Neeru Gupta

Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma

Glaucoma is a leading cause of world blindness, and retinal ganglion cell death is its pathological hallmark. There is accumulating evidence that glaucomatous damage extends from retinal ganglion cells to vision centers in the brain. In an experimental primate model of unilateral glaucoma, degenerative changes are observed in magnocellular, parvocellular, and koniocellular pathways in the lateral geniculate nucleus, and these changes are presented in relation to intraocular pressure and the severity of optic nerve damage. Neuropathological findings are also present in lateral geniculate nucleus layers driven by the unaffected fellow eye. Finally, there is information on changes in the visual cortex in relation to varying degrees of retinal ganglion cell loss. The implications of these findings for refining concepts regarding the pathobiology of progression, and the detection and treatment of glaucoma, are discussed.

Glaucoma as a neurodegenerative disease

Purpose of review Glaucoma is a leading cause of irreversible world vision loss characterized by progressive retinal ganglion cell death. Elevated eye pressure is a major risk factor for glaucoma; however, despite effective medical and surgical therapies to reduce intraocular pressure, progressive vision loss among glaucoma patients is common. These observations suggest that mechanisms independent of intraocular pressure are also implicated in glaucomatous degeneration. Numerous similarities exist between glaucoma and neurodegenerative diseases such as Alzheimers and Parkinsons diseases. Similarities include the selective loss of neuron populations, transsynaptic degeneration in which disease spreads from injured neurons to connected neurons, and common mechanisms of cell injury and death. Recent findings Glaucomatous injury to retinal ganglion cells has profound effects on target vision structures within the brain, including the lateral geniculate nucleus and visual cortex in experimental primate and human glaucoma. Mechanisms involved in central visual system damage in glaucoma include oxidative injury and glutamate toxicity, as seen in neurodegenerative diseases. Summary Glaucoma as a neurodegenerative disease is a valid working hypothesis to understand neural injury in the visual system. This paradigm may stimulate the discovery of innovative intraocular pressure-independent strategies to help prevent loss of vision in glaucoma patients.

The Role of Glia, Mitochondria, and the Immune System in Glaucoma

Author(s): Tezel, Gulgun; Fourth ARVO/Pfizer Ophthalmics Research Institute Conference Working Group

Identification of lymphatics in the ciliary body of the human eye: A novel ''uveolymphatic'' outflow pathway

Impaired aqueous humor flow from the eye may lead to elevated intraocular pressure and glaucoma. Drainage of aqueous fluid from the eye occurs through established routes that include conventional outflow via the trabecular meshwork, and an unconventional or uveoscleral outflow pathway involving the ciliary body. Based on the assumption that the eye lacks a lymphatic circulation, the possible role of lymphatics in the less well defined uveoscleral pathway has been largely ignored. Advances in lymphatic research have identified specific lymphatic markers such as podoplanin, a transmembrane mucin-type glycoprotein, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). Lymphatic channels were identified in the human ciliary body using immunofluorescence with D2-40 antibody for podoplanin, and LYVE-1 antibody. In keeping with the criteria for lymphatic vessels in conjunctiva used as positive control, D2-40 and LYVE-1-positive lymphatic channels in the ciliary body had a distinct lumen, were negative for blood vessel endothelial cell marker CD34, and were surrounded by either discontinuous or no collagen IV-positive basement membrane. Cryo-immunogold electron microscopy confirmed the presence D2-40-immunoreactivity in lymphatic endothelium in the human ciliary body. Fluorescent nanospheres injected into the anterior chamber of the sheep eye were detected in LYVE-1-positive channels of the ciliary body 15, 30, and 45 min following injection. Four hours following intracameral injection, Iodine-125 radio-labeled human serum albumin injected into the sheep eye (n = 5) was drained preferentially into cervical, retropharyngeal, submandibular and preauricular lymph nodes in the head and neck region compared to reference popliteal lymph nodes (P < 0.05). These findings collectively indicate the presence of distinct lymphatic channels in the human ciliary body, and that fluid and solutes flow at least partially through this system. The discovery of a uveolymphatic pathway in the eye is novel and highly relevant to studies of glaucoma and other eye diseases.

Glaucoma of the brain: a disease model for the study of transsynaptic neural degeneration.

The identification of mechanisms precipitating neuronal death and injury is an intense area of investigation requiring reliable models to assess the effects of neuroprotective agents. Most are suboptimal since the effects of initial damage are diffuse and may not be reproducible or easily quantifiable. The ideal laboratory model should have the ability to (a) clearly detect evidence of neuronal injury and recovery, (b) accurately measure morphologically the extent of these changes, and (c) provide functional evidence for damage and recovery. Glaucoma is a disease of visual neurons in the eye and brain. In the visual system, neuroanatomical pathways and retinotopic organization are exquisitely defined, functional modalities are highly characterized and can be dissected physiologically, visual input parameters can be modified, visual functional output can be readily tested and measured, changes in the eye and the visual brain can be directly visualized and imaged, and pathological and compensatory changes in brain centers of vision can be examined and measured specifically. For these reasons, the glaucoma disease model is ideal for the study of response and recovery to injury in the central nervous system due to anterograde and retrograde degeneration from the eye to the brain and the brain to the eye, respectively. The study of this glaucoma model of transsynaptic brain injury may be relevant to understanding more complex pathways and point to new strategies to prevent disease progression in other neurodegenerative diseases.

Retinal tau pathology in human glaucomas

BACKGROUND Tau protein is a microtubule-associated protein critical to neuron structure and integrity. The abnormal hyperphosphorylated tau protein AT8 disrupts microtubules, interferes with axonal transport, and is associated with neuron injury in neurodegenerative diseases such as Alzheimers disease. The purpose of this study was to assess the presence of tau protein and abnormal tau protein AT8 in human glaucomas and to determine whether abnormal tau protein plays a role in glaucomatous neural degeneration. METHODS Sections from 11 surgical eye specimens with glaucoma from elevated intraocular pressure causes and 10 age-matched control eye specimens were immunostained for normal tau protein (BT2) and hyperphosphorylated tau protein (AT8). Postmortem specimens with incidental open-angle glaucoma (n = 6) were compared with controls (n = 3). Measurements of immunofluorescence intensity in glaucoma retinas were compared with those in control retinas. Abnormal tau AT8 and parvalbumin, a horizontal cell-specific marker, were studied with double-immunofluorescence techniques to determine colocalization. RESULTS In surgical glaucoma specimens, normal tau protein was decreased in both the optic nerve and retina compared with age-matched controls. Abnormal tau AT8 was evident within the posterior retina, predominantly at the outer border of the inner nuclear layer in surgical glaucoma specimens, and this was not observed in controls or incidental glaucoma cases. Quantitative immunofluorescence techniques demonstrated significantly increased abnormal tau AT8 in surgical glaucoma specimens compared with controls. Abnormal tau AT8 colocalized with parvalbumin in horizontal cells of the retina. INTERPRETATION Abnormal tau AT8, a marker of injury in various neurological diseases, is present in human glaucomas with uncontrolled intraocular pressure. The finding of abnormal tau protein in retinal horizontal cells may relate to elevated intraocular pressure and (or) neural degeneration in glaucoma. Tau protein abnormality in glaucoma underscores shared pathways with other neurodegenerative diseases.

New definitions of glaucoma.

At this time, there is no comprehensive and specific definition of glaucoma. Diagnostic tests such as retinal nerve fiber layer observation, scanning laser polarimetry, and confocal scanning laser tomography may improve the diagnosis and detection of glaucoma. Also, new functional tests, including short-wave-length automated perimetry, may provide better detection of glaucoma.

Glaucoma and the brain.

The pathobiologic features of retinal ganglion cell death in glaucoma have been studied extensively at the level of the retina and optic nerve head. Retinal ganglion cell (RGC) axons form the optic nerve, chiasm, and optic tract and convey visual information to multiple nuclei in the brain. Most RGCs terminate in the lateral geniculate nucleus (LGN), the major vision center relaying information from the eye to the visual cortex. In each LGN, the complete contralateral hemifield of vision is represented, and parallel central visual pathways are segregated into anatomically distinct magnocellular, parvocellular, and koniocellular channels. The axons of relay LGN neurons form the optic radiations projecting to eye specific columns in the primary visual cortex. Recent investigations show evidence of extension of glaucomatous injury to these central visual stations and may offer additional insights into the nature of glaucomatous damage and vision loss.

Dendrite Plasticity in the Lateral Geniculate Nucleus in Primate Glaucoma

Neural degeneration in glaucoma involves retinal ganglion cells and neurons of their major target, the lateral geniculate nucleus (LGN). Dendrites of relay LGN neurons projecting to the visual cortex were studied by immunocytochemical and quantitative Sholl analysis in combination with confocal microscopy and 3D-morphometry. In non-human adult primate glaucoma, relay LGN neurons showed reduced dendrite complexity and length, and these changes were modified by NMDA receptor blockade. Dendrite plasticity of LGN relay neurons in adult primate glaucoma has implications for potential disease modification by treatment interventions.

Quantum dots trace lymphatic drainage from the mouse eye.

Glaucoma is a leading cause of blindness in the world, often associated with elevated eye pressure. Currently, all glaucoma treatments aim to lower eye pressure by improving fluid exit from the eye. We recently reported the presence of lymphatics in the human eye. The lymphatic circulation is known to drain fluid from organ tissues and, as such, lymphatics may also play a role in draining fluid from the eye. We investigated whether lymphatic drainage from the eye is present in mice by visualizing the trajectory of quantum dots once injected into the eye. Whole-body hyperspectral fluorescence imaging was performed in 17 live mice. In vivo imaging was conducted prior to injection, and 5, 20, 40 and 70 min, and 2, 6 and 24 h after injection. A quantum dot signal was observed in the left neck region at 6 h after tracer injection into the eye. Examination of immunofluorescence-labelled sections using confocal microscopy showed the presence of a quantum dot signal in the left submandibular lymph node. This is the first direct evidence of lymphatic drainage from the mouse eye. The use of quantum dots to image this lymphatic pathway in vivo is a novel tool to stimulate new treatments to reduce eye pressure and prevent blindness from glaucoma.