Parkinson's disease (PD) is caused by the progressive deterioration of about half a million brain cells in the portion of the brain that controls certain types of muscle movement. These cells secrete dopamine, a neurotransmitter (chemical messenger). Dopamine's function is to allow nerve impulses to move smoothly from one nerve cell to another. These nerve cells, in turn, transmit messages to the muscles of the body to begin movement. When the normal supply of dopamine is reduced, the messages are not correctly sent, and the symptoms of PD appear.
The four early warning signs of PD are tremors, muscle stiffness, unusual slowness, and a stooped posture. Medications can control initial symptoms, but as time goes on they become less effective. As the disease worsens, patients develop tremors, causing them to fall or jerk uncontrollably. (The jerky body movements that patients with PD experience are known as dyskinesias.) At other times rigidity sets in, rendering patients unable to move. About one-third of patients also develop dementia, an impairment of cognition (thought processes).
Treatment of Parkinson's Disease
Management of PD is individualized and includes drug therapy and a program that stresses daily exercise. Exercise often can reduce the rigidity of muscles, prevent weakness, and improve the ability to walk.
The main goal of drug treatment is to restore the chemical balance between dopamine and another neurotransmitter, acetylcholine. The standard treatment for most patients is levodopa (L-dopa), which was first approved for use in 1970. L-dopa is a compound that the body converts into dopamine to replace it in the body and help alleviate symptoms. (Without dopamine, signals from the brain cannot "transmit" properly to the body, and movement is impaired.) Treatment with L-dopa does not, however, slow the progressive course of the disease or even delay the changes in the brain that PD produces, and it may produce some unpleasant side effects because of its change to dopamine before reaching the brain. Simultaneously administering substances that inhibit this change allows a higher concentration of levodopa to reach the brain and also considerably decreases the side effects.
Five classes of drugs are used to treat the symptoms of PD, including anticholinergics, COMT (catechol-O-methyltransferase) inhibitors, MAO-B inhibitors, and amantadine. Anticholinergics work to relieve tremor and rigidity. COMT inhibitors act by prolonging the effectiveness of a dose of levodopa by preventing its breakdown. MAO-B inhibitors slow the breakdown of dopamine in the brain. And amantadine has demonstrated effectiveness in reducing dyskinesias.
Genetic Link to PD
In January 2006 researchers at the Albert Einstein College of Medicine and Beth Israel Medical Center in New York published an article in the New England Journal of Medicine in which they described their discovery of a single genetic mutation on a gene called LRRK2 (leucine-rich repeat kinase 2) that accounts for as many as 30% of all cases of PD in Arabs, North Africans, and Jews. People with the mutation make an abnormal version of a protein called dardarin (a form of the Basque word for tremor) in which a single amino acid—number 2,019—is glycine instead of serine. This finding may help to direct development of a drug to modify the impact of this mutation to prevent or substantially delay onset of the disease (Suzanne Lesage et al, "LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs," and Laurie J. Ozelius et al., "LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews," New England Journal of Medicine, vol. 354, no. 4, January 26, 2006).
Experimental Therapies
GENE THERAPY
As of 2006 gene therapy had been tried in only a few PD patients and remained highly experimental. In January 2006 actor Michael J. Fox, who has been diagnosed with PD, gave $4.2 million to a University of Pittsburgh Medical Center affiliate called RheoGene Inc. to develop gene therapy for Parkinson's disease (Byron Spice, "UPMC Affiliate Gets $4.2 Million Grant to Develop Gene Therapy for Parkinson's," Pittsburgh Post-Gazette, January 6, 2005, http://www.post-gazette.com/pg/06006/633543.stm).
The therapy entails inserting a beneficial gene into brain cells using technology developed by RheoGene that allows investigators to turn the gene on or off as needed, an important safety feature if the proteins it produced had some unanticipated, harmful effect. It also permits investigators to custom-tailor the activity of the gene based on the individual needs of each patient.
One of the genes that will be inserted produces glial cell line-derived growth factor (GDNF), a protein that appears to strengthen brain cells more and helps prevent the death of sick cells. In animal studies GDNF has been shown to stop the progression of the disease and perhaps even reverse it. The challenge has been to find a way to deliver the growth factor.
There are other challenges for gene therapy in the treatment of this disease. Scant research has been performed in humans to date, and it is possible that the success reported in animal studies will not be replicated in human trials. There also are financial considerations—treatment with levodopa is much less costly than gene therapy, and although the drug is not optimally effective and patients develop increased tolerance to the drugs over time, newer drugs such as dopamine agonists may produce a better alternative.
THE FUTURE OF STEM CELL RESEARCH
The election of President George W. Bush in 2000 prompted concern among human embryonic stem cell researchers. President Bush had expressed his opposition to this field of stem cell research throughout his campaign and through the early days of his presidency, and researchers expected him to reinstate the ban during his presidency. Researchers and patients hoping to benefit from treatment based on this promising area of scientific study were partially relieved when, on August 9, 2001, President Bush announced that federal funds could be used to conduct stem cell research on existing stem cell lines. His decision bans the creation or use of new embryos for federally funded experimental purposes. This means that federal funds will not be completely withheld from researchers in this field, but it places significant limits on the scope of research that will be eligible for federal support.
The excitement and optimism about human embryonic stem cells centers on these cells' capacity to renew themselves and develop into specialized cell types. Unlike other cells that have predetermined roles and functions, such as heart or brain cells, stem cells can develop into nearly all the specialized cells of the body—with the potential to replace cells for the nervous system, heart, pancreas, kidneys, skin, bone, or blood.
Research is under way that uses stem cells to treat neurologic disorders by replacing diseased or malfunctioning cells in the brain and spinal cord. The results of this research could have life-changing consequences for people suffering from PD, MS, Alzheimer's disease (AD), and spinal cord injuries. Other research focuses on developing organs and tissues for transplantation, because there is an urgent need for donor organs. Still other investigators are looking at ways to induce stem cells to become insulin-producing cells of the pancreas to treat diabetes.
FETAL PIG BRAIN IMPLANTS
In late 1995 a team from the Harvard Medical School reported that transplants of fetal pig brain cells into the brains of rats relieved PD-like symptoms. Limited trials on human beings also have been successful, but in 2006 the APDA reports that two recent placebo-controlled studies found that consistent benefit was only observed in PD patients age sixty or younger and that some patients experienced serious side effects such as dyskinesias, even when they were not taking levodopa. Still, if future planned human trials can overcome these obstacles, the procedure could revolutionize the treatment of PD without raising the ethical and moral issues involved in stem cell research and fetal tissue transplants.
ELECTRODE IMPLANTS
Another procedure being tested is the use of electrical implants. Electrodes are surgically implanted in the brain and connected to a battery-operated device, also implanted in the body. The device allows patients to "turn off" the tremors that prevent them from performing the activities of daily living such as pouring a glass of milk and feeding themselves. One drawback is that the device's batteries must be surgically replaced every three to five years.
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