|FEATURES Spring 2003|
Using PET technology, Dr. Joel Perlmutter is examining the brain's interior to discover better treatments for diseases such as Parkinson's, essential tremor, and dystonia.
People who have Parkinson's disease and other movement disorders are troubled by stiffness, slowness, and trembling. But there's nothing wrong with their muscles. The problem must be sought deep in the brain, in the complex and still little-known system that transforms thought into action. Professor Joel S. Perlmutter and his team at the Movement Disorders Section at the School of Medicine are using powerful technology to watch the way this system works.
"Dr. Perlmutter's research harnesses established strengths in brain imaging at Washington University to make important contributions to understanding complex brain mechanisms," notes David B. Clifford, the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology and head of the Department of Neurology. The primary tool is the PET (positron emission tomography) scan, which uses radioactive substances to track metabolic changes. Perlmutter uses PET to measure blood flow, "because the blood flow in different parts of the brain reflects how active the nerve cells are in that part of the brain," he explains.
Parkinson's disease afflicts more than a million people in North America. It affects speech, balance, and sexual function in addition to movement. Though it is generally thought of as a disease of old age, 5 percent of the patients Perlmutter's team sees developed it before age 40. For most patients, the disease steadily gets worse, and there is no cure. While people may inherit a vulnerability to the disease and toxins in their surroundings may trigger it, the cause of Parkinson's remains unknown.
What scientists do know is that when a person has Parkinson's, nerve cells in a part of the brain called the substantia nigra are dying. This causes a loss of the neurotransmitter dopamine, a key chemical messenger in the brain. With this vital communication system disrupted, people lose control of their movements. But why do the nerve cells die? Possibly because of a defect in the mitochondria, the powerhouse of the cell. Perlmutter says, "It may be a problem with how the cell uses oxygen to burn sugar."
Perlmutter studies many aspects of this energy production process. Last year, he was an investigator in a preliminary but encouraging study that found giving patients a naturally occurring compound called coenzyme Q10 may slow disease progression, possibly by boosting mitochondrial function. He will soon study a new drug developed by Laura Dugan, associate professor of neurology, using PET technology and an animal model of Parkinson's he has developed. The researchers hope the drug will not only slow the progress of the disease but actually reverse its effects. In another study, he is collaborating with William Powers, professor of neurology, to use PET scans to measure oxygen and sugar consumption in the brain, comparing how efficiently the mitochondria are producing energy in newly diagnosed patients with Parkinson's disease to determine whether this energy defect contributes to the development of Parkinsonism.
Perlmutter's father, who was diagnosed with Parkinson's a few years ago, took part in one study. Perlmutter says, "If we proved that this energy problem exists, it would suggest a whole new avenue of treatment. It is my hope that my dad will benefit from it." The knowledge that Parkinson's runs in his own family gives urgency to Perlmutter's work. "My dad has Parkinson's," he says. "His only brother had Parkinson's. So I better well cure this before I get it."
"While the search for a cure goes on, Dr. Perlmutter seeks to improve existing treatments that give Parkinson's patients some relief from their symptoms. Again, the PET scan is an important tool. ...
While the search for a cure goes on, Perlmutter seeks to improve existing treatments that give Parkinson's patients some relief from their symptoms. Again, the PET scan is an important tool. Levodopa (L-dopa), which the body converts to dopamine, is one drug that has long been in use. Dopamine, a chemical messenger that allows nerve cells to communicate with each other, is produced in the substantia nigra. As cells there die, dopamine is lost. Replacing the dopamine makes patients better able to move and function. Unfortunately, as the patient uses L-dopa, subsequent doses wear off more and more quickly, so dosages are increased. Many patients then begin to have wild, uncontrollable movements called dyskinesia, which can twist their entire bodies. "If we reduced the dose enough to make the dyskinesia go away, the patient may get no benefit from the drug," Perlmutter explains.
To see what happens in the brain in response to the drug, Perlmutter's team, including Tamara Hershey, instructor in psychiatry, took PET scans of patients at different stages of the disease, gave them L-dopa, and then took another scan. They discovered that the brain responded differently in patients who had developed dyskinesia. Different signaling pathways were being activated. "This suggests that L-dopa may be working in a completely different way in this part of the brain than we thought," he says. "So if we understand that, we hope we'll be able to design drugs that work better and do not cause dyskinesia."
Deep brain stimulation reduces symptoms
A newer treatment for Parkinson's is deep brain stimulation. Stimulators, comparable to the pacemakers used for heart patients, are placed in the brain. "Some people with Parkinson's get markedly better," Perlmutter says. "They may, on average, reduce their medicine by almost two-thirds. Some are able to do without drugs. We have people who could hardly walk and now they're playing golf."
Dramatic as the results have been, the researchers did not know how deep brain stimulation worked. Many thought it reduced involuntary movements by blocking the flow of signals along the axons. Perlmutter had a different idea, based on the study of another movement disorder called essential tremor (ET). Placing a patient with ET in the PET scanner, his team measured blood flow in different parts of the brain with the stimulator turned off, then on. They found that the stimulator increased activity along signaling pathways. "This was the first evidence that stimulators really are driving axons, not blocking," he notes.
Perlmutter wanted to try a similar experiment with Parkinson's patients but faced a difficulty: When essential tremor patients' hands are at rest as they lie in the PET scanner, they do not shake. Parkinson's patients, however, may tremble at any time. These movements cause feedback in the brain, clouding the researchers' picture. Perlmutter's team had to watch carefully for tremors and discard half the scans they took. But enough remained to show that the stimulators affected brain activity in Parkinson's much as they did in ET.
"Under both conditions, we see that directly connecting areas have increased blood flow," Perlmutter says. "This may be important work in showing us where to place stimulators and how to adjust their settings to drive axons most effectively, maximizing the benefit and minimizing side effects."
Those in Perlmutter's Movement Disorders Section, with colleagues Josh Dowling, assistant professor of neurological surgery, and Keith Rich, associate professor of neurological surgery, run the leading center in North America for deep brain stimulation treatment. It has been certified as a Huntingdon's Disease Center of Excellence and as an Advanced Center for Parkinson's Disease Research. Staff members, who include seven physicians, residents, nurses, occupational therapists, and social workers, care for some 6,000 patients, of whom more than 1,900 have Parkinson's and another 1,200 have dystonia.
Dystonia is a mysterious ailment that distorts posture and movement. The cause is unknown, and it was previously classified as a psychiatric condition. "But we've looked at what's going on in the brain using PET and proven fairly clearly that it's a dysfunction of dopamine-mediated pathways in the brain," Perlmutter says. To pass on a message, dopamine has to stick to a specific spot on the receiving cell. There are several kinds of these receptors; Perlmutter's group has done extensive work on one called D2 and found it lacking in dystonia patients. His group has developed an animal model to continue the research and is collaborating with Jonathan Mink, associate professor of neurology and pediatrics, at the University of Rochester.
Becoming a leading researcher of movement disorders
Perlmutter came to the University in 1980 as a resident in neurology. Working with patients who had movement disorders, he became fascinated by the subject. "People were troubled by these mysterious movements, and most neurologists were baffled. I felt this was an area where I could make a contribution."
Now a professor of neurology and neurological surgery, of radiology, and of anatomy and neurobiology, Perlmutter's achievements are widely recognized. "He is an extraordinarily gifted physician and scientist," says Dr. David Clifford. "He is also a leader in computer-based record-keeping. The system he developed for his section is now in use in several leading research hospitals." Rather than thumbing through charts, physicians can find out which medicines patients are taking and check on possible side effects with the click of a mouse. The system saves money and speeds research. "And the writing is computer-generated, so there are no errors due to a pharmacist's inability to read the doctor's handwriting," Perlmutter notes with a smile.
"Joel is a research leader in the area of movement disorders," says William Peck, executive vice chancellor for medical affairs and dean of the School of Medicine. "Furthermore, he is a fine educator and wonderful citizen of our medical school. He cares for his patients with great expertise, compassion, and sensitivity."
Perlmutter believes in tailoring therapy to the individual patient. "We can make a big difference just by opening our eyes and paying attention and listening to the patient, because they'll tell us what's wrong with them," he says.
William M. Landau, professor of neurology and former department head, says, "He is doing terrific work, bringing together clinical practice, basic science, imaging technology, and new animal models. We still don't understand these disorders, but through researchers like Perlmutter we are beginning to."