The evidence for glaucoma as a neurodegenerative disease

 By Y. Yücel

http://www.glaucom.com/Supplement/MFG2006/Session4.php#neuro 

Retinal ganglion cell death is the pathologic correlate of glaucomatous damage. As 90% of RGCs project to the lateral geniculate nucleus (LGN), there is a good reason for believing that this damage extends from RGCs to vision centers in the brain. Indeed, work in experimental monkey models showed that neurodegenerative changes due to glaucoma occurred in the LGN cell layers (Weber, 2000; Yücel et al., 2000; Yücel et al., 2003). The extent of these changes wasrelated to the severity of optic nerve damage (Yücel et al., 2003), and neuronal shrinkage showed a linear relationship with IOP level and optic nerve damage (Yücel et al., 2001). This shrinkage was seen even when no optic nerve fiber loss was detected (i.e., in eyes with OHT or early glaucoma), suggesting that post-synaptic changes might occur before changes are seen in the optic nerve. In fact, studies using functional and metabolic markers of neurons in the LGN, such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cytochorome-oxidase, have indicated that post-synaptic neurochemical changes occurred at a very early stage (Crawford et al., 2000; Vickers et al., 1997; Yücel et al., 2003). The visual cortex has been found to be affected by neuronal changes in the LGN as relay neurons projecting from the LGN to the cortex underwent considerable shrinkage in glaucoma (Crawford et al., 2001; Yücel et al., 2001). Pathologic neurodegenerative changes were also seen in the LGN layers connected to the unaffected fellow eye of the monkey model (Yücel et al., 2003).

Fig. 18. MRI shows reduced-sized LGN in glaucoma (B) compared with control (A). Nissl staining reveals shrunken LGN in glaucoma (D) compared with control (C). (E): LGN volume in glaucoma (black) is also reduced compared with controls (grey). (Reproduced with permission from N. Gupta; BJO 2006;90:674-678.) (click to enlarge)

Data in patients with glaucoma are still limited but seem to confirm the relevance of these brain changes in animal models (Gupta et al., 2006a). Neuropathologic changes have been investigated post-mortem in a 79-year-old patient who died of acute viral myocarditis 18 months after diagnosis of POAG with superior VF loss in both eyes (Gupta et al., 2006a). Compared with age-matched controls, MRI showed overall neuronal shrinkage of the LGN, with the LGN volume in glaucoma reduced by nearly 30% compared with controls (Fig. 18).Magnocellular and parvocellular neurons appeared smaller in glaucoma, and thinning of the visual cortex was visible (Fig. 19. The locations of the neuro degenerative changes in the intracranial optic nerve, LGN and visual cortex correspond well with the superior VF defect.

The potential pathogenic mechanisms underlying neuronal degeneration are common to neurodegenerative diseases and include oxidative stress, glutamate-related excitotoxicity and nerve growth factor deprivation. As with AD, another possible mechanism responsible for neurodegeneration is the abnormal phosphorylation of the tau protein involved in microtubule assembly (Gupta et al., 2006b). In AD, tau becomes abnormally hyperphosphorylated and accumulates as neurofibirillary tangles (Kopke et al., 1993).

Ongoing research in the field of neurodegeneration will bring new perspectives to the understanding of the pathogenesis and progression of glaucoma, which will help the physician in the diagnosis and treatment of the disease. For example, diagnosis can be improved bymonitoring binocular functions (Gupta et al., 2006c), to understand better changes at the level of the visual cortex. In terms of treatment, methods to protect neuronal cells by addressing the lack of supply of nerve growth factor, for instance, may help decrease the susceptibility RGCs to injuries and increase their survival. For the new neuroprotective modalities to provide adequate efficacy, it is essential that they are able to reach not only the back of the eye but also the brain, perhaps by crossing the blood-brain barrier. New drug delivery systems are to be developed and a multidisciplinary approach (e.g., electrophysiology, neuro-imaging, psychophysics, etc.) should be adopted to monitor the efficacy of candidate treatments.

Fig. 19. Thinning of the inferior bank of the visual cortex in glaucoma (A) compared with control (B). (Reproduced with permission from N. Gupta; BJO 2006;90:674-678.) (click to enlarge)

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