NEW STRATEGIES TO PREVENT BLINDNESS

The study of brain changes in glaucoma may provide new insights into the pathobiology of glaucomatous damage and disease progression and stimulate new detection and therapeutic strategies to prevent blindness, according to Neeru Gupta MD, PhD.

'There is now abundant evidence that glaucoma is a neurodegenerative disease that affects the central visual system. This is borne out by our own research over the last decade as well as work from other laboratories around the world. It is clear that if we want to do something about glaucoma we should be tackling the eye but also remembering that we need to follow up with the connections to the brain, focusing on structures such as the retinal ganglion cell and lateral geniculate nucleus,' Dr Gupta told delegates attending the World Glaucoma Congress.

Dr Gupta, professor and Dorothy Pitts chair of ophthalmology and vision sciences, and laboratory medicine and pathobiology at St Michael's Hospital, University of Toronto, said that it was important to consider other factors beyond optic disc changes in recognising and treating glaucoma.

'If we want to move forward, it may be worthwhile to explore some of the processes that go into the visual aspects that take place in the brain,' she said. While a lot of work in glaucoma research and treatment has focused on measures to lower intraocular pressure, Dr Gupta said that the elephant in the room is the fact that many patients will continue to lose sight despite treatment.

One promising avenue of research has been to focus on the target of retinal ganglion cells, the lateral geniculate nucleus (LGN), a structure located in the thalamus of the brain which serves as the primary relay centre for visual information received from the retina.

Dr Gupta described the LGN as a very special structure exquisitely organised into six distinctive layers: the ventral two magnocellular layers and the dorsal four parvocellular layers. An additional set of neurons, known as the koniocellular sublayers, are found ventral to each of the magnocellular and parvocellular layers.

In studies of experimental monkey glaucoma with optic nerve fibre loss, the LGN was shown to undergo significant degenerative changes, including overall LGN shrinkage and reduced neuron size and number, said Dr Gupta.

There is also evidence that the same process holds true for humans. In 2006, Dr Gupta's group published the results of a post-mortem human glaucoma case with bilateral visual-field loss in which reduced LGN and neuron size were observed by histomorphometry and ex vivo MRI scans compared with age-matched controls. In the same study, pre-chiasmal optic nerve and visual cortex changes were also seen. In 2009, Dr Gupta and colleagues looked at patients with glaucoma, and evaluated the structure of the LGN by MRI. This work provides evidence of significant LGN atrophy in human disease.

New techniques
The use of latestgeneration imaging technologies, in particular MRI scanning techniques, is helping to transform understanding of the role of the brain in glaucoma, said Dr Gupta. Functional magnetic resonance imaging (fMRI), a non-invasive means of inferring function-specific neuronal activity, enables researchers to evaluate glaucomatous changes in neuronal activity throughout the visual pathway in vivo.

Recent glaucoma research has focused on the potentially protective effects of memantine, a neuroprotective agent used in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In a 2006 study of memantine in monkey glaucoma, Yucel et al showed that memantine attenuates LGN neuron shrinkage.

Following up this work, more recently, Dr Gupta's group used Sholl analysis to demonstrate that dendrites in monkey LGN have reduced complexity.

'We specifically evaluated dendrite complexity under the microscope and saw a significant increase in dendrite complexity in glaucoma subjects treated with oral memantine compared to those with glaucoma that received only vehicle. This tells us that there is an opportunity to change the wiring in the brain with new treatments as we learn more about visual system degeneration in glaucoma,' she said.