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Quantitative imaging of the clearance systems in the eye and the brain [Editorial]
Deng, Wenyu; Liu, Crystal; Parra, Carlos; Sims, Jeffrey R; Faiq, Muneeb A; Sainulabdeen, Anoop; Song, Hana; Chan, Kevin C
PMCID:6960420
PMID: 31956524
ISSN: 2223-4292
CID: 4269542
Widespread brain reorganization perturbs visuomotor coordination in early glaucoma
Trivedi, Vivek; Bang, Ji Won; Parra, Carlos; Colbert, Max K; O'Connell, Caitlin; Arshad, Ahmel; Faiq, Muneeb A; Conner, Ian P; Redfern, Mark S; Wollstein, Gadi; Schuman, Joel S; Cham, Rakie; Chan, Kevin C
Glaucoma is the world's leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls.
PMID: 31578409
ISSN: 2045-2322
CID: 4116332
Intracameral Injection of a Chemically Cross-Linked Hydrogel to Study Chronic Neurodegeneration in Glaucoma
Chan, Kevin C; Yu, Yu; Han Ng, Shuk; Mak, Heather K; Yip, Yolanda W Y; van der Merwe, Yolandi; Ren, Tianmin; Yung, Jasmine S Y; Biswas, Sayantan; Cao, Xu; Chau, Ying; Leung, Christopher K S
Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinylsulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14±3 and 24±3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse, confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. Statement of Significance A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinylsulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.
PMID: 31176841
ISSN: 1878-7568
CID: 3926752
Cholinergic nervous system and glaucoma: From basic science to clinical applications
Faiq, Muneeb A; Wollstein, Gadi; Schuman, Joel S; Chan, Kevin C
The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.
PMID: 31242454
ISSN: 1873-1635
CID: 3963732
In vivo imaging of structural, metabolic and functional brain changes in glaucoma
Kasi, Anisha; Faiq, Muneeb A; Chan, Kevin C
Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease.
PMCID:6334611
PMID: 30539811
ISSN: 1673-5374
CID: 4113482
Changes in visual function and visual pathway in experimental glaucoma induced by intracameral injection of a chemically cross-linked hydrogel [Meeting Abstract]
Ren, Tianmin; Chan, Kevin C.; Yu, Yu; Ng, Shuk Han; Mak, Heather; Yip, Wong Ying; Van Der Merwe, Yolandi; Yung, Jasmine S.; Biswas, Sayan; Cao, Xu; Chau, Ying; Leung, Christopher Kai-Shun
ISI:000488628100202
ISSN: 0146-0404
CID: 4154172
Role of Central Insulin Resistance in Glaucoma [Meeting Abstract]
Faiq, Muneeb Ahmad; Dada, Tanuj; Sengupta, Trina; Nath, Madhu; Velpandian, Thirumurthy; Chan, Kevin
ISI:000488628101265
ISSN: 0146-0404
CID: 4154192
Structure and Metabolism in the Brains of the Congenitally Blind Using Magnetic Resonance Imaging and Spectroscopy [Meeting Abstract]
Chan, Kevin C.; Charles, Antoinette J.; Bang, Ji Won; Hamilton-Fletcher, Giles; Parra, Carlos; Murphy, Matthew C.; Nau, Amy C.
ISI:000488800703093
ISSN: 0146-0404
CID: 4154442
Non-invasive Detection of Visual Pathway Abnormalities in Genetic Experimental Models of Glaucoma Using Diffusion Tensor MRI [Meeting Abstract]
Colbert, Max; van der Merwe, Yolandi; Ho, Leon C.; McLellan, Gillian J.; Hurley, Samuel A.; Fingert, John H.; Parra, Carlos; Faiq, Muneeb A.; Wollstein, Gadi; Schuman, Joel; Chan, Kevin C.
ISI:000488800703170
ISSN: 0146-0404
CID: 4154452
Applications of Manganese-Enhanced Magnetic Resonance Imaging in Ophthalmology and Visual Neuroscience
Deng, Wenyu; Faiq, Muneeb A; Liu, Crystal; Adi, Vishnu; Chan, Kevin C
Understanding the mechanisms of vision in health and disease requires knowledge of the anatomy and physiology of the eye and the neural pathways relevant to visual perception. As such, development of imaging techniques for the visual system is crucial for unveiling the neural basis of visual function or impairment. Magnetic resonance imaging (MRI) offers non-invasive probing of the structure and function of the neural circuits without depth limitation, and can help identify abnormalities in brain tissues in vivo. Among the advanced MRI techniques, manganese-enhanced MRI (MEMRI) involves the use of active manganese contrast agents that positively enhance brain tissue signals in T1-weighted imaging with respect to the levels of connectivity and activity. Depending on the routes of administration, accumulation of manganese ions in the eye and the visual pathways can be attributed to systemic distribution or their local transport across axons in an anterograde fashion, entering the neurons through voltage-gated calcium channels. The use of the paramagnetic manganese contrast in MRI has a wide range of applications in the visual system from imaging neurodevelopment to assessing and monitoring neurodegeneration, neuroplasticity, neuroprotection, and neuroregeneration. In this review, we present four major domains of scientific inquiry where MEMRI can be put to imperative use - deciphering neuroarchitecture, tracing neuronal tracts, detecting neuronal activity, and identifying or differentiating glial activity. We deliberate upon each category studies that have successfully employed MEMRI to examine the visual system, including the delivery protocols, spatiotemporal characteristics, and biophysical interpretation. Based on this literature, we have identified some critical challenges in the field in terms of toxicity, and sensitivity and specificity of manganese enhancement. We also discuss the pitfalls and alternatives of MEMRI which will provide new avenues to explore in the future.
PMCID:6530364
PMID: 31156399
ISSN: 1662-5110
CID: 3923332