Glaucoma as a neurodegenerative disease Neeru Guptaa,b,c,d and Yeni H. Yu¨cela,b,c,e
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 Alzheimer’s and Parkinson’s 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. Keywords Alzheimer’s disease, lateral geniculate nucleus, optic nerve, Parkinson’s disease, retinal ganglion cells, visual cortex
Abbreviations ALS CNS IOP LGN MRI RGC
amyotrophic lateral sclerosis central nervous system intraocular pressure lateral geniculate nucleus magnetic resonance imaging retinal ganglion cell
ß 2007 Lippincott Williams & Wilkins 1040-8738
Introduction Glaucoma, a major cause of world blindness, is projected to affect 79.6 million people by 2020 . The disease may be recognized by characteristic optic nerve head changes and corresponding visual field defects. In most glaucomas, elevated intraocular pressure (IOP) is a major risk factor for glaucoma . Current medical and surgical therapies are directed at reducing IOP, and evidence from randomized multicentered trials supports this treatment approach to reduce the progression of vision loss [3,4]. Lowering IOP may also help to preserve vision in glaucoma patients without elevated IOP . There are many patients who continue to lose sight despite well controlled IOP, however [6–8], suggesting that IOP-independent mechanisms contribute to disease progression. These mechanisms may be similar to those first described in neurodegenerative diseases. Neurodegenerative diseases are a heterogeneous group of disorders with clinical and pathological diversity, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). Let us consider some of the similarities between glaucoma and common neurodegenerative diseases.
Loss of specific neuron populations Curr Opin Ophthalmol 18:110–114. ß 2007 Lippincott Williams & Wilkins. a
Departments of Ophthalmology & Vision Sciences, Laboratory Medicine & Pathobiology, St Michael’s Hospital, University of Toronto, Canada, cHealth Sciences Research Center, St Michael’s Hospital, Toronto, Canada, dGlaucoma and Nerve Protection Unit, St Michael’s Hospital, Toronto, Canada and eOphthalmic Pathology Laboratory, University of Toronto, Canada Correspondence to Neeru Gupta, MD, PhD, FRCSC, DABO, Glaucoma and Nerve Protection Unit, University of Toronto, St Michael’s Hospital, 30 Bond Street, Suite 8-072, Toronto, Ontario, M5B 1W8, Canada Tel: +1 416 864 5444; e-mail: [email protected]
Current Opinion in Ophthalmology 2007, 18:110–114
A fundamental process shared by neurodegenerative diseases is the loss of specific neuron populations. Vision loss and dysfunction in glaucoma result from retinal ganglion cell (RGC) death , atrophy  and axon degeneration extending to central visual targets in the brain [11–14,15]. Loss of specific neuron populations is seen in many neurodegenerative diseases and the clinical disorder correlates with the functions of the specific neuron set . For example, in Alzheimer’s disease, the loss of hippocampal and cortical neurons manifests as a memory and cognitive disorder. In Parkinson’s disease, the relatively selective loss of nigrostriatal dopaminergic neurons manifests as a progressive movement disorder [17,18]. Upper and lower motor neuron loss in the cortex and spinal cord leads to motor disturbances and
Glaucoma as a neurodegenerative disease Gupta and Yu¨cel
a diagnosis of ALS. Neurodegenerative diseases typically show a progressive decline in function related to the loss of relevant neuron systems, as seen in glaucomatous vision loss increasing with RGC loss [19,20].
Disease spread by transsynaptic degeneration The mode of disease spread in neurodegenerative disorders is called transsynaptic degeneration. Specifically, disease is transmitted from sick neurons to healthy neurons through synaptic connections along anatomic and functional neural pathways. This spread of disease between communicating neurons is a well known feature of Alzheimer’s disease  and ALS , and has more recently been described in experimental and human glaucoma .
Glaucoma from the eye to the brain As in human glaucoma, elevated IOP in the monkey eye can produce RGC death, with characteristic optic nerve head changes including excavation . Glaucoma is generally considered to be a disease of the eye; however, most of the RGC axon is extra-ocular, with prechiasmal, chiasmal and postchiasmal components. Furthermore, 90% of RGCs project to the lateral geniculate nucleus (LGN), the first major vision center located deep within the brain. The LGN conveys three major visual channels, namely, the magnocellular (motion), parvocellular (red-green) and koniocellular (blue-yellow) pathways. This thalamic structure is organized into six principal layers of neurons from ventral to dorsal with magnocellular neurons located in layers 1 and 2, parvocellular neurons in layers 3 –6, and koniocellular neurons sandwiched between principal layers of the LGN. Attention to pathology within the length of the RGC axon and also its LGN target may shed new light into the underlying pathology and progressive nature of glaucoma. In primate glaucoma, pathological examination of the LGN reveals marked degenerative changes, including shrinkage and loss of neurons. Quantitative assessment using three-dimensional techniques shows significant neural degeneration in magnocellular and parvocellular neurons that project to the visual cortex [11,12,14]. Koniocellular neurons also show obvious neurochemical alterations in glaucoma . Reduced mitochondrial activity observed in LGN layers driven by the glaucoma eye [25,26] may relate to loss of RGC input, neurons, and/or synaptic activity. As optic nerve damage increases, degeneration of neurons in magnocellular and parvocellular pathways appears to increase . Furthermore, a linear relationship between optic nerve fiber loss and shrinkage of surviving neurons has been described in these pathways . Thus, optic nerve damage appears to be accompanied by neuropathological changes in
magnocellular, parvocellular and koniocellular LGN neurons in experimental primate glaucoma. Relay neurons of the LGN project to the visual cortex where motion, depth and form are processed. In the primary visual cortex in glaucoma, metabolic changes have been mapped to ocular dominance columns driven by the glaucomatous eye [13,27,28]. These data also implicate degenerative changes in the visual cortex in the pathobiology of glaucoma. Central visual pathway degeneration in glaucoma is a process that may begin early in the disease. For example, in primate glaucoma, elevated IOP without measurable optic nerve fiber loss induces shrinkage of target LGN neurons . Chronic ocular hypertension also induces significant dendrite pathology in the LGN . Transsynaptic injury to LGN neurons may thus be induced following RGC injury in the absence of detectable RGC death. In a case of human glaucoma, postmortem analysis of the visual system correlated optic nerve damage and visual field deficits, and revealed neuropathology in the intracranial optic nerve, LGN and visual cortex in a retinotopic fashion . Human glaucoma with LGN density changes  has also been described. Findings in human glaucoma support observations of central neural degeneration in experimental primate glaucoma. The transsynaptic spread of disease to target CNS visual neurons in experimental primate and human glaucoma is similar to that seen in neurodegenerative diseases.
Mechanisms of cell injury Neurodegenerative diseases share a number of characteristic pathological processes leading to cell death. Neuron loss in glaucoma and at least some of the neurodegenerative diseases has been linked to a form of programmed cell death termed apoptosis . Initiating factors include oxidative injury [31,32], glutamate excitotoxicity , and abnormal protein accumulations . Cells undergoing oxidative stress accumulate reactive oxygen species that react with nitric oxide to form peroxynitrite, and modify cell components to trigger cell death pathways. Peroxynitrite can mediate protein nitration to produce nitrotyrosine, a footprint of oxidative injury associated with Alzheimer’s disease , Parkinson’s disease , and ALS [37,38]. In glaucoma, nitrotyrosine is observed in the human optic nerve head  and appears in the LGN in experimental primate glaucoma . Excitotoxicity, through excessive glutamate and stimulation of its receptors, seems to be important to a number of neurodegenerative diseases including Alzheimer’s disease , Parkinson’s disease [42,43], and ALS .
Although evidence for glutamate excess in human and primate glaucoma is unclear [45,46], blockage of the NMDA receptor in experimental monkey glaucoma protected against injury to retinal ganglion cells  and their target LGN neurons . Following neural injury, glial cells may respond by increased release of molecules implicated in inflammatory processes called cytokines. Excessive production of cytokines such as tumor necrosis factor-alpha (TNF-a) is implicated in Alzheimer’s disease and Parkinson’s disease . In glaucoma, TNF-a is observed in the human optic nerve head , and may be implicated in experimental glaucoma . Abnormal protein accumulation is a key feature of several neurodegenerative diseases . Beta-amyloid is a protein accumulated extracellularly within the senile plaque, a hallmark of Alzheimer’s disease. In glaucoma, although evidence for abnormal protein accumulation is limited, abnormal processing amyloid precursor protein has been observed in rat glaucoma . The characteristic lesion of Parkinson’s disease is the Lewy body, and it contains the intracellular protein alpha synuclein . A key feature of Alzheimer’s disease is intracellular protein accumulations such as neurofibrillary tangles that contain abnormally phosphorylated tau protein. Recent findings of abnormal tau protein in human glaucomatous retina suggest common abnormalities in the cascade of events that characterize neural degeneration (N. Gupta, J. Fong, E. Girard et al., unpublished observation). The incidence of neurodegenerative diseases tends to increase with aging and this is also observed in glaucoma . Susceptibility factors, such as apolipoprotein epsilon 4 allele, relevant to neurodegenerative diseases such as Alzheimer’s disease may also be relevant to glaucoma .
Implications of glaucoma as a neurodegenerative disease Glaucoma is a disease affecting the RGCs, with evidence of neuropathology at multiple central visual stations. Examination of the optic nerve head in patients may represent a very small window into the clinical disease, with glaucomatous damage extending anywhere from the retina to the visual cortex, depending on the severity of disease. In fact, by the time significant visual field deficits are detected, extensive CNS pathology may well be present .
damage despite well controlled IOP. While treatment to lower IOP prior to significant RGC loss will remain important to prevent the spread of damage from RGCs to visual target neurons in the brain, future adjunctive strategies to more effectively treat glaucoma may need to protect neurons in the retina and central visual system. Treatments for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are becoming more relevant to glaucoma. Memantine, an NMDA open channel blocker, is a widely prescribed medication used to treat moderate and severe Alzheimer’s disease, and has been used as therapy for Parkinson’s disease for over 20 years . A large prospective multicentered randomized double-blind clinical trial to test memantine in glaucoma patients has just been completed. The results of the clinical trial will soon tell us whether memantine as an adjunct to IOP-lowering medications, can also help to protect visual function in glaucoma patients. Detailed assessment of the visual pathways using multiple approaches may help to uncover specific neural deficits in patients. New paradigms may lead to the detection of dysfunction possibly linked to visual cortex pathology, as in binocular functions . Modern structural neuroimaging using magnetic resonance imaging (MRI) is able to visualize the lateral geniculate nucleus  and may be useful in assessing shrinkage of some of the visual structures along the geniculo-cortical pathway in the brain . Using functional neuroimaging (fMRI), the blood oxygen level dependent (BOLD) fMRI response in the human primary visual cortex was shown to be altered in primary open-angle patients in a manner consistent with the loss of visual function . In the future, modern neuroimaging technologies may become more useful in assessing the extent of glaucomatous involvement and spread within the CNS. Strategies to detect and evaluate disease progression in neurodegenerative diseases include the detection of abnormal peptides and excess degraded normal constitutive molecules  , or an immune response to peptides . The study and identification of biomarkers in glaucoma may be a surrogate to determining progressive neural degeneration, and may help to identify those patients likely to respond to specific treatment options. Further studies are needed to determine the best biomarkers to assess glaucomatous damage.
Conclusion In those patients with inadequate IOP control and progressive loss of RGCs, progressive degeneration in the visual system might be expected. Furthermore, marked central visual system degeneration may be associated with patients who show progressive glaucomatous
Glaucoma as a neurodegenerative disease is a valid working hypothesis. This IOP-independent paradigm may serve as a window to new opportunities to assess and treat glaucoma. Glaucoma would be the most common of all neurodegenerative diseases should accumulating
Glaucoma as a neurodegenerative disease Gupta and Yu¨cel
evidence determine unequivocally that glaucoma is a ‘vision disorder’ falling within the group of neurodegenerative diseases.
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The work was supported by the Canadian Institutes of Health Research and the Glaucoma Research Society of Canada.
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