Researchers believe that at least 500,000 people in the
Parkinson's disease belongs to a group of conditions called movement disorders. The four main symptoms are tremor, or trembling in hands, arms, legs, jaw, or head; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance. These symptoms usually begin gradually and worsen with time. As they become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. Not everyone with one or more of these symptoms has PD, as the symptoms sometimes appear in other diseases as well.
PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. It is not contagious. Although some PD cases appear to be hereditary, and a few can be traced to specific genetic mutations, most cases are sporadic — that is, the disease does not seem to run in families. Many researchers now believe that PD results from a combination of genetic susceptibility and exposure to one or more environmental factors that trigger the disease.
PD is the most common form of parkinsonism, the name for a group of disorders with similar features and symptoms. PD is also called primary parkinsonism or idiopathic PD. The term idiopathic means a disorder for which no cause has yet been found. While most forms of parkinsonism are idiopathic, there are some cases where the cause is known or suspected or where the symptoms result from another disorder. For example, parkinsonism may result from changes in the brain's blood vessels.
Parkinson's disease occurs when nerve cells, or neurons, in an area of the brain known as the substantia nigra die or become impaired. Normally, these neurons produce an important brain chemical known as dopamine. Dopamine is a chemical messenger responsible for transmitting signals between the substantia nigra and the next "relay station" of the brain, the corpus striatum, to produce smooth, purposeful movement. Loss of dopamine results in abnormal nerve firing patterns within the brain that cause impaired movement. Studies have shown that most Parkinson's patients have lost 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra by the time symptoms appear. Recent studies have shown that people with PD also have loss of the nerve endings that produce the neurotransmitter norepinephrine. Norepinephrine, which is closely related to dopamine, is the main chemical messenger of the sympathetic nervous system, the part of the nervous system that controls many automatic functions of the body, such as pulse and blood pressure. The loss of norepinephrine might help explain several of the non-motor features seen in PD, including fatigue and abnormalities of blood pressure regulation.
Many brain cells of people with PD contain Lewy bodies – unusual deposits or clumps of the protein alpha-synuclein, along with other proteins. Researchers do not yet know why Lewy bodies form or what role they play in development of the disease. The clumps may prevent the cell from functioning normally, or they may actually be helpful, perhaps by keeping harmful proteins "locked up" so that the cells can function.
Scientists have identified several genetic mutations associated with PD, and many more genes have been tentatively linked to the disorder. Studying the genes responsible for inherited cases of PD can help researchers understand both inherited and sporadic cases. The same genes and proteins that are altered in inherited cases may also be altered in sporadic cases by environmental toxins or other factors. Researchers also hope that discovering genes will help identify new ways of treating PD.
Although the importance of genetics in PD is increasingly recognized, most researchers believe environmental exposures increase a person's risk of developing the disease. Even in familial cases, exposure to toxins or other environmental factors may influence when symptoms of the disease appear or how the disease progresses. There are a number of toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or MPTP (found in some kinds of synthetic heroin), that can cause parkinsonian symptoms in humans. Other, still-unidentified environmental factors also may cause PD in genetically susceptible individuals.
Viruses are another possible environmental trigger for PD. People who developed encephalopathy after a 1918 influenza epidemic were later stricken with severe, progressive Parkinson's-like symptoms. A group of Taiwanese women developed similar symptoms after contracting herpes virus infections. In these women, the symptoms, which later disappeared, were linked to a temporary inflammation of the substantia nigra.
Several lines of research suggest that mitochondria may play a role in the development of PD. Mitochondria are the energy-producing components of the cell and are major sources of free radicals — molecules that damage membranes, proteins, DNA, and other parts of the cell. This damage is often referred to as oxidative stress. Oxidative stress-related changes, including free radical damage to DNA, proteins, and fats, have been detected in brains of PD patients.
Other research suggests that the cell's protein disposal system may fail in people with PD, causing proteins to build up to harmful levels and trigger cell death. Additional studies have found evidence that clumps of protein that develop inside brain cells of people with PD may contribute to the death of neurons, and that inflammation or overstimulation of cells (because of toxins or other factors) may play a role in the disease. However, the precise role of the protein deposits remains unknown. Some researchers even speculate that the protein buildup is part of an unsuccessful attempt to protect the cell. While mitochondrial dysfunction, oxidative stress, inflammation, and many other cellular processes may contribute to PD, the actual cause of the dopamine cell death is still undetermined.
In 2003, researchers studying inherited PD discovered that the disease in one large family was caused by a triplication of the normal alpha-synuclein gene on one copy of chromosome 4. This triplication caused people in the affected family to produce too much of the normal alpha-synuclein. This study showed that an excess of the normal form of the protein could result in PD, just as the abnormal form does.
Other genes linked to PD include parkin, DJ-1, PINK1, and LRRK2. Parkin, DJ-1, and PINK-1 cause rare, early-onset forms of PD. The parkin gene is translated into a protein that normally helps cells break down and recycle proteins. DJ-1 normally helps regulate gene activity and protect cells from oxidative stress. PINK1 codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress.
LRRK2, which is translated into a protein called dardarin, was originally identified in several English and Basque families and causes a late-onset form of PD. Subsequent studies have identified this gene in other families with PD as well as in a small percentage of people with apparently sporadic PD.
Researchers are continuing to investigate the normal functions and interactions of these genes in order to find clues about how PD develops. They also have identified a number of other genes and chromosome regions that may play a role in PD, but the nature of these links is not yet clear.
About 50,000 Americans are diagnosed with PD each year, but getting an accurate count of the number of cases may be impossible because many people in the early stages of the disease assume their symptoms are the result of normal aging and do not seek help from a physician. Also, diagnosis is sometimes difficult and uncertain because other conditions may produce symptoms of PD and there is no definitive test for the disease. People with PD may sometimes be told by their doctors that they have other disorders, and people with PD-like diseases may be incorrectly diagnosed as having PD.
PD strikes about 50 percent more men than women, but the reasons for this discrepancy are unclear. While it occurs in people throughout the world, a number of studies have found a higher incidence in developed countries, possibly because of increased exposure to pesticides or other toxins in those countries. Other studies have found an increased risk in people who live in rural areas and in those who work in certain professions, although the studies to date are not conclusive and the reasons for the apparent risks are not clear.
One clear risk factor for PD is age. The average age of onset is 60 years, and the incidence rises significantly with increasing age. However, about 5 to 10 percent of people with PD have "early-onset" disease that begins before the age of 50. Early-onset forms of the disease are often inherited, though not always, and some have been linked to specific gene mutations. People with one or more close relatives who have PD have an increased risk of developing the disease themselves, but the total risk is still just 2 to 5 percent unless the family has a known gene mutation for the disease. An estimated 15 to 25 percent of people with PD have a known relative with the disease.
In very rare cases, parkinsonian symptoms may appear in people before the age of 20. This condition is called juvenile parkinsonism.
It is most commonly seen in
Early symptoms of PD are subtle and occur gradually. Affected people may feel mild tremors or have difficulty getting out of a chair. They may notice that they speak too softly or that their handwriting is slow and looks cramped or small. They may lose track of a word or thought, or they may feel tired, irritable, or depressed for no apparent reason. This very early period may last a long time before the more classic and obvious symptoms appear.
Friends or family members may be the first to notice changes in someone with early PD. They may see that the person's face lacks expression and animation (known as "masked face") or that the person does not move an arm or leg normally. They also may notice that the person seems stiff, unsteady, or unusually slow.
As the disease progresses, the shaking or tremor that affects the majority of Parkinson's patients may begin to interfere with daily activities. Patients may not be able to hold utensils steady or they may find that the shaking makes reading a newspaper difficult. Tremor is usually the symptom that causes people to seek medical help.
People with PD often develop a so-called parkinsonian gait that includes a tendency to lean forward, small quick steps as if hurrying forward (called festination), and reduced swinging of the arms. They also may have trouble initiating movement (start hesitation), and they may stop suddenly as they walk (freezing).
PD does not affect everyone the same way, and the rate of progression differs among patients. Tremor is the major symptom for some patients, while for others, tremor is nonexistent or very minor.
PD symptoms often begin on one side of the body. However, as it progresses, the disease eventually affects both sides. Even after the disease involves both sides of the body, the symptoms are often less severe on one side than on the other. The four primary symptoms of PD are:
A number of other symptoms may accompany PD. Some are minor; others are not. Many can be treated with medication or physical therapy. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms varies from person to person.
A number of disorders can cause symptoms similar to those of PD. People with symptoms that resemble PD but that result from other causes are sometimes said to have parkinsonism. Some of these disorders are listed below.
MSA, corticobasal degeneration, and progressive supranuclear palsy are sometimes referred to as "Parkinson's-plus" diseases because they have the symptoms of PD plus additional features.
There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal. Since many other diseases have similar features but require different treatments, making a precise diagnosis as soon as possible is essential so that patients can receive the proper treatment.
PD is not by itself a fatal disease, but it does get worse with time. The average life expectancy of a PD patient is generally the same as for people who do not have the disease. However, in the late stages of the disease, PD may cause complications such as choking, pneumonia, and falls that can lead to death. Fortunately, there are many treatment options available for people with PD.
The progression of symptoms in PD may take 20 years or more. In some people, however, the disease progresses more quickly. There is no way to predict what course the disease will take for an individual person. One commonly used system for describing how the symptoms of PD progress is called the Hoehn and Yahr scale.
Hoehn and Yahr Staging of Parkinson's Disease
Symptoms on one side of the body only.
Symptoms on both sides of the body. No impairment of balance.
Balance impairment. Mild to moderate disease. Physically independent.
Severe disability, but still able to walk or stand unassisted.
Wheelchair-bound or bedridden unless assisted.
Another commonly used scale is the Unified Parkinson's Disease Rating Scale (UPDRS). This much more complicated scale has multiple ratings that measure mental functioning, behavior, and mood; activities of daily living; and motor function. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much treatments are helping them.
With appropriate treatment, most people with PD can live productive lives for many years after diagnosis.
At present, there is no cure for PD. But medications or surgery can sometimes provide dramatic relief from the symptoms.
Medications for PD fall into three categories. The first category includes drugs that work directly or indirectly to increase the level of dopamine in the brain. The most common drugs for PD are dopamine precursors – substances such as levodopa that cross the blood-brain barrier and are then changed into dopamine. Other drugs mimic dopamine or prevent or slow its breakdown.
The second category of PD drugs affects other neurotransmitters in the body in order to ease some of the symptoms of the disease. For example, anticholinergic drugs interfere with production or uptake of the neurotransmitter acetylcholine. These drugs help to reduce tremors and muscle stiffness, which can result from having more acetylcholine than dopamine.
The third category of drugs prescribed for PD includes medications that help control the non-motor symptoms of the disease, that is, the symptoms that don't affect movement. For example, people with PD-related depression may be prescribed antidepressants.
Levodopa is very successful at reducing the tremors and other symptoms of PD during the early stages of the disease. It allows the majority of people with PD to extend the period of time in which they can lead relatively normal, productive lives.
Although levodopa helps most people with PD, not all symptoms respond equally to the drug. Levodopa usually helps most with bradykinesia and rigidity. Problems with balance and other non-motor symptoms may not be alleviated at all.
People who have taken other medications before starting levodopa therapy may have to cut back or eliminate these drugs in order to feel the full benefit of levodopa. People often see dramatic improvement in their symptoms after starting levodopa therapy. However, they may need to increase the dose gradually for maximum benefit. A high-protein diet can interfere with the absorption of levodopa, so some physicians recommend that patients taking the drug restrict their protein consumption during the early parts of the day or avoid taking their medications with protein-rich meals.
Levodopa is often so effective that some people may temporarily forget they have PD during the early stages of the disease. But levodopa is not a cure. Although it can reduce the symptoms of PD, it does not replace lost nerve cells and it does not stop the progression of the disease.
Levodopa can have a variety of side effects. The most common initial side effects include nausea, vomiting, low blood pressure, and restlessness. The drug also can cause drowsiness or sudden sleep onset, which can make driving and other activities dangerous. Long-term use of levodopa sometimes causes hallucinations and psychosis. The nausea and vomiting caused by levodopa are greatly reduced by combining levodopa and carbidopa, which enhances the effectiveness of a lower dose.
Dyskinesias, or involuntary movements such as twitching, twisting, and writhing, commonly develop in people who take large doses of levodopa over an extended period. These movements may be either mild or severe and either very rapid or very slow. The dose of levodopa is often reduced in order to lessen these drug-induced movements. However, the PD symptoms often reappear even with lower doses of medication. Doctors and patients must work together closely to find a tolerable balance between the drug's benefits and side effects. If dyskinesias are severe, surgical treatment may be considered. Because dyskinesias tend to occur with long-term use of levodopa, doctors often start younger PD patients on other dopamine-increasing drugs and switch to levodopa only when those drugs become ineffective.
Other troubling and distressing problems may occur with long-term levodopa use. Patients may begin to notice more pronounced symptoms before their first dose of medication in the morning, and they may develop muscle spasms or other problems when each dose begins to wear off. The period of effectiveness after each dose may begin to shorten, called the wearing-off effect. Another potential problem is referred to as the on-off effect — sudden, unpredictable changes in movement, from normal to parkinsonian movement and back again. These effects probably indicate that the patient's response to the drug is changing or that the disease is progressing.
One approach to alleviating these side effects is to take levodopa more often and in smaller amounts. People with PD should never stop taking levodopa without their physician's knowledge or consent because rapidly withdrawing the drug can have potentially serious side effects, such as immobility or difficulty breathing.
Fortunately, physicians have other treatment choices for some symptoms and stages of PD. These therapies include the following:
When recommending a course of treatment, a doctor will assess how much the symptoms disrupt the patient's life and then tailor therapy to the person's particular condition. Since no two patients will react the same way to a given drug, it may take time and patience to get the dose just right. Even then, symptoms may not be completely alleviated.
Medications to Treat the Motor Symptoms of Parkinson's Disease
Drugs that increase brain levels of dopamine
Drugs that mimic dopamine (dopamine agonists)
Drugs that inhibit dopamine breakdown (MAO-B inhibitors)
Drugs that inhibit dopamine breakdown (COMT inhibitors)
Drugs that decrease the action of acetylcholine anticholinergics)
Drugs with an unknown mechanism of action for PD
Medications for Non-Motor Symptoms. Doctors may prescribe a variety of medications to treat the non-motor symptoms of PD, such as depression and anxiety. For example, depression can be treated with standard anti-depressant drugs such as amitriptyline or fluoxetine (however, as stated earlier, fluoxetine should not be combined with MAO-B inhibitors). Anxiety can sometimes be treated with drugs called benzodiazepines. Orthostatic hypotension may be helped by increasing salt intake, reducing antihypertension drugs, or prescribing medications such as fludrocortisone.
Hallucinations, delusions, and other psychotic symptoms are often caused by the drugs prescribed for PD. Therefore reducing or stopping PD medications may alleviate psychosis. If such measures are not effective, doctors sometimes prescribe drugs called atypical antipsychotics, which include clozapine and quetiapine. Clozapine also may help to control dyskinesias. However, clozapine also can cause a serious blood disorder called agranulocytosis, so people who take it must have their blood monitored frequently.
Treating PD with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.
Pallidotomy and Thalamotomy. The earliest types of surgery for PD involved selectively destroying specific parts of the brain that contribute to the symptoms of the disease. Investigators have now greatly refined the use of these procedures. The most common of these procedures is called pallidotomy. In this procedure, a surgeon selectively destroys a portion of the brain called the globus pallidus. Pallidotomy can improve symptoms of tremor, rigidity, and bradykinesia, possibly by interrupting the connections between the globus pallidus and the striatum or thalamus. Some studies have also found that pallidotomy can improve gait and balance and reduce the amount of levodopa patients require, thus reducing drug-induced dyskinesias and dystonia. A related procedure, called thalamotomy, involves surgically destroying part of the brain's thalamus. Thalamotomy is useful primarily to reduce tremor.
Because these procedures cause permanent destruction of brain tissue, they have largely been replaced by deep brain stimulation for treatment of PD.
Deep Brain Stimulation. Deep brain stimulation, or DBS, uses an electrode surgically implanted into part of the brain. The electrodes are connected by a wire under the skin to a small electrical device called a pulse generator that is implanted in the chest beneath the collarbone. The pulse generator and electrodes painlessly stimulate the brain in a way that helps to stop many of the symptoms of PD. DBS has now been approved by the U.S. Food and Drug Administration, and it is widely used as a treatment for PD.
DBS can be used on one or both sides of the brain. If it is used on just one side, it will affect symptoms on the opposite side of the body. DBS is primarily used to stimulate one of three brain regions: the subthalamic nucleus, the globus pallidus, or the thalamus. However, the subthalamic nucleus, a tiny area located beneath the thalamus, is the most common target. Stimulation of either the globus pallidus or the subthalamic nucleus can reduce tremor, bradykinesia, and rigidity. Stimulation of the thalamus is useful primarily for reducing tremor.
DBS usually reduces the need for levodopa and related drugs, which in turn decreases dyskinesias. It also helps to relieve on-off fluctuation of symptoms. People who initially responded well to treatment with levodopa tend to respond well to DBS. While the benefits of DBS can be substantial, it usually does not help with speech problems, "freezing," posture, balance, anxiety, depression, or dementia.
One advantage of DBS compared to pallidotomy and thalamotomy is that the electrical current can be turned off using a handheld device. The pulse generator also can be externally programmed.
Patients must return to the medical center frequently for several months after DBS surgery in order to have the stimulation adjusted by trained doctors or other medical professionals. The pulse generator must be programmed very carefully to give the best results. Doctors also must supervise reductions in patients' medications. After a few months, the number of medical visits usually decreases significantly, though patients may occasionally need to return to the center to have their stimulator checked. Also, the battery for the pulse generator must be surgically replaced every three to five years, though externally rechargeable batteries may eventually become available. Long-term results of DBS are still being determined. DBS does not stop PD from progressing, and some problems may gradually return. However, studies up to several years after surgery have shown that many people's symptoms remain significantly better than they were before DBS.
DBS is not a good solution for everyone. It is generally used only in people with advanced, levodopa-responsive PD who have developed dyskinesias or other disabling "off" symptoms despite drug therapy. It is not normally used in people with memory problems, hallucinations, a poor response to levodopa, severe depression, or poor health. DBS generally does not help people with "atypical" parkinsonian syndromes such as multiple system atrophy, progressive supranuclear palsy, or post-traumatic parkinsonism. Younger people generally do better than older people after DBS, but healthy older people can undergo DBS and they may benefit a great deal.
As with any brain surgery, DBS has potential complications, including stroke or brain hemorrhage. These complications are rare, however. There is also a risk of infection, which may require antibiotics or even replacement of parts of the DBS system. The stimulator may sometimes cause speech problems, balance problems, or even dyskinesias. However, those problems are often reversible if the stimulation is modified.
Researchers are continuing to study DBS and to develop ways of improving it. They are conducting clinical studies to determine the best part of the brain to receive stimulation and to determine the long-term effects of this therapy. They also are working to improve the technology used in DBS.
A wide variety of complementary and supportive therapies may be used for PD. Among these therapies are standard physical, occupational, and speech therapy techniques, which can help with such problems as gait and voice disorders, tremors and rigidity, and cognitive decline. Other types of supportive therapies include the following:
Diet. At this time there are no specific vitamins, minerals, or other nutrients that have any proven therapeutic value in PD. Some early reports have suggested that dietary supplements might be protective in PD. In addition, a phase II clinical trial of a supplement called coenzyme Q10 suggested that large doses of this substance might slow disease progression in patients with early-stage PD. The NINDS and other components of the National Institutes of Health are funding research to determine if caffeine, antioxidants, and other dietary factors may be beneficial for preventing or treating PD. While there is currently no proof that any specific dietary factor is beneficial, a normal, healthy diet can promote overall well-being for PD patients just as it would for anyone else. Eating a fiber-rich diet and drinking plenty of fluids also can help alleviate constipation. A high protein diet, however, may limit levodopa's effectiveness.
Exercise. Exercise can help people with PD improve their mobility and flexibility. Some doctors prescribe physical therapy or muscle-strengthening exercises to tone muscles and to put underused and rigid muscles through a full range of motion. Exercises will not stop disease progression, but they may improve body strength so that the person is less disabled. Exercises also improve balance, helping people minimize gait problems, and can strengthen certain muscles so that people can speak and swallow better. Exercise can also improve the emotional well-being of people with PD, and it may improve the brain's dopamine synthesis or increase levels of beneficial compounds called neurotrophic factors in the brain. Although structured exercise programs help many patients, more general physical activity, such as walking, gardening, swimming, calisthenics, and using exercise machines, also is beneficial. People with PD should always check with their doctors before beginning a new exercise program.
Other complementary therapies that are used by some individuals with PD include massage therapy, yoga, tai chi, hypnosis, acupuncture, and the Alexander technique, which optimizes posture and muscle activity. There have been limited studies suggesting mild benefits with some of these therapies, but they do not slow PD and there is no convincing evidence that they are beneficial.
While PD usually progresses slowly, eventually the most basic daily routines may be affected — from socializing with friends and enjoying normal relationships with family members to earning a living and taking care of a home. These changes can be difficult to accept. Support groups can help people cope with the disease emotionally. These groups can also provide valuable information, advice, and experience to help people with PD, their families, and their caregivers deal with a wide range of issues, including locating doctors familiar with the disease and coping with physical limitations. A list of national organizations that can help patients locate support groups in their communities appears at the end of this brochure. Individual or family counseling also may help people find ways to cope with PD.
People with PD also can benefit from being proactive and finding out as much as possible about the disease in order to alleviate fear of the unknown and to take a positive role in maintaining their health. Many people with PD continue to work either full- or part-time, although eventually they may need to adjust their schedule and working environment to cope with the disease.
In most cases, there is no way to predict or prevent sporadic PD. However, researchers are looking for a biomarker — a biochemical abnormality that all patients with PD might share — that could be picked up by screening techniques or by a simple chemical test given to people who do not have any parkinsonian symptoms. This could help doctors identify people at risk of the disease. It also might allow them to find treatments that will stop the disease process in the early stages.
Positron emission tomography (PET) scanning may lead to important advances in our knowledge about PD. PET scans of the brain produce pictures of chemical changes as they occur. Using PET, research scientists can study the brain's dopamine receptors (the sites on nerve cells that bind with dopamine) to determine if the loss of dopamine activity follows or precedes degeneration of the neurons that make this chemical. This information could help scientists better understand the disease process and may potentially lead to improved treatments.
In rare cases, where people have a clearly inherited form of PD, researchers can test for known gene mutations as a way of determining an individual's risk of the disease. However, this genetic testing can have far-reaching implications and people should carefully consider whether they want to know the results of such tests. Genetic testing is currently available only as a part of research studies.
In recent years, Parkinson's research has advanced to the point that halting the progression of PD, restoring lost function, and even preventing the disease are all considered realistic goals. While the ultimate goal of preventing PD may take years to achieve, researchers are making great progress in understanding and treating PD.
One of the most exciting areas of PD research is genetics. Studying the genes responsible for inherited cases can help researchers understand both inherited and sporadic cases of the disease. Identifying gene defects can also help researchers understand how PD occurs, develop animal models that accurately mimic the neuronal death in human PD, identify new drug targets, and improve diagnosis.
As discussed in the “What Genes are Linked to Parkinson's Disease?" section, several genes have been definitively linked to PD in some people. Researchers also have identified a number of other genes that may play a role and are working to confirm these findings. In addition, several chromosomal regions have been linked to PD in some families. Researchers hope to identify the genes located in these chromosomal regions and to determine which of them may play roles in PD.
Researchers funded by NINDS are gathering information and DNA samples from hundreds of families with PD and are conducting large-scale gene expression studies to identify genes that are abnormally active or inactive in PD. They also are comparing gene activity in PD with gene activity in similar diseases such as progressive supranuclear palsy.
Some scientists have found evidence that specific variations in the DNA of mitochondria – structures in cells that provide the energy for cellular activity — can increase the risk of getting PD, while other variations are associated with a lowered risk of the disorder. They also have found that PD patients have more mitochondrial DNA (mtDNA) variations than patients with other movement disorders or Alzheimer's disease. Researchers are working to define how these mtDNA variations may lead to PD.
In addition to identifying new genes for PD, researchers are trying to learn how known PD genes function and how the gene mutations cause disease. For example, a 2005 study found that the normal alpha-synuclein protein may help other proteins that are important for nerve transmission to fold correctly. Other studies have suggested that the normal parkin protein protects neurons from a variety of threats, including alpha-synuclein toxicity and excitotoxicity.
Scientists continue to study environmental toxins such as pesticides and herbicides that can cause PD symptoms in animals. They have found that exposing rodents to the pesticide rotenone and several other agricultural chemicals can cause cellular and behavioral changes that mimic those seen in PD. Other studies have suggested that prenatal exposure to certain toxins can increase susceptibility to PD in adulthood. An NIH-sponsored program called the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER) focuses on how occupational exposure to toxins and use of caffeine and other substances may affect the risk of PD.
Another major area of PD research involves the cell's protein disposal system, called the ubiquitin-proteasome system. If this disposal system fails to work correctly, toxins and other substances may build up to harmful levels, leading to cell death. The ubiquitin-proteasome system requires interactions between several proteins, including parkin and UCH-L1. Therefore, disruption of the ubiquitin-proteasome system may partially explain how mutations in these genes cause PD.
Other studies focus on how Lewy bodies form and what role they play in PD. Some studies suggest that Lewy bodies are a byproduct of degenerative processes within neurons, while others indicate that Lewy bodies are a protective mechanism by which neurons lock away abnormal molecules that might otherwise be harmful. Additional studies have found that alpha-synuclein clumps alter gene expression and bind to vesicles within the cell in ways that could be harmful.
Another common topic of PD research is excitotoxicity – overstimulation of nerve cells that leads to cell damage or death. In excitotoxicity, the brain becomes oversensitized to the neurotransmitter glutamate, which increases activity in the brain. The dopamine deficiency in PD causes overactivity of neurons in the subthalamic nucleus, which may lead to excitotoxic damage there and in other parts of the brain. Researchers also have found that dysfunction of the cells' mitochondria can make dopamine-producing neurons vulnerable to glutamate.
Other researchers are focusing on how inflammation may affect PD. Inflammation is common to a variety of neurodegenerative diseases, including PD, Alzheimer's disease, HIV-1-associated dementia, and amyotrophic lateral sclerosis. Several studies have shown that inflammation-promoting molecules increase cell death after treatment with the toxin MPTP. Inhibiting the inflammation with drugs or by genetic engineering prevented some of the neuronal degeneration in these studies. Other research has shown that dopamine neurons in brains from patients with PD have higher levels of an inflammatory enzyme called COX-2 than those of people without PD. Inhibiting COX-2 doubled the number of neurons that survived in a mouse model for PD.
Since the discovery that MPTP causes parkinsonian symptoms in humans, scientists have found that by injecting MPTP and certain other toxins into laboratory animals, they can reproduce the brain lesions that cause these symptoms. This allows them to study the mechanisms of the disease and helps in the development of new treatments. They also have developed animal models with alterations of the alpha-synuclein and parkin genes. Other researchers have used genetic engineering to develop mice with disrupted mitochondrial function in dopamine neurons. These animals have many of the characteristics associated with PD.
Biomarkers for PD – measurable characteristics that can reveal whether the disease is developing or progressing – are another focus of research. Such biomarkers could help doctors detect the disease before symptoms appear and improve diagnosis of the disease. They also would show if medications and other types of therapy have a positive or negative effect on the course of the disease. Some of the most promising biomarkers for PD are brain imaging techniques. For example, some researchers are using positron emission tomography (PET) brain scans to try to identify metabolic changes in the brains of people with PD and to determine how these changes relate to disease symptoms. Other potential biomarkers for PD include alterations in gene expression.
Researchers also are conducting many studies of new or improved therapies for PD. While deep brain stimulation (DBS) is now FDA-approved and has been used in thousands of people with PD, researchers continue to try to improve the technology and surgical techniques in this therapy. For example, some studies are comparing DBS to the best medical therapy and trying to determine which part of the brain is the best location for stimulation. Another clinical trial is studying how DBS affects depression and quality of life.
Other clinical studies are testing whether transcranial electrical polarization (TEP) or transcranial magnetic stimulation (TMS) can reduce the symptoms of PD. In TEP, electrodes placed on the scalp are used to generate an electrical current that modifies signals in the brain's cortex. In TMS, an insulated coil of wire on the scalp is used to generate a brief electrical current.
One of the enduring questions in PD research has been how treatment with levodopa and other dopaminergic drugs affects progression of the disease. Researchers are continuing to try to clarify these effects. One study has suggested that PD patients with a low-activity variant of the gene for COMT (which breaks down dopamine) perform worse than others on tests of cognition, and that dopaminergic drugs may worsen cognition in these people, perhaps because the reduced COMT activity causes dopamine to build up to harmful levels in some parts of the brain. In the future, it may become possible to test for such individual gene differences in order to improve treatment of PD.
A variety of new drug treatments are in clinical trials for PD. These include a drug called GM1 ganglioside that increases dopamine levels in the brain. Researchers are testing whether this drug can reduce symptoms, delay disease progression, or partially restore damaged brain cells in PD patients. Other studies are testing whether a drug called istradefylline can improve motor function in PD, and whether a drug called ACP-103 that blocks receptors for the neurotransmitter serotonin will lessen the severity of parkinsonian symptoms and levodopa-associated complications in PD patients. Other topics of research include controlled-release formulas of PD drugs and implantable pumps that give a continuous supply of levodopa.
Some researchers are testing potential neuroprotective drugs to see if they can slow the progression of PD. One study, called NET-PD (Neuroexploratory Trials in Parkinson's Disease), is evaluating minocycline, creatine, coenzyme Q10, and GPI-1485 to determine if any of these agents should be considered for further testing. The NET-PD study may evaluate other possible neuroprotective agents in the future. Drugs found to be successful in the pilot phases may move to large phase III trials involving hundreds of patients. A separate group of researchers is investigating the effects of either 1200 or 2400 milligrams of coenzyme Q10 in 600 patients. Several MAO-B inhibitors, including selegiline, lazabemide, and rasagiline, also are in clinical trials to determine if they have neuroprotective effects in people with PD.
Nerve growth factors, or neurotrophic factors, which support survival, growth, and development of brain cells, are another type of potential therapy for PD. One such drug, glial cell line-derived neurotrophic factor (GDNF), has been shown to protect dopamine neurons and to promote their survival in animal models of PD. This drug has been tested in several clinical trials for people with PD, and the drug appeared to cause regrowth of dopamine nerve fibers in one person who received the drug. However, a phase II clinical study of GDNF was halted in 2004 because the treatment did not show any clinical benefit after 6 months, and some data suggested that it might even be harmful. Other neurotrophins that may be useful for treating PD include neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2).
While there is currently no proof that any dietary supplements can slow PD, several clinical studies are testing whether supplementation with vitamin B12 and other substances may be helpful. A 2005 study found that dietary restriction — reducing the number of calories normally consumed – helped to increase abnormally low levels of the neurotransmitter glutamate in a mouse model for early PD. The study also suggested that dietary restriction affected dopamine activity in the brain. Another study showed that dietary restriction before the onset of PD in a mouse model helped to protect dopamine-producing neurons.
Other studies are looking at treatments that might improve some of the secondary symptoms of PD, such as depression and swallowing disorders. One clinical trial is investigating whether a drug called quetiapine can reduce psychosis or agitation in PD patients with dementia and in dementia patients with parkinsonian symptoms. Some studies also are examining whether transcranial magnetic stimulation or a food supplement called s-adenosyl-methionine (SAM-e) can alleviate depression in people with PD, and whether levetiracetam, a drug approved to treat epilepsy, can reduce dyskinesias in Parkinson's patients without interfering with other PD drugs.
Another approach to treating PD is to implant cells to replace those lost in the disease. Researchers are conducting clinical trials of a cell therapy in which human retinal epithelial cells attached to microscopic gelatin beads are implanted into the brains of people with advanced PD. The retinal epithelial cells produce levodopa. The investigators hope that this therapy will enhance brain levels of dopamine.
Starting in the 1990s, researchers conducted a controlled clinical trial of fetal tissue implants in people with PD. They attempted to replace lost dopamine-producing neurons with healthy ones from fetal tissue in order to improve movement and the response to medications. While many of the implanted cells survived in the brain and produced dopamine, this therapy was associated with only modest functional improvements, mostly in patients under the age of 60. Unfortunately, some of the people who received the transplants developed disabling dyskinesias that could not be relieved by reducing antiparkinsonian medications.
Another type of cell therapy involves stem cells. Stem cells derived from embryos can develop into any kind of cell in the body, while others, called progenitor cells, are more restricted. One study transplanted neural progenitor cells derived from human embryonic stem cells into a rat model of PD. The cells appeared to trigger improvement on several behavioral tests, although relatively few of the transplanted cells became dopamine-producing neurons. Other researchers are developing methods to improve the number of dopamine-producing cells that can be grown from embryonic stem cells in culture.
Researchers also are exploring whether stem cells from adult brains might be useful in treating PD. They have shown that the brain's white matter contains multipotent progenitor cells that can multiply and form all the major cell types of the brain, including neurons.
Gene therapy is yet another approach to treating PD. A study of gene therapy in non-human primate models of PD is testing different genes and gene-delivery techniques in an effort to refine this kind of treatment. An early-phase clinical study is also testing whether using the adeno-associated virus type 2 (AAV2) to deliver the gene for a nerve growth factor called neurturin is safe for use in people with PD. Another study is testing the safety of gene therapy using AAV to deliver a gene for human aromatic L-amino acid decarboxylase, an enzyme that helps convert levodopa to dopamine in the brain. Other investigators are testing whether gene therapy to increase the amount of glutamic acid decarboxylase, which helps produce an inhibitory neurotransmitter called GABA, might reduce the overactivity of neurons in the brain that results from lack of dopamine.
Another potential approach to treating PD is to use a vaccine to modify the immune system in a way that can protect dopamine-producing neurons. One vaccine study in mice used a drug called copolymer-1 that increases the number of immune T cells that secrete anti-inflammatory cytokines and growth factors. The researchers injected copolymer-1-treated immune cells into a mouse model for PD. The vaccine modified the behavior of supporting (glial) cells in the brain so that their responses were beneficial rather than harmful. It also reduced the amount of neurodegeneration in the mice, reduced inflammation, and increased production of nerve growth factors. Another study delivered a vaccine containing alpha-synuclein in a mouse model of PD and showed that the mice developed antibodies that reduced the accumulation of abnormal alpha-synuclein. While these studies are preliminary, investigators hope that similar approaches might one day be tested in humans.
As a world leader in research on neurological disorders, including PD, the NINDS supports a wide range of basic laboratory
studies and clinical trials at its
The NINDS also supports 11 Morris K. Udall Parkinson’s Disease Research Centers of Excellence throughout the country. The Centers’ multidisciplinary research environment allows scientists to take advantage of new discoveries in the basic and technological sciences that could lead to clinical advances. Most of the Centers also provide state-of-the-art training for young scientists preparing for research careers investigating PD and related neurological disorders. Among other topics, the Centers carry out studies of genes, of proteins involved in cell death and degeneration, and of the brain chemicals involved in PD. They also study the brain using PET brain scans and test potential PD treatments in animals. The NINDS hopes that research at these Centers of Excellence will lead to clinical trials of new therapies in humans with PD.
The NINDS and the National Institute of Mental Health jointly support two national brain specimen banks. These banks supply research scientists around the world with nervous system tissue from patients with neurological and psychiatric disorders. They need tissue from patients with PD so that scientists can study and understand the disorder. Those who may be interested in donating should contact:
Rashed M. Nagra, Ph.D., Director
Human Brain and Spinal Fluid Resource Center
Neurology Research (127A) W. Los Angeles Healthcare Center
11301 Wilshire Boulevard, Building 212
Los Angeles, CA 90073
Francine M. Benes, M.D., Ph.D., Director
Harvard Brain Tissue Resource Center
115 Mill Street
Belmont, MA 02478
800-BRAIN BANK (272-4622)
Two other organizations also provide research scientists with nervous system tissue from patients with neurological disorders. Interested donors should write or call:
National Disease Research Interchange
1628 JFK Boulevard
8 Penn Center, 8th floor
UM/NPF Brain Endowment Bank
University of Miami Dept. of Neurology
1501 N.W. 9th Avenue, Room 4013 (D 4-5)
Miami, FL 33136
The Mohammed Ali Parkinson Center at the Barrow Neurological Institute in Phoenix, Arizona, has developed a national registry of people with PD in order to help in the development of new therapies and to allow researchers to quickly identify and notify people about research studies for which they are eligible. Anyone diagnosed with PD is eligible to take part in this registry. For more information, contact:
Some states, including California and Nebraska, also have registries of people with PD.
People with PD who wish to help with research on this disorder may be able to do so by participating in clinical studies designed to learn more about the disease or to test potential new therapies. Information about many such studies is available free of charge from the Federal government's database of clinical trials, clinicaltrials.gov.
A good source for finding clinical trials specifically on PD is the www.PDtrials.org web site, which lists studies sponsored by the National Institutes of Health and other federal agencies, as well as private industry and institutions at locations across the United States. This resource is sponsored by the Parkinson’s Disease Foundation in collaboration with the American Parkinson Disease Association, the Parkinson’s Action Network, the Parkinson Alliance, the Michael J. Fox Foundation for Parkinson’s Research, the National Parkinson Foundation, WE MOVE, and the NINDS.
For clinical trials taking place at the National Institutes of Health, additional information is available from the following office:
Patient Recruitment and Public Liaison Office
National Institutes of Health
Building 61, 10 Cloister Court
Bethesda, Maryland 20892-4754
TTY: 301-594-9774 (local), 866-411-1010 (toll free)
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:
P.O. Box 5801
Bethesda, MD 20824
Information also is available from the following organizations:
|American Parkinson Disease Association
135 Parkinson Avenue
Staten Island, NY 10305-1425
Tel: 718-981-8001 800-223-2732 Calif: 800-908-2732
Dedicated to funding Parkinson's disease research. Offers comprehensive medical information and extensive public/professional education and support services.
|National Parkinson Foundation
1501 N.W. 9th Avenue
Bob Hope Road
Miami, FL 33136-1494
Tel: 305-243-6666 800-327-4545
Provides research, patient services, clinical studies, public and professional education, and physician referrals at over 60 locations and through a nationwide network of chapters and support groups.
P.O. Box 308
Kingston, NJ 08528-0308
Tel: 609-688-0870 800-579-8440
Raises and distributes money for the most promising research leading to a cure for Parkinson's disease. Partners with the Tuchman Foundation to ensure that every dollar donated by individuals and all net proceeds of events go directly to research. The Alliance is also devoted to improving quality of life within the DBS-STN community through an affiliated resource, www.DBS-STN.org.
|Michael J. Fox Foundation
for Parkinson's Research
Grand Central Station
P.O. Box 4777
New York, NY 10163
Dedicated to advancing a cure for Parkinson’s disease by identifying promising research and raising funds for research support.
|Parkinson's Action Network (PAN)
1025 Vermont Ave., NW
Washington, DC 20005
Tel: 800-850-4726 202-638-4101
Non-profit education and advocacy organization that serves as a voice for the Parkinson's community by fighting for promising research that will produce effective treatments and a cure.
|Parkinson's Disease Foundation (PDF)
New York, NY 10018
Tel: 212-923-4700 800-457-6676
National nonprofit organization that supports Parkinson's disease research, education, and public advocacy programs.
1170 Morse Avenue
Sunnyvale, CA 94089-1605
Tel: 408-734-2800 800-786-2958
Non-profit organization conducting patient care and research activities in the neurological specialty area of movement disorders.
|Parkinson's Resource Organization
74-090 El Paseo Drive
Palm Desert, CA 92260-4135
Tel: 760-773-5628 877-775-4111 877-775-4111
Helps families affected by Parkinson’s by offering emotional and educational support programs, publishing a monthly newsletter about quality of life and family issues, providing information and referral services, promoting advocacy and public awareness, and providing respite for family caregivers.
|WE MOVE (Worldwide Education & Awareness for Movement Disorders)
204 West 84th Street
New York, NY 10024
WE MOVE provides movement disorder information and educational materials to physicians, patients, the media, and the public.
|Bachmann-Strauss Dystonia & Parkinson Foundation
Mt. Sinai Medical Center One Gustave L. Levy Place
P.O. Box 1490
New York, NY 10029
Non-profit foundation that supports patients, family members, researchers, clinicians, and volunteers working in partnership to find better medical treatments and a cure for dystonia and Parkinson's disease.
NIH Publication No. 06-139
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.
All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.
Last updated January 29, 2009