Study suggests potential underlying cause for dementia after cancer treatment

WINSTON-SALEM, N.C. -- Researchers at Wake Forest University School of Medicine have identified changes in brain chemistry that may be associated with the dementia that many cancer patients develop after whole-brain radiation treatment.

"By identifying exactly how radiation causes these side effects, our hope is that we can find a way to prevent or reverse them," said Lei Shi, M.D., Ph.D., lead author and a research fellow.

Whole-brain radiation is widely used to treat recurrent brain tumors as well as to prevent breast cancer, lung cancer and malignant melanoma from spreading to the brain. About 200,000 people receive the treatments annually. Starting at about a year post-treatment, up to one-half develop progressive memory problems.

Researchers don't know precisely how radiation injures the brain, but suspect it causes changes in the brain's communication system. To test this theory, Shi and colleagues evaluated rats that had been treated with radiation and developed learning and memory impairments.

Today, at the annual meeting of the Radiation Research Society in Philadelphia, the researchers said they found changes in brain receptors for glutamate a neurotransmitter, or molecule that carries signals between nerve cells. They said the receptors change in composition as a result of whole-brain irradiation and that the changes seem to be associated with cognitive deficits.

These findings are significant because they may lay the groundwork for developing new therapies to prevent or reverse these potentially devastating impairments induced by whole-brain irradiation.

"There is a growing concern about the cognitive consequences of whole-brain radiation," said Judy Brunso-Bechtold, Ph.D., a professor of neurobiology and anatomy and senior researcher. "Our findings suggest that very subtle changes may be critical and that glutamate receptors may be one of those changes."

The researchers focused on middle-age rats because middle-age adults are most prone to the cancers that require whole-brain irradiation treatment. Half of the rats received doses of whole-brain radiation similar to what humans receive. The other half received "sham" treatments that involved no radiation. One year later, researchers tested the rats' learning and memory using a water maze.

The rats that had received radiation performed significantly worse than the untreated animals. Additional experiments were conducted to determine if these deficits were associated with cell-to-cell communication in the hippocampus, a region of the brain associated with learning and memory.

The scientists specifically looked at glutamate receptors that lie on cell membranes. There are several different subtypes of the receptors that differ in the types of brain chemicals that most readily bind to them. They found that the composition of these subtypes was different in the animals receiving whole-brain irradiation.

"This shift in composition could impair synaptic communication and lead to the spatial learning and memory deficits measured in the treated rats," said Shi.

Next, the researchers will see if the chemical changes also extend to the synapses themselves. They also want to focus on why some animals and people experience cognitive deficits while others don't. Eventually, they hope to test drug therapies that may prevent the effects.

Shi received the 2006 Marie Curie Award from the Radiation Research Society for the research.

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Embargoed for 6 p.m. ET on Monday, Nov. 6, 2006

The research is supported by a recently funded grant from the National Institutes of Health and is part of a broad collaboration among researchers led by Michael Robbins, Ph.D., in the Department of Radiation Oncology. Other co-researchers were Michelle Adams, Ph.D., Michelle Nicolle, Ph.D., William Sonntag, Ph.D., and Kenneth Wheeler, Ph.D., all from Wake Forest.

Media Contact: Shannon Koontz, shkoontz@wfubmc.edu, 336-716-4587.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in family medicine, 20th in geriatrics, 25th in primary care and 41st in research among the nation's medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.


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