aimed at preventing the spread of disease to visual centers in the brain and presumably disease progression.

Visual cortex in glaucoma

In the primary visual cortex, neurons are arranged into six layers subdivided into sublayers. The M, P, and K geniculate axons terminate in sublayers of layer 4 and superficial layers in eye-specific columns (Callaway, 2004). In monkeys with unilateral glaucoma, a relative decrease in metabolic activity was detected with cytochrome oxidase activity in ocular dominance columns driven by the glaucomatous eye, compared to those driven by the fellow non-glaucoma eye (Vickers et al., 1997; Crawford et al., 2000, 2001; Yu¨cel et al., 2003) (Fig. 6). Additional evidence of neuroplasticity of the visual system in primate glaucoma is suggested by neurochemical changes in the visual cortex involving the presynaptic molecule, growth-cone-associated protein-43 (GAP43), and inhibitory neurotransmitter receptor GABA A

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receptor subtype (Lam et al., 2003). Inspite of observed metabolic and neurochemical changes, evidence of neuronal loss in the primary visual cortex in this model is lacking. However, relative changes in metabolic activity of ocular dominance columns appeared more pronounced with increasing optic nerve fiber loss (Yu¨cel et al., 2003).

Neuropathology of glaucoma in the visual pathways in the human brain

In a case of advanced human glaucoma compared to age-matched normal controls, neuropathological analysis of visual pathways revealed degeneration in the intracranial optic nerve, LGN, and visual cortex, corresponding to the visual field defects (Gupta et al., 2006a). In the presence of vision loss in glaucoma patients, pathology in vision centers of the brain may exist. In a previous report of human glaucoma, LGN neuron density appeared decreased (Chaturvedi et al., 1993). Findings of degenerative changes in the central visual pathways in human glaucoma are consistent

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with changes observed in experimental primate glaucoma (Gupta et al., 2006a).

Mechanisms of glaucoma damage in the central visual pathways

Among a number of proposed initiating mechanisms of RGC and optic nerve degeneration (Weinreb and Khaw, 2004), there is evidence that oxidative injury (Luthra et al., 2005) and glutamate excitotoxicity (Yu¨cel et al., 2006) are implicated in transsynaptic degeneration in experimental primate glaucoma.

In oxidative injury, the accumulation of reactive oxygen species alters cellular and molecular pathways to induce cell death (Chong et al., 2005). Oxygen species can react with nitric oxide to form peroxynitrite, which mediates protein nitration to produce nitrotyrosine (Bian et al., 2006). In neurodegenerative diseases, the finding of nitrotyrosine is considered a footprint of peroxynitratemediated oxidative injury (Nunomura et al., 2001). Nitrotyrosine has been found in the neural parenchyma and blood vessels of the LGN in experimental primate glaucoma, suggesting a role for oxidative injury in the LGN in the blood vessels and neuronal layers connected to glaucomatous eye (Luthra et al., 2005). Oxidative injury in LGN layers connected to the fellow nonglaucoma eye might suggest differential metabolic needs between LGN layers driven by the glaucoma eye and the intercalated layers driven by the nonglaucoma fellow eye, challenging the autoregulatory capacity of common supplying blood vessels.

The glutamatergic system is ubiquitous and responsible for excitatory neurotransmission in the brain. Under conditions of excessive stimulation, neuron toxicity can occur, leading to intracellular calcium overload and neuron death (Hynd et al., 2004). This pathological process called glutamate excitotoxicity is implicated in a number of neurodegenerative diseases (Hynd et al., 2004) as in glaucomatous neural degeneration in the retina and optic nerve (Hare et al., 2001). Using pharmacological agents such as memantine, an open-channel blocker of the N-methyl-D-aspartic acid (NMDA) subtype, overstimulation of the glutamatergic

system can be blocked. Memantine crosses the blood–brain barrier in monkey glaucoma and may block NMDA receptors at the levels of LGN (Tighilet et al., 1998), retina (Grunert et al., 2002), and visual cortex (Rosier et al., 1993). Monkeys with glaucoma, given daily doses of memantine and compared to vehicle-treated glaucoma monkeys, showed attenuated neuronal shrinkage of LGN relay neurons (Yu¨cel et al., 2006). However, the same glaucoma animals treated with memantine did not show statistically significant differences in neuronal numbers compared to vehicle-treated glaucoma animals, suggesting that blockage of excitotoxicity by memantine (4 mg/kg) had no significant effect on neuronal death in LGN in experimental glaucoma.

LGN and visual cortex damage by glaucoma and/or neurodegenerative diseases may increase the susceptibility of surviving RGCs to ongoing injury by reducing their LGN trophic support and contribute to glaucomatous progression. Although the exact role of trophic factors in transsynaptic degeneration is not known, ocular delivery of BDNF has been shown to have a protective effect on RGCs (Martin et al., 2003). BDNF might be an anterograde trophic factor for survival of target neurons as seen during development (Caleo et al., 2000). Neurotrophic factors may play their effects by acting on different neural targets, such as LGN (Riddle et al., 1995), intracortical circuitry, and subcortical afferents (Berardi and Maffei, 1999).

Implications of central visual system injury in glaucoma

Glaucoma is a disease affecting the entire RGC with intraocular and intracranial components. Understanding within geniculo-cortical pathways has major implications for the diagnosis and management of the disease to slow progressive loss of sight.

In Alzheimer’s disease, disease progression has been studied by measuring hippocampal atrophy (Mungas et al., 2005). Similarly, assessment of visual pathways using modern neuroimaging such as magnetic resonance imaging (MRI) to visualize the LGN (Horton et al., 1990; Fujita et al., 2001) may be useful to assess structural changes in vision

centers along the components within retino- geniculo-cortical pathway in the brain. Infact, a recent 1.5 Tesla MRI study showed LGN atrophy in glaucoma patients compared to controls (Gupta et al., 2008a). Functional neuroimaging (fMRI), using the blood oxygen level dependent (BOLD) fMRI response, was decreased in human primary visual cortex in patients with primary open-angle glaucoma (Duncan et al., 2007). In future, modern functional and structural neuroimaging technologies may prove useful in assessing the spread of glaucomatous damage within the CNS. Multifocal and evoked electrophysiological measurements may be relevant to the detection of dysfunction along visual pathways (Korth et al., 1994; Klistorner and Graham, 1999; Graham et al., 2000; Hood and Greenstein, 2003). Optimization of the techniques to identify and measure structural and functional parameters in vivo in glaucoma patients is needed to better characterize brain changes in glaucoma. The choice of a reliable biomarker would help detect progression and/or a population at a high risk of progression. Non- geniculo-cortical pathways involved in eye movements and reflexes may be worth exploring in glaucoma. For example, the superior colliculus is an important visual structure for eye movements. In glaucomatous monkeys, reduced RGC terminals expressing vesicular glutamate transporter-2, a presynaptic marker of RGC terminals, were observed in superficial layers of the superior colliculus compared to controls (Alarcon-Martinez et al., unpublished data).

Cortical binocular functions such as stereovision (Bassi and Galanis, 1991; Essock et al., 1996; Gupta et al., 2006b) may also be useful to assess visual dysfunction in glaucoma.

The loss of visual field in moderate-to-advanced disease is a representation of damage to central visual pathways in glaucoma. Teasing apart visual functions selective for specific central vision pathways provides an opportunity to understand their relative contributions to visual disturbances in patients with glaucoma, and to functionally assess potential effects of candidate neuroprotective drugs in pathways with preferential functions such as magno-, parvo-, and koniocellular pathways.

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Increased susceptibility of RGCs to ongoing glaucomatous injury has been described as a determinant in progression of the disease (Abedin et al., 1982). We suggest that degeneration with neuronal loss and atrophy of target neurons in the LGN may alter the normal function of surviving RGCs in glaucoma. In fact, degenerative changes in RGCs are observed following the loss of target cells in the LGN (Payne et al., 1984; Pearson and Stoffler, 1992) and lesions of the striate cortex (Cowey et al., 1989; Johnson and Cowey, 2000). Changes in the visual stations may deplete growth factor sources to be transported back to the retina, contributing to the susceptibility of surviving RGCs to ongoing glaucomatous injury and progression, and studies are needed to test this hypothesis.

Some cellular mechanisms in glaucoma appear similar to neurodegenerative diseases. Abnormal tau protein, a pathological hallmark of neurodegenerative diseases such as Alzheimer’s, has also been detected in human glaucoma retina, in horizontal cells (Gupta et al., 2008b). A susceptibility gene for Alzheimer’s disease complicated in neural repair, apolipoprotein epsilon 4 allele, is reported to be associated with low-tension glaucoma in a population (Vickers et al., 2002), but could not be confirmed in other populations (Lam et al., 2006; Zetterberg et al., 2007). The coexistence of glaucoma and Alzheimer’s disease might not be purely coincidental (Bayer et al., 2002; McKinnon, 2003; Gupta and Yu¨cel, 2007).

Comparing brain changes in experimental glaucoma and human glaucoma to those seen in other types of injury such as ischemic optic neuropathy (Orgu¨l et al., 1996; Brooks et al., 2004), optic nerve transection, enucleation, and monocular visual deprivation (Hendry, 1991; Riddle et al., 1995) is needed. These experiments may help to elucidate how altered retinal input to relay cells with less than 10% of total synaptic input can cause such atrophy. Can this model of glaucoma help us to better understand the role of the thalamus beyond a relay station between retina and cortex (Sherman and Guillery, 2004)? Some of these questions might be best answered by well-characterized rodent models of glaucoma (Morrison et al., 1997; Lindsey and Weinreb, 2005; Morrison, 2005; Weinreb and Lindsey, 2005).

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Recent epidemiologic evidence showed that ocular perfusion pressure, a parameter that is based on the difference between blood pressure and IOP, is a risk factor for incident glaucoma (Leske et al., 2008) and for the progression of the disease (Leske et al., 2007). The relationship between glaucoma and cerebrovascular diseases requires further elucidation. For example, small blood vessels with small silent infarcts and white matter lesions may occur in watershed areas of terminal cerebral arteries supplying posterior visual pathways. It is unclear how this might alter visual function in glaucoma patients and contribute to progression of vision loss (Yu¨cel and Gupta, 2008).

Treatment to lower IOP prior to significant RGC loss is likely an important strategy to prevent the transsynaptic spread of damage to target visual neurons. In addition to lowering IOP, future strategies to treat glaucoma may consider protecting visual neurons in the retina and brain. Since retinal cell survival is dependent on its ability to effectively connect to target neurons, assessment of the health of target neurons (Yu¨cel and Gupta, 2007) is critical for new treatment strategies such as ocular neuroprotection (Weinreb, 2007), gene therapy (Sieving et al., 2006; Liu et al., 2007; MacDonald et al., 2007), and stem cell transplant strategies (Levin et al., 2004; Wallace, 2007). In this context, aberrant axonal outgrowth may alter visual function while adequate axonal outgrowth may restore it. New strategies to improve axonal outgrowth such as graft after peripheral nerve injury may be relevant (Lundborg, 2003).

Further studies of plasticity in the brain following LGN degeneration in glaucoma are needed.

Conclusion

Elevated IOP and injury to RGCs can trigger degeneration in distant connected neurons in major vision centers of the brain. Lowering IOP is an important strategy to prevent RGC death in the eye and may reduce the risk of CNS degeneration in glaucoma. In patients with progressive vision loss despite adequate IOP control, secondary pathological changes occur in visual

centers of the brain. Thus, IOP-lowering strategies combined with therapies to protect retina and central visual system neurons offer new opportunities to prevent blindness from glaucoma.

Glaucomatous injury to the visual system is an ideal model to study transsynaptic degeneration, as it relates to neurodegenerative diseases such as Alzheimer’s. The effects of initial damage are readily apparent, reproducible, and measurable, as are the effects of subsequent injury along welldefined anatomical and functional connections within vision pathways of the brain. Mechanisms elucidated from this glaucoma model of transsynaptic brain injury may be highly relevant to other neurodegenerative diseases, helping to understand complex pathways and to identify future strategies to prevent progressive functional decline in disease states.

Acknowledgments

This work was supported in part by Canadian Institutes of Health Research, Glaucoma Research Society of Canada and The Fred Jarvis Fund.

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Glaucoma is a heterogeneous group of disorders with a resultant common denominator: optic neuropathy leading eventually to blindness. Glaucoma is the second leading cause of blindness worldwide and is characterized by loss of retinal ganglion cells (RGCs) through a process whose pathophysiology is not fully understood. The most common subtype of glaucoma in the United States is open-angle glaucoma, a chronic disease exhibiting progressive loss of RGCs and their axons. Its clinical manifestations include excavation of the optic disc and progressive loss of visual field. Several models of glaucoma in monkeys (Quigley and Hohman, 1983) and rats (Shareef et al., 1995;

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Morrison et al., 1997) have been used experimentally to increase intraocular pressure (IOP), which leads to RGC death and generates features similar to those of human glaucoma.

RGCs in chronic glaucoma do not die at the same time; rather, RGC death is protracted over the course of several months or years. Therefore, the progression of optic neuropathy over the time provides avenues in which to study the state of still-living cells and to save them from death. RGC death also occurs when the optic nerve is transected. RGC death in the glaucomatous retina or following optic nerve transection is apoptotic and not necrotic (Garcia-Valenzuela et al., 1994, 1995; Quigley et al., 1995). It is reasonable to assume that the signal for apoptotic cell death is received approximately at the same time in all RGCs in the animals with optic nerve transection,