Parkinson’s Puzzle


Researchers Think Outside The Box to Halt Slide of Degenerative Disorder

Award-winning actor Michael J. Fox and former U.S. Attorney General Janet Reno have it, as did Pope John Paul II. In fact, Parkinson’s disease—a degenerative disorder that causes tremors, rigidity and mental decline—affects an estimated 1.5 million people in the United States, with 50,000 new cases appearing each year.

The disease is clearly becoming more common as our population ages. Among the world’s 15 largest nations, Parkinson’s numbers are expected to double by 2030, reaching 8.7 million cases, according to predictions made last year by researchers at the University of Rochester in New York, who wanted to draw attention to the global growth spurt of Parkinson’s.

Parkinson’s can be devastating, although it’s often overshadowed by AIDS, cancer and other long-term diseases. Parkinson’s is a motor-control disorder associated with the central nervous system whose trademark is the destruction of dopamine-producing neurons in a particular part of the brain.

Because dopamine is a messenger chemical that affects movement, muscle control, mood and memory, the loss of dopamine typically shows up as small tremors at first—a trembling hand, for example, or depression, or minor balance problems. But Parkinson’s usually gets worse. It slowly progresses, in some cases for 15 or 20 years, and can conclude in dementia and death. Although symptoms can be controlled through drugs or surgery, there’s currently no cure.

Search for Early Clues “Age is the biggest risk factor for it,” said Dr. Howard J. Federoff of the Georgetown University Medical Center. Georgetown recruited Federoff—one of the nation’s leading Parkinson’s researchers—from the University of Rochester and appointed him executive vice president for health sciences and executive dean of the Georgetown University School of Medicine. He brought much of his research team with him, and they all think “outside the box.”

“Parkinson’s is not just a brain disease,” Federoff said. “Parkinson’s is now believed to begin outside the brain. It’s not confined to the central nervous system.”

Federoff—who spoke about the subject at a “Mini-Med School” program at Georgetown last October—points to research implicating the immune system and inflammation throughout the body. He also cited pre-motor Parkinson’s symptoms that feature, for example, bowel problems and disordered heart rhythms.

As a practicing physician, Federoff’s concern is not academic: By the time most patients show up for a Parkinson’s diagnosis, 60 percent to 70 percent of their dopamine-producing neurons are already gone, according to Federoff. The question then, he said, becomes, “How many cells are still alive and hanging on?”

In contrast, at the earliest Parkinson’s stages when the dopamine cells begin dying, there are no motor symptoms such as tremors or stumbles. Although treatments to replace or ramp up missing dopamine exist, Federoff said it’s imperative to catch and treat the disease early.

That’s precisely what he’s working on. Federoff’s team is looking for a biomarker in the bloodstream that could indicate the disease is developing before any motor symptoms appear. If Parkinson’s is systemic throughout the entire body, and if it involves the immune system, there should be a way to identify it with a simple blood test that looks at the white blood cells protecting us from disease, said Federoff, who noted that research to find a “signature” of the disease in the blood is still in its early stages.

But clearly such efforts are urgent, and a number of clinicians are trying to develop better tests for early Parkinson’s identification. Some are analyzing symptom clusters discovered within the last five years, trying to develop sensitive and standardized tests for them.

Some of these possible symptom clusters that are proposed to be at the earliest stage of Parkinson’s include bowel dysfunction—consisting of constipation and a longer transit time for food in the intestinal tract—as well as excessive daytime sleepiness, a diminished sense of smell, and an irregular heartbeat. One striking symptom candidate is REM Sleep Behavior Disorder (RBD), in which an individual acts out violent dreams and can harm himself or a sleeping partner in the process.

However, an informal diagnosis using this symptom cluster is tough to do, Federoff said, because symptoms such as drowsiness or constipation can accompany any number of conditions. They can also be the temporary result of harmless changes in somebody’s diet or daily schedule.

Mystery of Parkinson’s Origins Parkinson’s disease is the product of a genetic-environmental interaction, Federoff said, although that mix varies. If the disease appears in someone younger than 50, it’s likely there’s a strong genetic component to it—a notion supported by studies of identical twins. However, when it appears in a person who’s older, the more common course, it’s likely caused by an inherited vulnerability plus something in the environment, Federoff said.

But what is that something? There are a number of outside-cause candidates, including viral infections, prenatal problems, blows to the head and industrial chemicals.

Indeed, pesticides frequently come up in the Parkinson’s debate. A 2000 study by Emory University neurologist J. Timothy Greenamyre showed that the pesticide rotenone can create Parkinson’s symptoms in rats. Rochester researchers produced similar results by exposing mice to farm chemicals, noting that farmers, people who live in rural areas, and those who drink well water are all more likely to have the disease.

Additionally, a new study published in the Journal of the American Neurological Association said there is strong evidence that the industrial chemical trichloroethylene (TCE) is a risk factor for Parkinsonism, a group of nervous disorders with symptoms similar to Parkinson’s. TCE is widely used in manufacturing and found in drinking water, surface water and soil through industrial runoff—and it’s listed as a contaminant present in almost 60 percent of the hazardous U.S. sites marked for priority cleanup by the U.S. Environmental Protection Agency.

Federoff cautioned that although such population studies can be suggestive, they track factors that occur together, perhaps accidentally, and thus cannot prove cause and effect.

There is, however, one good example of Parkinson’s proof: In the 1970s and early 1980s, a number of drug users in California and Maryland took synthetic heroin that was mistakenly synthesized and wound up injecting a neurotoxin called MPTP. They all subsequently developed symptoms of Parkinson’s disease. These people were treated and recovered, but one later died from a cocaine overdose, and an autopsy revealed that MPTP had destroyed his dopamine neurons.

It is likely that there are many different causes of the disease, Federoff observed; however, they all wind up on the same path to cell injury and cell death.

Treatments Old and New Current treatments for Parkinson’s include a wide array of drug options and several kinds of surgery—but these only address symptoms and none are cures.

The most effective drug is the oldest, levodopa or L-dopa, which is converted to dopamine in the brain. However, L-dopa, which is usually boosted with additional drugs, creates troubling side effects and eventually loses its effectiveness.

The most common surgical procedure, typically used when other treatments no longer work, is deep brain stimulation (DBS). It features the equivalent of a heart pacemaker and blocks brain signals that create symptoms such as tremors. A thin wire is inserted into the brain, with the wire attached to an electronic pulse generator typically implanted under the skin of the patient’s chest.

Researchers are also developing gene therapies that use virus “vectors” to insert new DNA into dysfunctional parts of a Parkinson patient’s brain in an effort to improve them. Although some gene therapies for other conditions and diseases have run into major problems, including patient deaths and trials that have had to be stopped, a number of gene-therapy treatments for Parkinson’s are successfully winding their way through clinical trials in human patients.

Three sets of clinical trials to test gene therapies in Parkinson’s patients are currently under way—two designed to look at symptom relief and one at trying to change the disease’s progress. According to a review of these trials first published last year in Experimental Neurology by Krystof Bankiewicz and colleagues, the trials offer reasons “for optimism on several fronts.” First, there have been no serious patient problems and no patient deaths. Second, the virus shuttle being used to deliver the genes, which was the same in all three trials, appeared to work well. And third, signs of effectiveness were “trending in the right direction.”

In a recent update, Federoff said the trials were advancing and that we’ll know the practical results of these trials and the likelihood of their therapeutic use, if any, in about five years.

In contrast, a number of stem cell initiatives designed to introduce normal dopamine neurons or dopamine-releasing cells into the brain are progressing more slowly. The advent of therapies using stem cells from adults rather than embryos, along with recent news out of Massachusetts that scientists cultivated several colonies of human embryonic stem cells without harming the embryos, have reduced the controversy level of the issue somewhat.

Nevertheless, the complexity of any stem cell undertaking and the difficulty of getting these cells to function in a normal fashion are daunting. “We don’t know how to do it yet, and it could be years or decades before we do,” Federoff said. “We can put the stem cells in, but they’re not getting incorporated” at this point.

The Prevention Question A review looking at the future of Parkinson’s therapies noted that there was some evidence that over-the-counter anti-inflammatory painkillers such as aspirin or ibuprofen could reduce the risk of getting the disease. However, according to Federoff, the evidence is mixed and regular use raises the risk of stomach irritation or internal bleeding. “I wouldn’t recommend it,” he said.

Similarly, the jury is out on green tea—touted as an antioxidant and Parkinson’s preventive that is currently being tested in rats by Beijing scientists. Although drinking tea can’t do any harm and may be good for your overall health, there’s not enough evidence that it’s effective in preventing Parkinson’s disease in human beings. “The idea is valid and it’s still being tested,” Federoff said, but he added that he couldn’t endorse it at this time.

About the Author

Carolyn Cosmos is a contributing writer for The Washington Diplomat.