Parkinson's Disease - Basic Science
Parkinson's disease (PD) is caused by progressive cell death in a small part of the brain that helps control movements by releasing the chemical dopamine. Levodopa is the mainstay of PD therapy, but must be converted in the brain into dopamine by an enzyme called AADC (aromatic L-amino acid decarboxylase). Researchers in California presented results of a long-term gene therapy trial in monkeys with a condition that mimics PD. They introduced the gene for AADC into the affected parts of the brains of four monkeys, using a virus as a carrier. After three-and-a-half years, the gene was still making the enzyme widely throughout the affected part of the brain, and the monkeys required much less levodopa to control their PD symptoms. Importantly, the dose of levodopa could be lowered to the point that it no longer caused uncontrolled movements called dyskinesias, which are a major complication of late-stage PD treatment. These promising results suggest that this approach may work in PD patients as well. [S28.004]
Parkinson's Disease - Genetics
Most cases of PD are thought to result from a combination of genes and environmental factors such as pesticides and other poisons. Genes that cause PD by themselves are rare. An exception is found in a pair of families from Greece and Italy, who carry a mutation in a gene for a brain protein called alpha-synuclein. While this mutation is exceedingly rare, it has already taught PD researchers much about the disease. A new study extends this research by revealing another genetic risk factor for PD within this family. Researchers from New Jersey examined genetic contributions to the age of symptom onset within members of these two families. They discovered that earlier onset age was linked to possession of a specific form of a gene called GST (glutathione S-transferase), which detoxifies a wide variety of toxins in the body. This same gene had previously been linked to the risk for PD among people who had used pesticides. These results confirm the importance of both environmental factors and specific forms of common genes in the development of PD. [S18.003]
Parkinson's Disease - Treatment
An experimental treatment in a very small group of patients has created a very large amount of interest among movement disorder specialists. The treatment delivered GDNF (glial-cell derived neurotrophic factor) directly into the brains of five PD patients, using a pump implanted in the abdomen and a tube that carried the GDNF up over the skull and down into the brain. A similar technology is an established treatment for delivery of the drug baclofen to the spines of patients with spasticity. GDNF has been shown in animal models to protect nerve cells from death and help restore their function. A previous trial of GDNF in PD patients, which delivered it to the ventricles (cavities that circulate fluid throughout the brain) was unsuccessful, as the GDNF did not reach the portion of the brain affected by PD. In the current trial, a group of researchers from the United Kingdom demonstrated that direct delivery of GDNF to the striatum led to a 40 percent improvement in PD symptoms. This change was mirrored by improvements seen on neuroimaging that suggest an increase in sprouting of the remaining dopamine-producing neurons. Several caveats remain, however - this was an open-label trial in a small number of patients, and only autopsy results can confirm beneficial effects on the cells within the brain. A larger double-blind trial is underway, and results are expected in the fall of 2004. [S38.001]
A new treatment for Parkinson's disease is now available in the United States. Unlike all other current medications, apomorphine is injected under the skin, and is extremely fast acting. Researchers in New York demonstrated that within 10 minutes, apomorphine can "rescue" a patient from sudden immobility, a common and distressing complication of advanced PD. While its effects only last up to two hours, this is enough time for a patient to take another dose of levodopa, the standard medication for symptom control. While apomorphine has long been used in Europe, it has only recently received approval by the United States Food and Drug Administration for the treatment of advanced PD. [P04.135]
A drug that has long been used to treat PD has recently come under intense scrutiny for a previously unrecognized side effect. Pergolide is a dopamine agonist, a drug that acts like dopamine in the brain. Researchers from Texas presented evidence that pergolide use is associated with an increased risk for disease of the heart's valves. Echocardiograms of 46 patients indicated some degree of valve "regurgitation" due to improper closing in 90 percent of the patients, which they correlated with length of pergolide treatment. While these changes did not lead to cardiac symptoms in most patients, that was not the case in several others. Follow-up on one patient who stopped taking pergolide indicated an improvement in valve function. This study confirms results from several other recent studies showing the same adverse effect from this treatment. As of yet, no studies have examined whether other dopamine agonists can cause the same problem, although unlike other commonly used agonists, pergolide is derived from ergot. Ergot-derived compounds, including pergolide, have been previously associated with increase in fibrosis within the chest cavity. [P04.142]
Dystonia is a condition characterized by sustained twisting postures. It can be genetically inherited, caused by a variety of poisons or a side effect of certain drugs. The brain changes that bring about dystonia symptoms are largely unknown, although suspicion has centered on the dopamine system in a part of the brain known as the striatum. The most common genetic form is due to a mutation in the DYT1 gene, which is more common in Ashkenazi Jewish populations. Not everyone with the mutated gene displays symptoms; those who do not are known as non-manifesting carriers. Research presented by a group in New York indicates that even non-manifesting carriers have significant changes in their striatal dopamine system, with fewer available binding sites for dopamine than non-carriers, but more than manifesting carriers. These results further implicate the dopamine system in dystonia, and suggest that manifestation of symptoms is due to more severe loss of binding sites. [S48.006]
Treatment for dystonia is often unsatisfactory. Within the past several years, a form of brain surgery called deep brain stimulation (DBS) has emerged as a promising therapy. In DBS, electrodes are placed in the brain to alter signals causing the dystonia. Researchers from San Francisco reported their results on 15 patients receiving DBS. As has been seen in other studies, there was a wide range of benefit, from complete normalization of movements to only modest effects. Also consistent with previous studies, those with the DYT1 mutation did best, while those with "secondary" dystonia, from carbon monoxide poisoning or other acquired causes, did least well. DBS has become a standard treatment for Parkinson's disease, and the accumulation of studies such as this are bringing DBS closer to being a standard therapy for dystonia. [S15.001]
Psychogenic Movement Disorders
Psychogenic movement disorders (PMDs) are due not to a genetic or environmental cause, but to a psychological problem the patient is manifesting as a physical problem (a so-called "conversion disorder"). PMDs are often a manifestation of trauma or extreme distress. Researchers in South Carolina tested the ability of 12 weeks of psychotherapy and antidepressants or antianxiety medications to treat PMD in 10 patients, whose symptoms had persisted for at least eight months. Tremor and dystonia were the most common forms of movement disorders. After treatment, the severity of the patients' movement disorders were significantly reduced, and they were better able to function in their activities of daily living. They also had less depression and anxiety. [S58.005]
The American Academy of Neurology, an association of more than 18,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson's disease, autism and multiple sclerosis.
For more information about the American Academy of Neurology, visit its website at www.aan.com/press.