September 28, 2009
New Hope in Neuroprotection? — A Parkinson’s Disease Update
By Juliann Schaeffer
For The Record
Vol. 21 No. 18 P. 34
Neuroprotection has become the focus of efforts aimed at slowing the progression of Parkinson’s disease.
One of the most common neurologic disorders that elders experience, Parkinson’s disease (PD) is a devastating diagnosis affecting approximately two of every 1,000 older adults. Although there is currently no cure and current treatments help alleviate only the symptoms rather than the disease’s progression, fresh hope lies in new research focused on neuroprotection.
Based on the concept that at-risk dopamine-producing neurons in the brain could be protected from the degenerative process that causes premature cell injury or death, neuroprotection has researchers considering dietary supplements and other unexpected drugs for possible utilization in PD therapy, with hopes that it could be the first type of treatment to actually slow or stop the disease’s progression.
PD, the causes of which are unknown, is a chronic, progressive brain disorder that belongs to a larger class of disorders called movement disorders. In PD, one particular population of brain cells—those that produce a chemical messenger called dopamine—become impaired and are lost over time. “The loss of these brain cells causes circuits in the brain to function abnormally, and those abnormal circuits result in movement problems,” says Beth-Anne Sieber, PhD, program director for the Neurodegeneration Cluster at the National Institute of Neurological Disorders and Stroke.
Researchers have found that, in many cases, the presence of PD appears to be sporadic or random, although several risk factors have been identified, with the greatest being age, followed by genetics and environment. “While genetic risk factors are being defined, the genetics of Parkinson’s disease are not yet completely clear,” says Sieber. “But most [researchers] do think it’s a combination of genetics and environment. Some researchers think that the combination of genetics and environment might actually speed up a normal aging trajectory. There are some people that say that if everyone lived to be 110, we’d all have Parkinson’s disease or Alzheimer’s—that this is an aging brain and that somehow the trajectory has sped up. Researchers are not quite sure about that. We do know that there’s damage at some point or lack of function of these dopamine cells at some point in life, but we’re not sure where it is or for how long it goes on. The early signs of the disease may help us understand the progress of the disease because it’s more than just these [dopamine] cells in the brain; it affects other cells as well that we’re learning more and more about every day.”
More men than women are afflicted with PD, and “other risk factors seem to be people who live in developed countries or in a rural environment, and the rural environment has been linked to possible exposure to pesticides,” Sieber says of one theory.
The average age of PD onset is about 60, and the risk increases with age. Why is that the case? “This is an area of research emphasis, as scientists are not certain,” says Sieber. “One theory suggests that the disease process begins long before symptoms become evident and that a younger, more plastic brain is able to compensate and function relatively normally for some amount of time. The brain is an incredibly complex organ and can possibly deal will some small blips in the system; however, the aging process may lessen the ability to compensate, larger numbers of dopamine neurons are lost, and classic disease symptoms emerge.”
Symptoms and Diagnosis
Movement problems are a classic sign of PD and can vary among individuals in prevalence and severity. “Each person may have one or more of these symptoms, some slightly worse than others,” Sieber says. Common PD motor symptoms include the following:
• tremor or trembling;
• stiffness (eg, elders’ limbs or bodies become more rigid);
• bradykinesia (eg, elders start to move more slowly); and
• postural instability (eg, impaired balance).
Sieber says initial symptoms can be so subtle that patients often easily mistake them for facets of normal aging. “[Symptoms] might be really subtle initially,” she says. “Someone might notice that their handwriting gets smaller, that their hand starts to shake, that they may have more difficulty standing up, or that they’re a little unsteady or slow. Now, most of those things are something you might think would happen as you get older, but what starts to happen is they become gradually worse, and they start to affect daily activities—things like talking, walking, eating, or reading a newspaper. At that point, that’s when people usually start to go to the doctor.”
There are also common symptoms that often precede PD’s motor signs, including trouble sleeping, changes in sense of smell, fatigue, restless legs, and constipation.
“There’s quite a bit of research right now going on [into] what these early signs might mean and if that could help predict an improved diagnosis and treatment of the disorder,” says Sieber.
A PD diagnosis is usually guided by presenting symptoms because there is no blood or other test to diagnose the disease. Although one might think a brain scan such as an MRI may be successful for detecting PD, “in a scan like magnetic resonance imaging, which shows structural changes in the brain, they appear normal in Parkinson’s disease because these cells that die off are a very small population, yet they have a huge impact on the patient’s movement,” says Sieber.
Diagnosis can also be complicated by the fact that other disorders can have similar symptoms to those exhibited with PD. After older adults are put on PD treatments for their symptoms, a more definitive diagnosis can be made. “Parkinson’s disease may be difficult to diagnose initially, but the classic PD symptoms and response to medications are supportive factors,” says Sieber.
Treatment: Then and Now
The balance of treatment for PD is very individualized because older adults can have varying degrees of symptoms, and no two patients react in exactly the same way. The gold standard for treating PD, which has been used for many years as its primary treatment, is levodopa (L-dopa). A kind of dopamine-replacement therapy, “It’s a compound that is naturally found in plants and animals, and it’s a precursor to dopamine,” explains Sieber, noting that it is typically given with another compound called carbidopa to ensure its ability to cross the blood-brain barrier and get into the brain.
“When it gets into the brain, the brain cells convert L-dopa into dopamine, [which] reduces the tremor and some of the motor symptoms and allows the patients to lead relatively normal lives,” says Sieber, who notes that L-dopa does not help with balance and other nonmotor symptoms.
Sieber says, however, that L-dopa can create its own problems. “One thing that happens with L-dopa is that, as patients are on it for a longer period of time, they start to have side effects called dyskinesias, [which] are sudden involuntary movements,” she says, noting that they can affect older adults’ quality of life. “Imagine you’re having a really hard time walking and this drug makes it better, but suddenly you get these very strange movements. One of the challenges facing therapeutic development for PD is discovering the means to improve motor function and decrease involuntary movements while maintaining quality of life for the individual and providing as full a range of motion as possible.”
According to Sieber, there are different categories of dopamine-replacement drugs that, by targeting different parts of the dopamine metabolic pathway as L-dopa does, increase the production of dopamine. Compounds such as Azilect, a monoamine oxidase B inhibitor, can block the degradation of dopamine and still others enhance the activity of dopamine at its receptor (a dopamine signal). “[These drugs] all basically improve dopamine signaling in the brain to help the damaged circuits,” she explains.
Another category of drugs is used to balance other brain chemicals that are also affected after the dopamine cells die, and there’s also a third class of drugs that will affect the nonmotor symptoms PD patients may experience, such as anxiety, depression, and orthostatic hypotension.
For patients whose symptoms are minimally improved by medication, deep brain stimulation has been implemented and can be a successful treatment for some because it may reduce the need for medication and improve dyskinesias. “Recent evidence suggests that deep brain stimulation significantly improves movement and quality of life in PD patients. Consultation with a physician is necessary to determine whether this surgical procedure is the best course of action for an individual patient,” says Sieber.
New Hope in Neuroprotection?
Although several treatments and medications are being utilized for older adults with PD, all the current medications work on managing symptoms, but none can stop the disease’s progression. New research into neuroprotection is trying to change that. “[Neuroprotection] is where research is headed right now because L-dopa, as far as we know, does not stop the progression of the disease. None of the drugs that are available stop the progression,” Sieber says. “So there is extensive effort in this area right now in both basic research and clinical trials.”
Sieber says neuroprotection has researchers looking down new avenues for a cure, such as dietary supplements and drugs that have been used in the treatment of other disorders. For example, several ongoing clinical trials are examining the effects of creatine, which is commonly used to build muscle, and coenzyme Q10, which “works through cellular structures called mitochondria, the power plants of cells, to clear any harmful substances that are produced if the mitochondria are not working to capacity. For example, if a power plant were releasing harmful chemicals into the air, coenzyme Q10 would serve as a filter to prevent this from happening and keep the environment clear, allowing those around to breathe better,” says Sieber.
Both of these compounds are neuroprotective in animal models and have been well tolerated in humans, “so there is significant focus on using dietary supplements and drugs that have been utilized for other disorders that in animal models have an effect,” says Sieber.
As an example of a compound researchers are currently studying, Sieber mentions isradipine, a calcium blocker typically used to treat high blood pressure that is the subject of research currently being led by Dalton James Surmeier, PhD, at Northwestern Medical School in Chicago. Interpreting Surmeier’s results to date, Sieber says, “Dr. Surmeier has found that isradipine makes old dopamine cells young again by changing the pattern of communication of these cells with brain circuits. Dr. Surmeier and his colleagues are pursuing basic and clinical research to determine whether isradipine and similar compounds will improve the function of dopamine cells and provide a new therapy for PD.”
Sieber says other clinical trials are now examining urate’s effect on PD. “A large study has shown that high levels of urate may actually be protective in Parkinson’s disease,” she says, noting that there are many studies ongoing in this area right now, both at basic research and clinical trial levels.
While Sieber would love nothing more than to say a cure for PD can be expected any day now, no one knows how close—or far away—that cure may be. But she says there is a great deal of high-quality directed research that is currently being funded by the National Institutes of Health and nonprofit foundations, including the Michael J. Fox Foundation, the Parkinson’s Disease Foundation, and the National Parkinson Foundation, to bring that goal closer to reality.
“Researchers have made rapid progress in defining potential causes of PD,” she says. “Currently, significant efforts in basic and clinical research are directed toward development of improved treatments, including the identification of neuroprotective strategies that can slow disease progression. As scientists continue to discover more about the function of genes, risk factors, and brain circuits involved in PD, they work steadily toward a cure.”— Juliann Schaeffer is assistant editor of For The Record.