The list of celebrities who have largely disappeared from public view because of Parkinson's disease has become familiar to many: boxer Muhammad Ali, former attorney general Janet Reno, actor Michael J. Fox. Pope John Paul II and others have died from the brain disorder. But they are only the most visible of its many victims: today four million people worldwide have the disease, with 500,000 to one million in North America. About 1 percent of the population older than 60 acquires Parkinsons, and as life expectancies climb, the number of victims is predicted to double by 2040. And yet fully half of all patients show symptoms before age 60, in some cases as early as 35 or 40. Medical science is increasingly challenged to find the cause and to develop effective therapies.

Although investigators have bettered their understanding, the cause of Parkinson's remains unclear--and until it is pinned down, the disease cannot be prevented or stopped. Nevertheless, recent insights into how the ailment prompts brain proteins to malfunction and into the root genetic causes of those malfunctions and other harmful molecular processes are providing some optimism for new treatments.

Cause Not Clear
When diagnosed early, Parkinson's symptoms can be managed fairly successfully with drugs for as long as eight to 15 years. But often the malady is not recognized soon enough, because it begins with very nonspecific symptoms. Tense muscles in an arm or shoulder, for example, tend to send people to orthopedists, not neurologists. Fatigue, depression or sudden outbreaks of sweating are typically pegged to other common problems.

These conditions often remain mild for a long time; nine to 12 years can pass before the disease fully asserts itself. But by then a large percentage of cells in certain brain regions have already died. Individuals begin to lose their fine-motor coordination: they cannot thread a needle, and their handwriting becomes tiny and hard to read. Soon everyday tasks such as combing hair, buttoning a shirt or tying shoes become impossible. Telltale tremors--uncoordination among larger muscle groups--can set in. Patients become dependent on others, and their quality of life declines dramatically. As movement slows, so do mental processes. Thinking drags, and speech drawls. Half of all patients suffer from depression or anxiety disorders, and a third slip into full-blown dementia.

British physician and pharmacist James Parkinson first described the condition that now bears his name in 1817. Because of his patients' striking tremors, he dubbed it "shaking palsy." This was a double misnomer, we now know, because Parkinson's is not a palsy and does not necessarily lead to trembling. The cardinal symptom is a general and progressive difficulty with movement, followed by deterioration in mental function.

Scientists have known since the late 1920s that as the disease advances, neurons in the midbrain die off. Most affected is the basal ganglia, which controls the automatic execution of learned movements [see box on opposite page], such as walking or reacting to a sudden slip on ice. The part of the basal ganglia most critically affected is the substantia nigra, a nugget of neurons that produce dopamine. This neurotransmitter is vital to the fluid execution of all body movements and also regulates mood. When dopamine production sags, the midbrain cannot function properly, exacerbating the problem.

The thalamus, which serves as a central switchboard for the midbrain, also depends on dopamine. As dopamine levels fall, the thalamus can no longer work well with the cerebral cortex, and certain mental functions become difficult to carry out. Neurons in other regions may try to compensate, with some success early on. And yet the cooperation can also lead to highly synchronized impulses that can cause a person's fingers, hands or legs to tremble, as if signals are falling into a reverberation that tells muscles to twitch repeatedly.

Neuroscientists still cannot say definitively what triggers the trouble. In some cases, physical brain damage from accidents or blows to the head from boxing, for example, may start the process. Heavy metals and pesticides such as paraquat as well as rotenone, used in organic farming, have also been implicated by some epidemiological and animal studies.

Though lacking a culprit, experts concur that some mechanism causes brain proteins to misfold, which in turn kills neurons. A genetic defect is involved in 5 to 10 percent of cases, and the aberrations provide interesting clues. To date, researchers have identified defects in nine gene loci, and at least four of them affect protein processing. In some cases, neurons become fatally clogged with their own proteins. In other instances, the genetic control of energy usage in neuron mitochondria--the cells' power plants--falters, and the cells shut down. As cells die, dopamine production wanes.

Drugs Treat Symptoms
Propping up dopamine production has been the central strategy in alleviating Parkinson's symptoms. The crucial breakthrough was development of the drug levodopa, or L-dopa, a precursor compound that the brain converts into dopamine. Unlike dopamine, L-dopa can pass through the blood-brain barrier--a membrane that surrounds the brain and prevents harmful substances from entering.

The initial effects of L-dopa are impressive: muscle mobility returns, and patients can once again take part in life. But after a few years doctors find it increasingly difficult to determine the right dosage, because the dopamine receptors in the striatum become extremely sensitive as the disease progresses. Also, only a few neurons may remain that can control and moderate levels of dopamine in the brain. Overdoses lead to uncontrollable, exaggerated movements, whereas underdoses offer no help at all. Many patients swing between the extremes and report that this experience is worse than the symptoms would be without medication.

Another class of substances, called dopamine agonists, can help by imitating the function of dopamine. These include bromocriptine, cabergoline, pramipexole and ropinirole, among others. Even though they are not initially as effective as L-dopa, over time they are easier to dose correctly. Yet patients--especially older ones--may suffer from nausea, vomiting or even hallucinations. For some people, combining an agonist with L-dopa seems to offer the best relief.

Difficulty finding the right combination and level of drugs has focused a large portion of Parkinson's research on better medication protocols. The many years of experiments, testing and safety proofs have driven the costs of drugs that do make it to market sky high. A typical regimen costs $200 or more a month.

An alternative therapy target, which may be more effective, is a growth factor called GDNF, for glial cell linederived neurotrophic factor, a protein important to the survival of nerve cells. In apes the substance has been found to aid in cell regeneration and to slow the death of additional neurons. In 2002 Steven Gill and his colleagues at the University of Bristol in England administered the protein to five patients with advanced Parkinson's disease via a catheter that led directly to the striatum, the main recipient of dopamine normally produced by the basal ganglia. Symptoms were lessened, and dopamine uptake was improved. But in a larger trial in 2004 by Amgen Corporation, patients who received GDNF fared no better than those who received placebos. Amgen later announced concerns about GDNF's safety, too.

A naturally occurring protein called KDI tripeptide might provide another answer. In November 2005 researchers from the University of Helsinki in Finland announced promising test results at the Society for Neuroscience annual meeting. They first gave rats a drug known as 6-hydroxy-dopamine, which is widely used to mimic Parkinson's disease. Rats who later received an injection of KDI did not show the subsequent, massive neuron destruction that took place in rats that did not receive the tripeptide. More rat tests with KDI are under way.

Deep-Brain Stimulation
The sad reality is that for many patients, drugs eventually lose their effectiveness. Neurosurgery is then the only option. In the 1960s and 1970s surgeons simply cut out compromised parts of the brain or destroyed them by injecting alcohol. Since the mid-1990s doctors have increasingly improved the more elegant approach of deep-brain stimulation. A surgeon implants several thin platinum wires--electrodes--into one of two regions of the basal ganglia, near the thalamus. A battery and controller implanted under the skin near the collarbone or abdomen send tiny, timed currents into the region to improve neuron firing.

The surgery is extremely difficult and expensive, demanding incredibly delicate procedures in the core of the brain. For one thing, the electrodes must not damage any blood vessels, which could cause stroke or paralysis. On the plus side, because no pain receptors exist in the brain, the patient can be conscious during the operation. Being awake and aware is a decisive advantage--surgeons ask patients questions, and the responses can indicate whether any important brain function is being damaged.

If the operation succeeds, a substantial reduction in muscle tremors and rigidity often occurs. Using a remote control to adjust the stimulation, patients who once could hardly move can now walk smoothly across a room. This state of improvement can last for years and allows people to decrease their drug dosages significantly. But deep-brain stimulation does not sharpen mental functions or stop the disease from progressing and can affect adjacent parts of the brain, which can lead to deafness, speech disorders and balance problems.

The ultimate goal for researchers, of course, is a cure. One idea is to simply replace the neurons that have died. But almost all attempts at transplanting cells from the patient's own body or from animal donors have failed. One prospect lies in the implantation of human retinal epithelial pigment cells. These cells, taken from infants who have unfortunately died, are capable of producing L-dopa and grow well in the lab. In a 2002 pilot study Ray L. Watts, now at the University of Alabama at Birmingham, implanted such cells into the striatum of six Parkinson's patients. Using a standard rating scale to measure their progress, Watts found that six months later all the patients had improved, on average, by 42 percent. Larger studies are now under way.

Physicians are also placing great hopes on stem cells, which can mature into any type of cell. They are found not just in embryos but in adults as well. A reservoir lies in the subventricular zone of the midbrain, a source of new neurons that are needed to preserve the brain's plasticity. The hippocampus, necessary for memory, is particularly reliant on a constant flow of these cells.

Jun Takahashi of Kyoto University in Japan is trying to transform embryonic stem cells into dopamine-producing neurons by means of natural growth factors. These cells would then be transplanted into patients. In January 2005 Takahashi was able to reverse some Parkinson's symptoms in monkeys using this approach. Stem cell methods are fraught with ethical and political complications, however, because in many lines of research they are much more effective when obtained from fetuses than from adults.

That is one reason why researchers are looking deeper, into genetic programming itself. Ultimately, if faulty genes cause Parkinsons, testing those genes and fixing them could offer a cure. Several groups are now experimenting with gene-based therapies. The idea is to use specially modified viruses to carry genes into the midbrain. The genes would then activate certain enzymes that release or transport dopamine. Initial animal tests show promise, but many scientists remain skeptical about gene therapy because there is too little experience so far to gauge its benefits and risks adequately.

As research continues, and even if potential cures are found, a patient's quality of life is a critical factor in weighing treatment plans. A caring social environment can often reduce psychological symptoms to a heartening degree, and regular therapeutic exercises can promote mobility.

Many victims are very inventive in how they deal with daily life. Some wear headphones and blast themselves with music, which forces them to speak louder and more clearly. They place patterns on the carpet to guide their footsteps. They wear special glasses, crafted with what is called the Parkaid system, that lessen the risk of perceptual faults that lead to falls. And they use a special computer mouse, such as those designed by IBM, that enables them to deftly move a cursor across a screen despite their tremors.

Other individuals try to engage in practices that naturally boost dopamine levels--practices that could help forestall the disease if it is detected early enough. Regular athletic activity, which may raise dopamine levels, can lessen symptoms. A 2005 study by Alberto Ascherio of the Harvard School of Public Health indicated that for men, athletics halves the risk of Parkinson's onset.

The same effect has also recently been ascribed to nicotine and caffeine. A 2004 study by Nancy L. Pedersen of the Karolinska Institute in Stockholm confirmed results of earlier work: smokers apparently fall victim to Parkinson's disease less frequently than nonsmokers. In tests on lab animals, nicotine (not the tobacco itself, which has long-known deleterious effects) seems to stimulate the release of dopamine in the striatum, and caffeine seems to enhance the uptake of dopamine. More research is needed in clinical trials to determine if these substances actually help people.