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Neurodegeneration in Glaucoma May Provide New Avenues for Neurology Research

Rukovets, Olga

doi: 10.1097/01.NT.0000414822.83366.9e
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A review paper posits that glaucoma be viewed as a neuro-ophthalmological disorder and points to opportunities for interdisciplinary research among ophthalmologists and neurologists.

Glaucoma, the leading cause of irreversible blindness, has been primarily thought of as a group of eye disorders that result in damage to the optic nerve due to increased intraocular pressure. But the authors of a review paper published in the Feb. 18 online journal Ophthalmology present a broader paradigm of the disease, characterizing it as a neurodegenerative, neuro-ophthalmologic disorder — one that may open up new avenues for interdisciplinary research, experts say.

Reducing intraocular pressure continues to be a treatment goal, study author Jeffrey L. Goldberg, MD, PhD, an associate professor of ophthalmology at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine, told Neurology Today in a telephone interview. But, he said, the neuroprotection and neuroenhancement of the retinal ganglion cells (RGCs), or neurons of the innermost layer of the retina, are now a vital focus.

The review is essentially a “call to action” for neurologists and ophthalmologists to think in a more unified fashion in researching treatment for patients with glaucoma and other optic neuropathies, said Dr. Goldberg. This unified approach will be essential in identifying effective treatments and “has given us a next generation of understanding of therapeutic targets by which to maintain RGC survival, protect or rebuild RGC connections in the retina and brain, and enhance RGC function,” Dr. Goldberg and co-author Elma E. Chang, MD, wrote in the review.

Kathleen B. Digre, MD, professor of neurology and ophthalmology at the University of Utah School of Medicine, said all neurologists should be excited about this review, not just neuro-ophthalmologists. “Glaucoma is an interesting optic neuropathy because it's a degenerative condition and there are a lot of parallels between other degenerative neurologic problems, for example, Alzheimer disease or motor neuron disease, where there is also neuronal cell death.

“What's so accessible about this degenerative condition is that it's in the eye, where you can actually look at the optic nerve; you're able to observe and even do studies to see what happens to neurons in a human being,” she told Neurology Today.



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Dr. Goldberg, who also holds secondary appointments to the graduate faculty in cell biology and anatomy, the program in neuroscience, and molecular and cellular pharmacology at the University of Miami Miller School of Medicine, said that there are currently a lot of treatments in the pipeline directed at the optic retina and optic nerve, and not just at the pressure in the eye.

In theory, he added, these new and different kinds of treatments should be useful not just for glaucoma but for other optic neuropathies, such as ischemic optic neuropathy or optic neuritis, which are also commonly seen by neuro-ophthalmologists.

The review discusses some therapies commonly used for other neurodegenerative diseases, such as Alzheimer and Parkinson disease, which are now in clinical trials for glaucoma. Commenting, Dr. Digre said: “Perhaps neurologists might want to use some of these models or, at least, partner with people who do glaucoma research to try to understand what might be neuroprotective for ganglion cells.”

One of the most discussed approaches for neuroprotection in glaucoma, the authors wrote, has been blocking glutamate excitotoxicity. Trialists are examining the potential of the Alzheimer drug memantine, an NMDA (N-methyl-D-aspartate) glutamate receptor antagonist, for glaucoma, for example.



Researchers are also looking to neurotrophic factors to enhance the survival of RGCs and the growth of axons in glaucoma patients. “A number of neurotrophins have been tested in human clinical trials, including BDNF [brain-derived neurotrophic factor] for amyotrophic lateral sclerosis, CNTF [ciliary neurotrophic factor] for amyotrophic lateral sclerosis and macular degeneration, glial cell line-derived neurotrophic factor for Parkinson disease, and nerve growth factor for Alzheimer disease, although despite this promise, none have yet succeeded in humans, in part because of complications associated with having to deliver them to the brain,” the authors wrote. They added that specific delivery to the eye may overcome some of these difficulties.

Finally, Drs. Chang and Goldberg wrote, stem cells may hold answers for neurodegenerative diseases, such as glaucoma. Though “coaxing stem cells to turn into RGCs and connect from the eye to the brain may take considerably more work,” they wrote, in the short-term, stem cells may address the RGCs that are still alive in glaucoma. Stem cells were found to enhance RGC axon survival in preclinical models.

Much of this research in neuro-protection, Dr. Goldberg told Neurology Today, is done in neurology and neuroscience departments “because the retina and optic nerve are developmentally an outgrowth of the brain, and the RGCs are fundamentally CNS neurons that connect to other nervous system neurons.”

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Neuro-ophthalmologist Steven Galetta, MD, pointed out that neurologists don't typically see patients for the evaluation and treatment of glaucoma. But he agreed that the neurodegenerative aspect of the disease lends itself to interdisciplinary research. “We have optical coherence tomography (OCT) and that allows us to measure the RGC layer in vivo. We don't have that type of imaging resolution for brain tissue so drugs that provide neuroprotection might be measured in an eye model first,” Dr. Galetta, the vice chairman of the department of neurology and director of Neuro-Ophthalmology Services at Penn Medicine in Philadelphia, said. The eye is going to be a great model to study drugs for neuroprotection and neuro-repair, he told Neurology Today.

Other significant takeaway points this review, he said, are that the optic nerve can sometimes have a glaucomatous appearance, which can result from an underlying neurological disorder; and some forms of glaucoma can mimic primary neurological disorders.

“In testing efficacies of therapies in other neurodegenerative diseases like Alzheimer's, we have to do behavioral testing, and in movement disorders we have to rely on clinical examination scales,” said Nancy J. Newman, MD, Leo Delle Jolley Professor of Ophthalmology and professor of neurology at Emory University School of Medicine. “In glaucoma, you not only can perform functional studies such as visual acuity and visual field assessment, but you can actually quantify the amount of axonal loss over time using OCT and similar assessments. Additionally, glaucoma, like other optic neuropathies, is a very accessible neurodegenerative disease because you can get therapies directly to the affected neurons.” Dr. Newman is also the director of the section of Neuro-Ophthalmology at Emory University School of Medicine.

What's important, Dr. Goldberg added, is that considering glaucoma to be a neuro-ophthalmic disease is improving “both our understanding of the basic pathophysiology of the disease, but is also leading us to think more broadly about potential new treatments….A lot of the fundamental neuroscience research going on in both neurology and ophthalmology departments, as well as in basic science departments, will be applicable for glaucoma and other optic neuropathies, just as it is applicable to other neurodegenerative diseases in the brain and spinal cord,” he said.



Dr. Digre added: “If neurologists understood how accessible the eye is to study, these models might really further our understanding of degenerative conditions that affect the brain and nervous system.”

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Recent research has shown more and more parallels between neurological and ocular health. A study published online before print in the March 14 issue of Neurology identified an association between retinopathy and changes in the brain and cognitive functioning in older women. The study looked at a population of 511 women over the age of 65 enrolled in both the Women's Health Initiative Memory Study and the Sight Examination Study.

Lead study author Mary Haan, DrPH, MPH, professor of epidemiology at the University of California, San Francisco department of epidemiology and biostatistics told Neurology Today, “In women with retinopathy, there was a greater decline in cognitive performance on the global test of cognitive function (MMSE) — approximately 10 to 15 percent more rapid decline over time than people who did not have retinopathy.”

We also learned, she said, that individuals with retinopathy have a larger number and size of ischemic lesions in the total brain. Interestingly, “we did not find that it was associated with brain atrophy…. It's actually been known for some time that there are two basic causes for retinopathy: diabetes and hypertension. We did adjust for those factors and it didn't change the result,” she said.

These findings put another link in the chain of association between cardiovascular-related disease and changes in the brain, she said. “That means when we're looking in the eye, and we see hemorrhages or exudates or other indicators of retinopathy, we should also be thinking of whether that person's brain is going to be affected, and look as well for cognitive impairment.”

There needs to be further study, Dr. Haan told Neurology Today, in men as well as in a younger population. If we can look at this association in individuals in their 50s, for example, she said, we might still be able to delay or try to prevent cognitive decline and dementia.

Olga Rukovets

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• Chang EE, Goldberg JL. Glaucoma 2.0: Neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 2012; E-pub 2012 Feb. 18.
    • Haan M, Espeland MA, Klein BA, et al. Cognitive function and retinal and ischemic brain changes: The Women's Health Initiative. Neurology 2012; E-pub 2012 Mar. 14.a
      © 2012 American Academy of Neurology