Researchers find measure of 'radiation brain'
Diffusion tensor imaging shows white matter changes after radiation therapy for cancer


by Kathlyn Stone

October 22, 2007

Radiation is sometimes the only viable therapy for people diagnosed with cancers of the brain and nervous system. In some cancer treatment centers, stereotactic radiosurgery using highly focused radiation beams has replaced surgery as the standard form of treatment. But even when radiation does as intended and removes the cancer, it sometimes introduces new problems.

Patients have reported a range of neurological side effects following radiation for brain tumors, as short-term as headaches and nausea to long-term loss of hearing, memory and other cognitive functions. Pediatric researchers see declines in both listening and concentration skills among children who underwent radiation therapy for brain tumors, pointing out that these children may need preventive and remedial help.

The National Cancer Institute estimates that 19,000 people in the United States are diagnosed with primary brain cancers each year; two-thirds will die within three years of the disease. But patients might wonder what they could lose when they sign on to potentially life-sustaining radiation therapy.

The suspected reason for the problems after treatment is some kind of adverse effect of radiation on white matter, the wiring through which the brain’s structures communicate. White matter consists of axons, the fibers along which messages pass between neurons; it gets its color from myelin, a substance ensheathing the wiring. But scientists understand little about how radiation affects the brain's white matter, its connective layers, and they can not predict what the side effects of radiation treatment might be. For cancer patients, knowing that they might have to sacrifice some cognitive abilities for a chance at survival can be a heavy burden. Caregivers can offer a patient no guarantees, merely the likelihood of survival expressed in statistics.  It all comes down to “What does the patient want?” said Kristofer Kainz, a medical physicist and assistant professor of radiation oncology at the Medical College of Wisconsin in Milwaukee.

Medical physicist Vijaya Nagesh, an expert in diffusion tensor imaging (DTI), is working to find some answers. Hypothesizing that radiation causes “changes in normal-appearing brain tissue and degradation in the brain’s structural integrity,” Nagesh led a team of investigators at the University of Michigan last year in a molecular-level study that measured the path radiation travels in the brain and any changes it leaves behind.

“Diffusion tensor imaging is a powerful tool,” Nagesh says. She has been involved with many imaging studies that evaluated white matter changes in ischemic stroke and other complex disorders. “In animal studies, radiation has been shown to cause neuroinflammation, demyelination and breakdown of the blood-brain barrier.”  The blood-brain barrier is a tight mesh of cells in the walls of the brain's blood vessels  that bars many substances in the bloodstream from entering the brain.

DTI tracks the movement, or what scientists refer to as the “diffusion,” of water through the brain. The enhanced resolution of DTI provides both 3-D views of the neural tissue structure and mapping of the diffusion path of water molecules.  Volume measurements taken at different voxels, or locations, produce 3-D renderings of the axon bundles and their protective myelin sheaths.

The Michigan team recruited 25 patients with cerebral tumor (17 men and 8 women with a median age of 60 years) to participate in the clinical studies. Study participants were being treated for high- and low-grade gliomas as well as benign tumors. All underwent 3-D image-guided radiotherapy.

They measured the normal brain tissues on the sides of the tumor at different stages: before therapy, at three and six week intervals during therapy, and post-therapy at 10 and 19 weeks from the therapy start date. Radiation doses varied from 50 to 81Gy (gray units of radiation energy), the common dose range for adults receiving conventional radiation therapy.

The researchers found that eigen-diffusivity – a measure indicating the degree of fluid motion at a specific location (the voxel) – increases in three areas, indicating damage in those areas. Various DTI measures pointed to abnormal fluid flow within normal tissue at 19 weeks post-radiation that didn’t exist before the radiation treatments.

 “The implication is that the radiation degraded these regions of the brain in such a way that fluid tends to flow more readily than it did before,” said Kainz, who was not involved with the research. He said the study was one of the first to quantify radiation effects.

“This means that the axons are basically ‘leaky,” says John Moffett, a neuroscientist working in the anatomy, physiology and genetics department at Uniformed Services University of the Health Sciences in Bethesda, Md. “Myelin sheathing prevents water from moving perpendicular to the orientation of the neuronal fibers that are myelinated, so any increase in water movement that appears to be moving across myelin sheathing is not normal.” He added that it’s likely the brain suffers both myelin breakdown and damage to the axons “since they go hand-in-hand.”

“This is an interesting finding for our lab because we are working on ways to improve myelination in damaged brains,” said Moffett.

This and future research will give medical oncology teams useful insights into how radiation travels along brain pathways, the duration of its effects, and specific regions most at risk – all information that may be factored into planning the best treatment.

Nagesh plans to continue investigating how the brain responds to radiation in terms of time and space. She says the study underscores the importance of minimizing radiation doses to the level where they are effective but the least destructive to complex brain structures and pathways.

Reference:

Nagesh V, Chenevert T, Tsien C et al. Quantification of Global Changes in Normal Appearing Brain Tissue of Cerebral Tumor Patients during Early-Delayed Phase after Radiation Therapy. Medical Physics: 34, 2547 (2007)