elsevier, 2021-07) Johnstone, Murray; Xin, Chen; Tan, James; Martin, Elizabeth; Wen, Joanne; Wang, Ruikang K.; Ophthalmology, School of Medicine
    We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm's canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.
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    Artificial Intelligence to Aid Glaucoma Diagnosis and Monitoring: State of the Art and New Directions
    (MDPI, 2022) Nunez, Roberto; Harris, Alon; Ibrahim, Omar; Keller, James; Wikle, Christopher K.; Robinson, Erin; Zukerman, Ryan; Siesky, Brent; Verticchio, Alice; Rowe, Lucas; Guidoboni, Giovanna; Ophthalmology, School of Medicine
    Recent developments in the use of artificial intelligence in the diagnosis and monitoring of glaucoma are discussed. To set the context and fix terminology, a brief historic overview of artificial intelligence is provided, along with some fundamentals of statistical modeling. Next, recent applications of artificial intelligence techniques in glaucoma diagnosis and the monitoring of glaucoma progression are reviewed, including the classification of visual field images and the detection of glaucomatous change in retinal nerve fiber layer thickness. Current challenges in the direct application of artificial intelligence to further our understating of this disease are also outlined. The article also discusses how the combined use of mathematical modeling and artificial intelligence may help to address these challenges, along with stronger communication between data scientists and clinicians.
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    Asian Race and Primary Open-Angle Glaucoma: Where Do We Stand?
    (MDPI, 2022-04-28) Belamkar, Aditya; Harris, Alon; Oddone, Francesco; Verticchio Vercellin, Alice; Fabczak-Kubicka, Anna; Siesky, Brent; Ophthalmology, School of Medicine
    Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by irreversible retinal ganglion cell damage and visual field loss. The global POAG prevalence is estimated to be 3.05%, and near term is expected to significantly rise, especially within aging Asian populations. Primary angle-closure glaucoma disproportionately affects Asians, with up to four times greater prevalence of normal-tension glaucoma reported compared with high-tension glaucoma. Estimates for overall POAG prevalence in Asian populations vary, with Chinese and Indian populations representing the majority of future cases. Structural characteristics associated with glaucoma progression including the optic nerve head, retina, and cornea are distinct in Asians, serving as intermediates between African and European descent populations. Patterns in IOP suggest some similarities between races, with a significant inverse relationship between age and IOP only in Asian populations. Genetic differences have been suggested to play a role in these differences, however, a clear genetic pattern is yet to be established. POAG pathogenesis differs between Asians and other ethnicities, and it may differ within the broad classification of the Asian race. Greater awareness and further research are needed to improve treatment plans and outcomes for the increasingly high prevalence of normal tension glaucoma within aging Asian populations.
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    An Assessment of the Fidelity of Two Different Interventions to Improve Adherence to Glaucoma Treatment in Patients of African Descent
    (Office of the Vice Chancellor for Research, 2015-04-17) Idowu, Eniola; Bigatti, Silvia M.; Racette, Lyne
    Glaucoma is a chronic eye disease, which is asymptomatic and can slowly lead to blindness if left untreated. Glaucoma is caused by damage to the optic nerve and can lead to irreversible loss of sight. The overall objective of this MURI study was to determine the impact of two different interventions on compliance to glaucoma medication in patients of African descent with open-angle glaucoma. Two types of intervention were used – Education and Motivational Interviewing (MI). The educational intervention involved sharing knowledge with patients about glaucoma, its causes, and its treatments, to help patients better understand glaucoma and the importance of adhering to the daily medication regimen. The MI intervention involved communicating with the patients and encouraging them to identify strategies that would help them better adhere to their medications. These sessions were video-recorded and the content of each video was transcribed verbatim. The transcripts were then scored to assess the fidelity of each session with the intervention type that was given; this was done to ensure that each patient in the MI group received intervention consistent with MI, and that each patient in the Education group received an intervention free of MI. The standard Motivational Interviewing Treatment Integrity 3.0 coding sheet was used to code the MI and Education sessions. Global ratings were given for empathy, direction, collaboration, evocation and autonomy/support on a scale ranging from 1 (Low) to 5 (High). The following behaviors were counted within each transcript: giving information, MI adherent (asking permission, affirm, emphasize control, support), MI Non-adherent (advise, confront, direct), questions (closed questions, open questions), and reflections (simple, complex). We expect that the MI interventions would have significantly higher scores on MI adherent behaviors and significantly lower on MI-non-adherent behaviors compared to the Education session.
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    Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells
    (Elsevier, 2022) Gomes, Cátia; VanderWall, Kirstin B.; Pan, Yanling; Lu, Xiaoyu; Lavekar, Sailee S.; Huang, Kang-Chieh; Fligor, Clarisse M.; Harkin, Jade; Zhang, Chi; Cummins, Theodore R.; Meyer, Jason S.; Medical and Molecular Genetics, School of Medicine
    Although the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls. Initial results indicated significant changes in OPTN(E50K) astrocytes, including evidence of autophagy dysfunction. Subsequently, co-culture experiments demonstrated that OPTN(E50K) astrocytes led to neurodegenerative properties in otherwise healthy RGCs, while healthy astrocytes rescued some neurodegenerative features in OPTN(E50K) RGCs. These results are the first to identify disease phenotypes in OPTN(E50K) astrocytes, including how their modulation of RGCs is affected. Moreover, these results support the concept that astrocytes could offer a promising target for therapeutic intervention in glaucoma.
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    Autophagy disruption reduces mTORC1 activation leading to retinal ganglion cell neurodegeneration associated with glaucoma
    (Cold Spring Harbor Laboratory, 2023-01-04) Huang, Kang-Chieh; Gomes, Cátia; Shiga, Yukihiro; Belforte, Nicolas; VanderWall, Kirstin B.; Lavekar, Sailee S.; Fligor, Clarisse M.; Harkin, Jade; Di Polo, Adriana; Meyer, Jason S.; Biology, School of Science
    Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor adenosine monophosphate-activated protein kinase (AMPK), along with subsequent neurodegeneration in RGCs differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated variant of Optineurin (OPTN-E50K). Similarly, the microbead occlusion model of glaucoma resulting in ocular hypertension also exhibited autophagy disruption and mTORC1 downregulation. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN-E50K RGCs. Taken together, these results highlight an important balance between autophagy and mTORC1 signaling essential for RGC homeostasis, while disruption to these pathways contributes to neurodegenerative features in glaucoma, providing a potential therapeutic target to prevent neurodegeneration.