May 6, 1998 BOSTON--April 30, 1998--Researchers at Harvard Medical School and Massachusetts General Hospital have developed a new imaging agent for Parkinson's disease that could allow clinicians to diagnose the disease more accurately and earlier in its progression than is currently possible, as well as to utilize imaging technologies that are cheaper, faster, and widely available.
In four articles to be published in the June Synapse, the scientists describe how the imaging agent Altropane visualized the degree of nerve loss in the brains of people in different stages of Parkinson's. The scientists suggest that the chemical, in addition to facilitating definitive diagnoses, could help researchers track the success of experimental treatments and possibly identify presymptomatic patients to use in studies of this common, but poorly understood neurodegenerative disease.
Bertha Madras, PhD, associate professor of psychobiology at Harvard Medical School and the New England Regional Primate Research Center, in collaboration with chemist Peter Meltzer, president of Organix Inc. in Woburn, Mass., and others reported their basic and preclinical research in three papers. Alan Fischman, MD, PhD, associate professor of radiology at Massachusetts General Hospital and Harvard Medical School, directed the clinical study and was lead author of the fourth paper.
Most cases of Parkinson's are diagnosed clinically. However, clinical diagnoses have been shown to be wrong one out of five times. In addition, while the diagnosis often is straightforward in severely affected patients who display the disease's hallmark symptoms, it is difficult, especially in young people, to distinguish early symptoms of Parkinson's, such as a tremor in one hand, from symptoms of other diseases that can masquerade as Parkinson's.
In a clinical study involving 15 people, Fischman and his colleagues found that Altropane accurately detected Parkinson's at different stages of the disease's progression. The researchers compared people with severe and moderate Parkinson's to healthy volunteers. People with moderate disease had weaker images than did the controls, and in people with severe disease had almost none of the agent was detected in the affected brain areas. The study even confirmed a suspected Parkinson's diagnosis for a 14-year-old boy.
Madras discovered Altropane in the course of her research on cocaine's action in the brain. In 1988, she found that a tropane, a chemical that has the basic skeleton of cocaine, bound specifically to the dopamine transporter. This protein sits on the terminals of dopamine-releasing neurons in the brain, where it regulates dopamine levels.
Research shows that in people with Parkinson's, dopamine neurons in the brain's substantia nigra region gradually die. Madras reasoned that an agent that lights up dopamine transporters on these neurons should be able to reflect the degree of neuronal loss and give insight into the progression of disease. In 1989, she and her collaborators synthesized a novel kind of tropane. They later attached a radioactive label to turn the tropane into an agent for single photon emission computed tomography (SPECT) imaging.
This ability to use SPECT imaging to diagnose Parkinson's will make the procedure faster and cheaper. The only Parkinson's imaging method currently available requires positron emission tomography (PET). This procedure is complicated and not widely available'only about seven centers use it nationwide. By contrast, SPECT imaging is available at most nuclear medicine department in hospitals around the country, and one round of PET-based Parkinson's imaging costs about $2,500, whereas a SPECT study with Altropane runs $1000 per patient.
The research also showed that Altropane is 10 times more selective than the most advanced competing product, which binds to transporters on both serotonin and dopamine neurons and thus complicates interpretation. Moreover, Altropane can be imaged shortly after injection, whereas other products require a one-day waiting period.
Madras and Fischman, who note that an early diagnosis of Parkinson's is truly useful only when followed by treatment, feel that Altropane could further scientists' efforts to devise experimental therapies for Parkinson's. First, it could help identify candidates for clinical trials by finding presymptomatic patients who have "silent" nerve degeneration. By the time clear symptoms appear, roughly 80 percent of the affected brain pathway has already been lost, limiting the usefulness of neuroprotective drugs. Secondly, repeated imaging of patients receiving experimental therapy would give researchers a window on whether the therapy works.
Altropane could also be used to help researchers explain why and how Parkinson's disease destroys neurons. The budding field of Parkinson's genetics could use the substance to identify presymptomatic yet affected relatives of Parkinson's patients to include in their study. Madras says that developing a solid base of information on the time course of Parkinson's will tell researchers what would be the best period for intervention. "We must begin long-term planning for Parkinson's disease now," Madras says. "That involves identifying a population at risk and watching the course of disease even while new therapies are not yet available."
These studies were funded by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and Boston Life Sciences.
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