Who's most likely to get Parkinson's disease?
In the U.S., the disease is more likely to affect men than women, more likely to affect white or Hispanic individuals than black or Asian people and much more likely to affect those over sixty than those younger, according to a study published in the American Journal of Epidemiology in 2003.
Other research suggests that globally, you're more likely to get Parkinson's if you live in an industrialized country like the U.S. than if you live in a less developed nation. However, there's no clear-cut data on the demographics.
"It's hard to believe that we don't have that data now," says Dr. J. William Langston, founder and director of the Parkinson's Institute, "but ... it's not available anywhere in the world." In part, this is because Parkinson's disease affects a relatively small population -- at most one to two percent in the United States -- and because of difficulties in consistently diagnosing the disorder.
Is the risk of getting this disease growing?
There's even less data on how the rate of Parkinson's cases have changed since it was first identified in 1817. The number of cases is rising as the global population ages, but it's not clear whether Parkinson's is affecting a larger percentage of the population than it has in the past. Some research has found that the risk of getting Parkinson's in the U.S. rose slightly between 1935 and 1985, but when it comes to tracing the history of the disease, major data holes remain.
"Certainly, there have been individuals described hundreds and hundreds of years ago that have what sounds very much like Parkinson's disease," says Dr. Michael Zigmond, a Parkinson's researcher at the University of Pittsburgh. However, he adds, "We can't easily evaluate people who are not here now, even through the eyes of a neurologist 50 or 100 years ago." What we call Parkinson's today, doctors might have diagnosed differently in the past. What doctors used to call Parkinson's we may now have identified as something else.
However, there are some new projects underway on the demographics of the disease. For example, the California Parkinson's Disease Registry will collect detailed information on every Parkinson's diagnosis in that state. Says Dr. Langston, "This will tell us for the first time, is the disease increasing, changing with time? Are there pockets or clusters of the disease? Are there differences in rural versus urban areas, socioeconomic differences, etc.?"
What causes Parkinson's?
Even though Parkinson's was formally identified almost 200 years ago, scientists are still trying to find out what causes it. "We still don't have a smoking gun, that's for sure," says Dr. Langston. "But that's what we're looking for."
The greatest obstacle to pinpointing what causes it is that there seems to be no single cause. In some cases, the disease appears to be a genetic defect, while in others, exposure to toxic substances or certain viruses seems to be a factor. Some scientists believe a mix of environmental exposures and underlying genetic sensitivities may ultimately explain what triggers the disease.
What about environmental factors?
Sorting out the possible environmental influences on Parkinson's disease is a big challenge.
In the early 1980s, after discovering the toxin MPTP -- very similar to a compound found in a common pesticide -- could induce Parkinson's virtually overnight, scientists expected to track down the chemicals responsible for causing the disease in a matter of a few years. Nearly three decades later, "Very few individual specific compounds have been identified," says Dr. Langston. "Most of these are modest risk factors, two to threefold increase in risk."
Scientists have tracked disparate leads in search of an environmental explanation. They've researched Parkinson's-like symptoms in an individual who ingested petroleum products, in Taiwanese women who'd contracted a herpes virus and in people from Guam who eat a type of seed known to contain a neurotoxin. While finding a common thread among these scenarios has proved nearly impossible, much of the research has led back to pesticide exposure as the leading suspect in causing a large number of Parkinson's cases.
How clear is the link between pesticide exposure and Parkinson's?
According to Dr. William Langston, "I don't think we're yet at the point of being able to say unequivocally that if you live in an area where there's more pesticides than other areas, you're at a higher risk." But new research may illuminate the link.
One study is mapping Parkinson's cases in California against areas known to have high pesticide use. Another is collecting data from over 50,000 licensed pesticide applicators in two states to track whether these individuals face an increased risk of getting Parkinson's. "This, I think, may really answer the question of not only whether pesticides are an increased risk, but also, specifically, which pesticides," Dr. Langston hopes. "Because it's their profession, they know what they use, as opposed to, I couldn't tell you what I sprayed with in the garage last week."
Is there a gene, or genes, that causes Parkinson's?
So far scientists have identified six forms of genetic Parkinson's and are searching for more. However, the number of cases with a genetic link is a tiny portion of the overall number of cases. Still, doctors hope that better understanding the genetic form of the disease could help unravel the mysteries about other forms of Parkinson's.
But the genetic component of Parkinson's has also proved more complicated than once thought. Scientists have determined there's no single gene for Parkinson's -- one gene may trigger the disease in one family, while a different gene triggers it in another family.
Scientists also suspect that in some cases, developing genetic Parkinson's may require having multiple trigger genes, because studies of families with a high incidence of the disorder have shown that some individuals can carry the main gene identified as causing Parkinson's yet never develop symptoms.
How far along are scientists in figuring out the interaction -- the connection -- between genes and the environment?
A large study of over 20,000 identical twins -- who share the same genetic code -- is underway to trace when different environmental exposures can trigger Parkinson's in one twin but not the other and under what circumstances both twins develop Parkinson's.
Why is Parkinson's so hard to diagnose?
Diagnosing Parkinson's can be a challenge in part because some mild Parkinson's symptoms at first just seem like the universal effects of aging -- a tremor in the hand, difficulty balancing and shuffling the feet.
"I think everybody gets a little Parkinsonian as you get older," says Dr. Clive Svendsen, who is studying stem cell therapies for Parkinson's at the University of Wisconsin. "And in fact, most of the literature points out a gradual reduction in dopamine neurons" -- the neurons whose death causes Parkinson's best-known physical symptoms -- "over time in everybody."
What are the hallmark symptoms? Do all patients have the same symptoms?
There's no clear epidemiological record of whether the specific symptoms doctors look for and patients express have evolved over time, but the hallmark of Parkinson's has always been tremors throughout the body. Making a definitive diagnosis has often proved difficult, however, because the exact nature of the symptoms can vary widely from patient to patient. Recent studies show that even members of the same family who share a single genetic form of Parkinson's may display very different symptoms. One patient may have foot tremors accompanied by difficulty sleeping, while another may have hand tremors and difficulty keeping his balance.
What are the new discoveries about Parkinson's symptoms?
In recent years scientists have found that Parkinson's is much more than a disease of shaking limbs.
"When I started my residency, this was a very simple disease," recalls Dr. William Langston. "A number of cells die in a small area of the brain that made a chemical called dopamine. When they died, you had no more dopamine. Without dopamine, it's difficult to move. ... And that's the way we diagnosed it. When dopamine's down, you got rigid, you developed a tremor, gait became slowed and shuffling, etc. Any neurologist can diagnose that."
But now, says Langston, "At this point in time, we know that Parkinson's is a much more complicated disorder. Many different areas of the brain can be affected. It probably evolves in a very specific order, starting in the low brain stem and then eventually affecting other areas, including the nigra, which causes Parkinsonism [the tremors]. But all of these other areas of the brain that are affected can also cause symptoms."
These newly-recognized symptoms range from loss of the sense of smell to digestive problems to depression.
Why has it taken doctors so long to recognize the wide array of symptoms now connected to Parkinson's? "Because [patients] don't come to neurologists if they have, say, sleep disorders or loss of sense of smell or even constipation, which is a very bothersome symptom in Parkinson's," says Langston.
How close are we to having an earlier, more accurate diagnosis of Parkinson's?
The National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, is working on improving its guidelines for diagnosing Parkinson's to reflect the latest science. Other researchers are focusing on finding new ways of identifying the disease altogether. Some are searching for a Parkinson's biomarker -- a biological trait displayed only in people who have or are at risk of developing the disease.
And now that sense of smell has been tied to Parkinson's, a study led by the Institute for Neurodegenerative Disorders and the University of Pennsylvania is seeking to determine if how well a person performs on a test to identify 40 common odors can predict the individual's likelihood of developing Parkinson's. So far, they've found the average person can identify 35 of the odors, while the average diagnosed Parkinson's patient can only correctly name 20.
How close are scientists to finding a cure?
As scientists learn more about the great complexity of Parkinson's disease, hopes for finding a cure within the next few years is fading. But all the new information is paving the way for inventing better treatments that won't cure Parkinson's completely but will minimize the disease's effects.
"What we have to think about is whether the patient would be happy with still having constipation, still having other side effects of the disease, but being able to maintain a movement without arresting tremor and being able to initiate their own movement," says Dr. Clive Svendsen. "We're looking for a treatment that ... isn't curing it, but it's making the quality of life better."
If there's no cure in sight in the near future, what are the treatment options?
Since the 1960s, the leading treatment for Parkinson's has been the drug Levodopa, or L-dopa, a compound that can counteract the loss of dopamine neurons that causes the tremor symptoms of the disease. In the past couple of decades, deep brain stimulation -- a treatment that involves implanting a pacemaker-like device to deliver electric shocks to the parts of the brain that are damaged in Parkinson's patients -- has become another widely-employed treatment that generally produces positive results.
But the effectiveness of L-dopa decreases the longer a patient uses it, and deep brain stimulation requires a highly invasive operation, so scientists continue to look for better Parkinson's treatments.
As explored in My Father, My Brother and Me, doctors have recently started studying the power of exercise as a therapy to not only keep Parkinson's patients physically healthy but beneficially alter their brain chemistry.
What are some of the newer treatments being pursued?
Another area that offers great promise is neuroprotection, explained by Dr. Langston as "the idea of protecting nerve cells from dying or damage, ... another great Holy Grail in the field of neurology."
Scientists studying neuroprotection are looking for chemical substances that, when introduced into the brain, could either blunt the effects of Parkinson's disease on a patient after he is diagnosed or, better yet, prevent Parkinson's altogether. "The problem is," according to Dr. Langston, "I think it's a laboratory concept that jumped into the clinical all too quickly. In a laboratory animal, you can actually measure nerve cells after an experiment. We can't do that in humans. We have no way to really show we've slowed down the progress of cell death in living humans."
With thousands of potentially helpful chemicals to test, and without the scientific ability to widely screen substances for their ability to protect human brains against damage, Langston suggests researchers focus less on the effects of these substances on the brain itself and more on their effects on the patient as a whole.
"For the moment, where I think we need to focus in clinical trials is delaying disability. We clinicians can measure that. So start a patient on your neuroprotective agent. We can't prove [the neuroprotection], but if disability is really delayed or completely stopped, I think that would be very compelling."
Other scientists are working on refining the mode of delivery for a known neuroprotective substance. "There are some very powerful drugs for Parkinson's disease that are very difficult to get into the brain," says Dr. Svendsen. "GDNF [glial cell derived neurotrophic factor] is one of those drugs. ... Even at late stage Parkinson's, you have lots of neurons left, they just don't have any dopamine left in them, and they're very shrunken. And in that sense, [growth factors like GDNF] might again be like the fertilizer. Put it onto those cells, and even though they've practically disappeared, the growth factor will make them rejuvenate and start to produce dopamine again."
The problem, says Svendsen, is, "You can give [GDNF] peripherally in the blood, but it doesn't penetrate the blood-brain barrier [to get into the brain]. The idea is to design stem cells that make this drug, put the stem cells in the brain, and then they'll deliver it -- rather like a Trojan Horse. The brain accepts the stem cell because it's [a brain cell] and it's going to integrate and migrate and get into the brain tissue. ... And that's how we can sneak drugs into the brain, [overcoming] this powerful blood-brain barrier, which usually blocks this process."
The major obstacle Svendsen needs to solve to implement this type of therapy is creating an off switch of sorts for the cells that will produce GDNF. "It does remind me of the Walt Disney Fantasia movie and 'The Sorcerer's Apprentice,'" he says, "when Mickey Mouse is in the basement with the sorcerer and he gets a great way to make the broomsticks carry the water up and down. And, of course, it goes horribly wrong because [they] carry too much water, and it's overflowing, [so he] chops the broomsticks in half [but] they just keep carrying the water up and down.
"I wake up at night with that dream in my head, thinking, boy, if we put cells in the brain that produce [GDNF] that we think it's great and then it has a toxic effect, we can't switch it off. ... But on the other hand, we need to move forward in these diseases. ... It's a difficult one."
Could Parkinson's be a "gateway disease?" Could solving it clear the way to understanding -- even curing -- other neurological conditions?
"I think there's a general sense in the scientific and medical community that solving any of these major diseases -- Parkinson's, Lou Gehrig Disease, Alzheimer's -- could have an enormous impact on the others," says Dr. William Langston. But for many years, Parkinson's received special attention.
"For many years, the thought was Parkinson's was the perfect disease to lead the way in terms of solving these diseases," Langston explains. "The main reason for that is we were totally focused on one small area of the brain known as substantia nigra -- literally, black stuff -- [a] small pigmented dark area in the brain that sits atop the brain stem. Now, that looked like a pretty easy target, not a big nucleus. We fix that, we get more of the normal chemistry restored in the brain, and we fix the disease. To some degree, I think, that's still true. But we're now learning that Parkinson's is actually much more complex."
As scientists have learned that the symptoms of Parkinson's go far beyond the movement problems linked to the decay of the substantia nigra, they've realized that the simplicity that once made this seem like an easy neurological disorder to crack -- the best candidate for a cure -- was an illusion.
Does that mean what's learned about Parkinson's will have no effect on our ability to solve neurological diseases?
No. The complex nature of Parkinson's doesn't rule out the ability of breakthroughs studying this disease to have an impact on the understanding and treatment of other disorders.
"I think you're going to see most surgical therapies carried out first in Parkinson's disease," says Langston, citing the disease's pronounced effect on a small area of the brain. "And that's already happening with gene therapy, where genes are inserted in the brain to try to make cells healthier. ... If we get to the point of stem cells going in, all of that will probably be done with Parkinson's first."
Dr. Clive Svendsen is studying how to use stem cells to deliver growth factor -- a chemical that can regenerate important nerve cells in the brain -- as a treatment for Parkinson's. He points out that, "The Department of Defense has funded work in Parkinson's disease for a number of years. ... I think some of this comes through lobbying of people like Muhammad Ali and Michael J. Fox, and certain senators, to try and get funds appropriated specifically for Parkinson's disease. A number of veterans get Parkinson's disease. [With] Gulf War syndrome, there's an increased performance of ALS [another neurodegenerative disease]. And just neuro injury in wartime conditions is important to the Army. They're looking to stem cells releasing growth factors as a potential treatment for their troops on the field and for their veterans." Solving even a part of Parkinson's could still help solve parts of other brain disorders.
Are stem cells key to finding a cure?
Theoretically, stem cells should be able to replace the damaged brain cells whose degeneration leads to Parkinson's symptoms.
"We have shown very clearly that our basic science work in the laboratory ... proved that we can restore ... brain function in patients," says Dr. Ole Isacson of the Parkinson's Research Center at Harvard Medical School. "But we do need a lot of work to overcome the obstacles of making this happen [in] every case and in a reliable way."
"When we started with neurotransplants -- and we started with fetal cells first, and eventually the hope was stem cells would replace those -- we thought this was gonna be easy," Dr. William Langston explains. "We just put the cells in, fix this one small area of the brain, and we cure the disease. And we were very disappointed when that didn't happen. I think now with our evolving concept of Parkinson's disease, treating this one small area of the brain that we can already treat pretty well with surgical therapies, [stem cell therapy is] important but I think it is no longer the Holy Grail."
Some patients who've received experimental cell transplants have seen their symptoms improve, while others have experienced no change or even gotten worse.
"Some more extreme critics of this field," says Dr. Clive Svendsen, "would say that we now have two types of Parkinson's. We have Parkinson's disease and Parkinson's plus transplant disease."
[Editors' Note: Researchers at MIT's Whitehead Institute for Biomedical Research have developed a new method of reprogramming the skin cells of Parkinson's patients into "an embryonic-stem-cell-like state," using "the resulting cells to derive dopamine-producing neurons, the cell type that degenerates in Parkinson’s disease patients." According to The New York Times, this method, "would in principle allow the brain cells that are lost in Parkinson's to be replaced with cells that carried no risk of immune rejection."]
Why haven't stem cell transplants worked so far?
There are many reasons scientists have encountered obstacles in engineering successful stem cell treatments for Parkinson's.
"The comparison I always use is, imagine trying to wire your house after it was built," says Langston. "I mean, when you build a house, all the wiring goes in very early. When the house is built, if you had to do all the wiring afterwards, that would be pretty tricky. Now imagine you're trying to do that in a living brain with 4 billion neurons."
Some stem cells revert from the type of cells they've been cultivated to become -- generally dopamine neurons when dealing with Parkinson's -- back into generic stem cells when they're placed in the brain. And an adult brain seems to have ways of recognizing embryonic stem cells as not belonging. "We're learning there're all types of signals in the adult brain that tell these little guys to go away," says Langston.
Furthermore, a stem cell's inherent ability to develop into any kind of cell -- the property that makes them useful -- can also be a hazard. Says Isaacson, "While we know that we can generate the dopamine neuron, it also tends to generate other cell types, including skin, and maybe even bone. So the challenge is, even though we can get the cell we want, [we need] to eliminate the other unwanted cells, lest they would grow into tissues that would be very problematic and even dangerous to the patient."
In some cases, says Langston, "We don't even understand the reasons why the attempts we've already done have failed."
The risk of stem cell procedures compared to the safety of other relatively effective Parkinson's treatments gives some scientists pause. "The patients will have [to] think about this," says Svendsen. "Am I gonna risk a new procedure that hasn't been tried or go with the steady state procedures which we know work?"
Two perspectives on the promise of stem cells...
Because of the practical difficulties surrounding stem cell procedures, some scientists no longer think of them as a potential wonder cure-all.
"It's not popular to say that stem cells aren't the answer, but I now believe they are not," says Langston. "I don't think we should give up with them. I think they're gonna help other diseases, and eventually they may really help Parkinson's. But I don't think that should be our major focus. The brain is not a pincushion. We can't keep plucking cells in all over the place."
Others are more optimistic, although they point out it may take many years to fix the current problems with stem cell transplant technologies.
"What we're facing is the same kind of problems that you see almost in engineering. If you think of the early development of airplanes, or flight, the first airplane crashed very quickly," says Ole Isacson.
"But many years, in a way, is still a short time in my world, because if you think about the kind of discoveries that are necessary to make a medical treatment available to a large group of patients, decades is the norm rather than the exception."
"We're looking at this through the Parkinson's window," says Clive Svendsen, "but if you look outside the Parkinson's window and go to the rest of the world, [there are] lots of places that this technology will be used, I'm sure."