|Tracking Parkinson's Disease with PET|
|Contact: Dan Krotz, email@example.com|
Berkeley Lab researchers are developing a way to use positron emission tomography (PET) scans to track the effectiveness of a gene therapy that promises to help patients with severe Parkinson's disease control their symptoms without dangerous side effects.
Their work, which focuses on refining the use of a PET-detectable chemical called a tracer, could allow scientists to evaluate how well the therapy jumpstarts the brain's ability to produce dopamine, a neurotransmitter that diminishes in Parkinson's patients. Recently, in an important milestone, the scientists administered the tracer to healthy people, then used PET to watch it accumulate in a dopamine-producing region of the brain that grows quiet as Parkinson's progresses.
"We need a way to see what's going on in the brain, and the PET tracer let's us do that," says Jamie Eberling of Berkeley Lab's Center for Functional Imaging, who is conducting the research along with fellow Berkeley Lab scientist Henry VanBrocklin. Other collaborators include Krys Bankiewicz, a professor of neurological surgery at the University of California at San Francisco, and Bill Jagust, head of the Life Sciences Division's neuroimaging program, who began the research with Bankiewicz in the early 1990s.
The ability to pinpoint the brain's dopamine-production centers could give researchers a quick and accurate way to gauge the gene therapy's success once clinical trials begin. Ultimately, the tracer could speed the development of a better way to treat the advanced cases of a disease that afflicts two million people in the United States and Europe.
They chose PET because of its unique ability to detect the metabolic and biochemical signatures of disease, which occur long before a disease causes anatomical changes and clinical symptoms. Other imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) can only detect structural changes.
"PET can be used to more quickly determine how the therapy is working," says VanBrocklin. "There's no better way to track the therapy in patients."
The tracer, fluorine methyl tyrosine, or FMT, was developed at the University of California at Los Angeles in the late 1980s. It's engineered to cross the highly selective blood brain barrier and enter only those neurons that contain an enzyme that converts dopa to dopamine. In Parkinson's, for reasons that are not fully understood, neurons that contain this enzyme decrease in number and the brain's dopamine levels dip precipitouslya phenomenon that leads to the tremors and muscular rigidity that mark the disease.
Because dopamine-producing neurons reside in very specific regions of
the brain, a PET scan of a healthy person given the FMT tracer should
yield an image with bright spots, indicating areas where the tracer accumulates.
Conversely, a PET scan of a Parkinson's patient should reveal darker areas,
indicating an absence of FMT and an absence of dopamine-producing neurons.
On a separate track, researchers from the Bay Area-based company Avigen have created a gene therapy that's designed to replace the dopamine-producing enzyme that disappears in Parkinson's patients. It works by delivering the gene that produces the enzyme directly to the striatum, the area of the brain that needs dopamine to control movement.
Although this therapy isn't intended to alleviate symptoms, it may allow patients with severe Parkinson's to take much smaller doses of the drug levodopa, the primary treatment for the disease. The drug, which is converted by the neurons' dopamine-producing enzymes into dopamine, successfully controls tremors in the early stages of the disease. But as the disease progresses, and the level of dopamine-producing enzymes drops, larger doses of levodopa are required to suppress symptoms.
Unfortunately, large doses of levodopa have severe side affects such as uncontrolled flailing, psychosis and hallucinations. Avigen researchers hope their gene therapy will replenish the enzymes lost in patients with advanced Parkinson's, enabling them to take safer doses of levodopa.
When Avigen begins evaluating the gene therapy in clinical trials, slated to take place at UCSF, they'll use the PET tracer developed at UCLA and refined at Berkeley Lab. Ideally, in a series of PET scans taken over several months, a Parkinson's patient's striatum will grow brighter and brighter as the gene therapy provides the striatum with a steady supply of dopamine-producing enzymes.
"The tracer is an excellent measure of gene expression," says Eberling. "It will allow researchers to follow patients throughout the course of therapy and make sure gene expression is sustained."