- What is Parkinson's Disease?
- What Causes Parkinson's Disease?
- What Genes are Linked to Parkinson's Disease?
- Who Gets Parkinson's Disease?
- What are the Symptoms of the Parkinson's Disease?
- What Other Diseases Resemble Parkinson's?
- How is Parkinson's Disease Diagnosed?
- What is the Prognosis for Parkinson's Disease?
- How is the Parkinson's Disease Treated?
- Drug Treatments
- Complementary and Supportive Therapies
- How Can People Cope with Parkinson's Disease?
- Can Scientists Predict or Prevent Parkinson's Disease?
- What Research is Being Done on Parkinson's Disease?
- What is the Role of the NINDS?
- What Can I Do to Help?
- Where Can I Get More Information on Parkinson's Disease?
Parkinson's disease (PD) is a degenerative disorder of the central nervous system. It was first described in 1817 by James Parkinson, a British physician who published a paper on what he called "the shaking palsy." In this paper, he set forth the major symptoms of the disease that would later bear his name.
Researchers believe that at least 500,000 people in the United States currently have Parkinson's disease, although some estimates are much higher. Society pays an enormous price for Parkinson's disease. The total cost to the nation is estimated to exceed $6 billion annually. The risk of Parkinson's disease increases with age, so analysts expect the financial and public health impact of this disease to increase as the population gets older.
What is Parkinson's Disease?
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 Parkinson's disease, as the symptoms sometimes appear in other diseases as well.
Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease results from a combination of genetic susceptibility and exposure to one or more environmental factors that trigger the disease.
Parkinson's disease is the most common form of parkinsonism, the name for a group of disorders with similar features and symptoms. Parkinson's disease is also called primary parkinsonism or idiopathic Parkinson's disease. 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.
What Causes Parkinson's Disease?
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 Parkinson's disease 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 Parkinson's disease, including fatigue and abnormalities of blood pressure regulation.
Many brain cells of people with Parkinson's disease 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 Parkinson's disease, and many more genes have been tentatively linked to the disorder. Studying the genes responsible for inherited cases of Parkinson's disease 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 Parkinson's disease.
Although the importance of genetics in Parkinson's disease 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 Parkinson's disease in genetically susceptible individuals.
Viruses are another possible environmental trigger for Parkinson's disease. 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 Parkinson's disease. 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 Parkinson's disease patients.
Other research suggests that the cell's protein disposal system may fail in people with Parkinson's disease, 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 Parkinson's disease 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 Parkinson's disease, the actual cause of the dopamine cell death is still undetermined.
What Genes are Linked to Parkinson's Disease?
Several genes have now been definitively linked to Parkinson's disease. The first to be identified was alpha-synuclein. In the 1990s, researchers at NIH and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial Parkinson's disease and found that their disease was related to a mutation in this gene. They found a second alpha-synuclein mutation in a German family with Parkinson's disease. These findings prompted studies of the role of alpha-synuclein in Parkinson's disease, which led to the discovery that Lewy bodies from people with the sporadic form of Parkinson's disease contained clumps of alpha-synuclein protein. This discovery revealed a potential link between hereditary and sporadic forms of the disease.
In 2003, researchers studying inherited Parkinson's disease 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 Parkinson's disease, just as the abnormal form does.
Other genes linked to Parkinson's disease include parkin, DJ-1, PINK1, and LRRK2. Parkin, DJ-1, and PINK-1 cause rare, early-onset forms of Parkinson's disease. 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 Parkinson's disease. Subsequent studies have identified this gene in other families with Parkinson's disease as well as in a small percentage of people with apparently sporadic Parkinson's disease.
Researchers are continuing to investigate the normal functions and interactions of these genes in order to find clues about how Parkinson's disease develops. They also have identified a number of other genes and chromosome regions that may play a role in Parkinson's disease, but the nature of these links is not yet clear.
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Who Gets Parkinson's Disease?
About 50,000 Americans are diagnosed with Parkinson's disease 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 Parkinson's disease and there is no definitive test for the disease. People with Parkinson's disease may sometimes be told by their doctors that they have other disorders, and people with Parkinson's disease-like diseases may be incorrectly diagnosed as having Parkinson's disease.
Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Japan but has been found in other countries as well. It usually begins with dystonia and bradykinesia, and the symptoms often improve with levodopa medication. Juvenile parkinsonism often runs in families and is sometimes linked to a mutated parkin gene.
What are the Symptoms of Parkinson's Disease?
Early symptoms of Parkinson's disease 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 Parkinson's disease. 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 Parkinson's disease 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).
Parkinson's disease 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.
Parkinson's disease 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 Parkinson's disease are:
- Tremor. The tremor associated with
Parkinson's disease has a
characteristic appearance. Typically, the tremor takes the form of a rhythmic
back-and-forth motion at a rate of 4-6 beats per second. It may involve the
thumb and forefinger and appear as a "pill rolling" tremor. Tremor often begins
in a hand, although sometimes a foot or the jaw is affected first. It is most
obvious when the hand is at rest or when a person is under stress. For example,
the shaking may become more pronounced a few seconds after the hands are rested
on a table. Tremor usually disappears during
sleep or improves with intentional movement.
- Rigidity. Rigidity, or a resistance to movement,
affects most people with Parkinson's disease. A major principle of body movement is that all
muscles have an opposing muscle. Movement is possible not just because one muscle becomes more active,
but because the opposing muscle relaxes. In Parkinson's disease, rigidity comes about when, in
response to signals from the brain, the delicate balance of opposing muscles is
disturbed. The muscles remain constantly tensed and contracted so that the
person aches or feels stiff or weak. The rigidity becomes obvious when another
person tries to move the patient's arm, which will move only in ratchet-like or
short, jerky movements known as "cogwheel" rigidity.
- Bradykinesia. Bradykinesia, or the slowing down and loss of spontaneous and
automatic movement, is particularly frustrating because it may make simple tasks
somewhat difficult. The person cannot rapidly perform routine movements.
Activities once performed quickly and easily — such as washing or dressing — may
take several hours.
- Postural instability. Postural instability, or impaired balance, causes patients to fall easily. Affected people also may develop a stooped posture in which the head is bowed and the shoulders are drooped.
A number of other symptoms may accompany Parkinson's disease. 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.
- Depression. This is a common problem and may appear
early in the course of the disease, even before other symptoms are noticed.
Fortunately, depression usually can be successfully treated with antidepressant
- Emotional changes. Some people with Parkinson's disease become fearful and insecure. Perhaps
they fear they cannot cope with new situations. They may not want to travel, go
to parties, or socialize with friends. Some lose their motivation and become
dependent on family members. Others may become irritable or uncharacteristically
- Difficulty with swallowing and chewing. Muscles used
in swallowing may work less efficiently in later stages of the disease. In these
cases, food and saliva may collect in the mouth and back of the throat, which can result in
choking or drooling.
These problems also may make it difficult to get adequate
Speech-language therapists, occupational therapists, and dieticians can often
help with these problems.
- Speech changes. About half of all Parkinson's disease patients have problems with speech.
They may speak too softly or in a monotone, hesitate before speaking, slur or
repeat their words, or speak too fast. A
speech therapist may be able to help
patients reduce some of these problems.
- Urinary problems or constipation. In some patients,
bladder and bowel
problems can occur due to the improper functioning of the autonomic nervous
system, which is responsible for regulating
smooth muscle activity. Some people
may become incontinent, while others have trouble urinating. In others,
constipation may occur because the intestinal tract operates more slowly.
Constipation can also be caused by inactivity, eating a poor diet, or drinking
too little fluid. The medications used to treat Parkinson's disease also can contribute to
constipation. It can be a persistent problem and, in rare cases, can be serious
enough to require hospitalization.
- Skin problems. In Parkinson's disease, it is common for the skin on the
face to become very oily, particularly on the forehead and at the sides of the
nose. The scalp may become oily too, resulting in
dandruff. In other cases, the skin can become very
dry. These problems are also the result of an improperly functioning autonomic
nervous system. Standard treatments for skin problems can help. Excessive
sweating, another common symptom, is usually controllable with medications used
for Parkinson's disease.
- Sleep problems.
Sleep problems common in
Parkinson's disease include difficulty staying
asleep at night, restless sleep, nightmares and emotional dreams, and drowsiness
or sudden sleep onset during the day. Patients with Parkinson's disease should never take
over-the-counter sleep aids without consulting their physicians.
- Dementia or other cognitive problems. Some, but not
all, people with Parkinson's disease may develop memory problems and slow thinking. In some of these cases, cognitive
problems become more severe, leading to a condition called Parkinson's
late in the course of the disease. This dementia may affect memory, social
judgment, language, reasoning, or other mental skills. There is currently no way
to halt Parkinson's disease dementia, but studies have shown that a drug called
slightly reduce the symptoms. The drug
Aricept ODT) also can reduce behavioral
symptoms in some people with Parkinson's disease-related dementia.
- Orthostatic hypotension.
Orthostatic hypotension is a
sudden drop in blood pressure when
a person stands up from a lying-down position. This may cause
lightheadedness, and, in extreme cases, loss of balance or
Studies have suggested that, in Parkinson's disease, this problem results from a loss of nerve
endings in the sympathetic nervous system that controls
heart rate, blood
pressure, and other automatic functions in the body. The medications used to
treat Parkinson's disease also may contribute to this symptom.
- Muscle cramps and
dystonia. The rigidity and lack of normal movement
associated with Parkinson's disease often causes
muscle cramps, especially in the legs and toes.
Massage, stretching, and applying heat may help with these cramps. Parkinson's
disease also can
be associated with dystonia — sustained muscle contractions that cause forced or
twisted positions. Dystonia in Parkinson's disease is often caused by fluctuations in the body's
level of dopamine. It can usually be relieved or reduced by adjusting the
- Pain. Many people with Parkinson's disease develop aching muscles and
joints because of the rigidity and abnormal postures often associated with the
disease. Treatment with levodopa
(Sinemet) and other dopaminergic drugs often alleviates
these pains to some extent. Certain exercises also may help. People with
Parkinson's disease also
may develop pain due to compression of nerve roots or dystonia-related muscle spasms. In rare
cases, people with Parkinson's disease may develop unexplained burning, stabbing sensations. This
type of pain, called "central pain," originates in the brain. Dopaminergic
drugs, opiates, antidepressants, and other types of drugs may all be used to
treat this type of pain.
- Fatigue and loss of energy. The unusual demands of
living with Parkinson's disease often lead to problems with fatigue, especially late in the day.
Fatigue may be associated with depression or sleep disorders, but it also may result from
muscle stress or from overdoing activity when the person feels well. Fatigue
also may result from akinesia – trouble initiating or carrying out movement.
Exercise, good sleep habits, staying mentally active, and not forcing too many
activities in a short time may help to alleviate fatigue.
- Sexual dysfunction. Parkinson's disease often causes erectile dysfunction because of its effects on nerve signals from the brain or because of poor blood circulation. Parkinson's disease-related depression or use of antidepressant medication also may cause decreased sex drive and other problems. These problems are often treatable.
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What Other Diseases Resemble Parkinson's?
A number of disorders can cause symptoms similar to those of Parkinson's disease. People with symptoms that resemble Parkinson's disease but that result from other causes are sometimes said to have parkinsonism. Some of these disorders are listed below.
- Postencephalitic parkinsonism. Just after the first
World War, a viral disease, encephalitis lethargica, attacked almost 5 million people throughout
the world, and then suddenly disappeared in the 1920s. Known as sleeping
sickness in the United States, this disease killed one third of its victims and
led to post-encephalitic parkinsonism in many others. This resulted in a
particularly severe form of movement disorder that appeared sometimes years
after the initial illness. (In 1973,
neurologist Oliver Sacks published
Awakenings, an account of his work in the late 1960s with surviving
post-encephalitic patients in a New York hospital. Using the then-experimental
drug levodopa, Dr. Sacks was able to temporarily "awaken" these patients from
their statue-like state). In rare cases, other viral infections, including
western equine encephalomyelitis, eastern equine encephalomyelitis, and Japanese
B encephalitis, have caused parkinsonian symptoms.
- Drug-induced parkinsonism. A reversible form of
parkinsonism sometimes results from use of certain drugs, such as chlorpromazine
and haloperidol (Haldol),
which are prescribed for patients with psychiatric disorders. Some drugs
used for stomach disorders [metoclopramide
(Reglan, Octamide, Maxolon)], high blood pressure
(Harmonyl)], and epilepsy (valproate) may also produce parkinsonian symptoms. Stopping the
medication or lowering the dosage of these medications usually causes the
symptoms to go away.
- Toxin-induced parkinsonism. Some toxins — such as
manganese dust, carbon disulfide, and carbon monoxide — can cause parkinsonism.
The chemical MPTP also causes a permanent form of parkinsonism that closely
resembles Parkinson's disease. Investigators discovered this reaction in the 1980s when heroin
addicts in California who had taken an illicit street drug contaminated with
MPTP began to develop severe parkinsonism. This discovery, which showed that a
toxic substance could damage
the brain and produce parkinsonian symptoms, caused a dramatic breakthrough in
Parkinson's research: for the first time, scientists were able to simulate
Parkinson's disease in
animals and conduct studies to increase understanding of the disease.
- Arteriosclerotic parkinsonism. Sometimes known as
pseudoparkinsonism, vascular parkinsonism, or atherosclerotic parkinsonism, arteriosclerotic
parkinsonism involves damage to the brain due to multiple small
is rare in this type of parkinsonism, while dementia — the loss of mental skills
and abilities — is common. Antiparkinsonian drugs are of little help to patients
with this form of parkinsonism.
- Parkinsonism-dementia complex of Guam. This disease occurs among the Chamorro populations of Guam and the Mariana Islands and may be accompanied by a
motor neuron disease resembling
amyotrophic lateral sclerosis (Lou Gehrig's
disease). The course of the disease is rapid, with death typically occurring
within 5 years.
- Post-traumatic parkinsonism. Also known as
post-traumatic encephalopathy or "punch-drunk syndrome," parkinsonian symptoms
can sometimes develop after a severe head injury or frequent head trauma that results from boxing or other
activities. This type of trauma also can cause a form of dementia called
- Essential tremor. Essential tremor, sometimes called
tremor or familial tremor, is a common condition that tends to run in families
and progresses slowly over time. The tremor is usually equal in both hands and
increases when the hands are moving. The tremor may involve the head but usually
spares the legs. Patients with essential tremor have no other parkinsonian
features. Essential tremor is not the same as Parkinson's disease, and usually does not lead to
it, although in some cases the two conditions may overlap in one person.
Essential tremor does not respond to levodopa or most other Parkinson's disease drugs, but it can
be treated with other medications.
- Normal pressure hydrocephalus.
Normal pressure hydrocephalus (NPH) is an
abnormal increase of cerebrospinal fluid
(CSF) in the brain's ventricles, or cavities. It occurs if the normal flow of
CSF throughout the brain and spinal cord is blocked in some way. This causes the
ventricles to enlarge, putting pressure on the brain. Symptoms include problems
with walking, impaired bladder control leading to urinary frequency or
incontinence, and progressive mental
impairment and dementia. The person also may have a general slowing of movements
or may complain that his or her feet feel "stuck." These symptoms may sometimes
be mistaken for Parkinson's disease. Brain scans,
intracranial pressure monitoring, and other
tests can help to distinguish NPH from Parkinson's disease and other disorders. NPH can sometimes
be treated by surgically implanting a CSF
shunt that drains
excess cerebrospinal fluid into the abdomen, where it is absorbed.
- Progressive supranuclear palsy.
Progressive supranuclear palsy (PSP), sometimes called
Steele-Richardson-Olszewski syndrome, is a rare, progressive brain disorder that
causes problems with control of gait and balance. People often tend to fall
early in the course of PSP. One of the most obvious signs of the disease is an
inability to move the eyes properly. Some patients describe this effect as a
blurring. PSP patients often show alterations of mood and behavior, including
depression and apathy as well as mild dementia. The symptoms of PSP are caused
by a gradual deterioration of brain cells in the brainstem. It is often
misdiagnosed because some of its symptoms are very much like those of
Parkinson's disease, Alzheimer's disease, and other brain disorders. PSP symptoms usually do not
respond to medication.
- Corticobasal degeneration. Corticobasal degeneration results from
of multiple areas of the brain, including the
cerebral cortex and the basal
ganglia. Initial symptoms may first appear on one side of the body, but
eventually affect both sides. Symptoms are similar to those found in Parkinson's
including rigidity, impaired balance and coordination, and dystonia. Other
symptoms may include cognitive and visual-spatial impairments,
apraxia (loss of
the ability to make familiar, purposeful movements), hesitant and halting
speech, myoclonus (muscular
jerks), and dysphagia (difficulty swallowing).
Unlike Parkinson's disease, corticobasal degeneration usually does not respond to medication.
- Multiple system atrophy. Multiple system atrophy (MSA) refers to a set of slowly progressive
disorders that affect the central and autonomic nervous systems. MSA may have
symptoms that resemble Parkinson's disease. It also may take a form that primarily produces poor
coordination and slurred speech, or it may have a mixture of these symptoms.
Other symptoms may include breathing and swallowing difficulties, male
impotence, constipation, and urinary difficulties. The
disorder previously called Shy-Drager syndrome refers to MSA with prominent
orthostatic hypotension — a fall in blood pressure every time the person stands
up. MSA with parkinsonian symptoms is sometimes referred to as striatonigral
degeneration, while MSA with poor coordination and slurred speech is sometimes
called olivopontocerebellar atrophy.
- Dementia with Lewy bodies.
Dementia with Lewy bodies
is a neurodegenerative disorder associated with abnormal protein deposits (Lewy
bodies) found in certain areas of the brain. Symptoms can range from traditional
parkinsonian symptoms, such as bradykinesia, rigidity, tremor, and shuffling
gait, to symptoms similar to those of Alzheimer's disease. These symptoms may
fluctuate, or wax and wane dramatically. Visual hallucinations may be one of the
first symptoms, and patients may suffer from other psychiatric disturbances such
as delusions and depression. Cognitive problems also occur early in the course
of the disease. Levodopa and other antiparkinsonian medications can help with
the motor symptoms of dementia with Lewy bodies, but they may make hallucinations
and delusions worse.
- Parkinsonism accompanying other conditions. Parkinsonian symptoms may also appear in patients with other, clearly distinct neurological disorders such as Wilson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, and Creutzfeldt-Jakob disease. Each of these disorders has specific features that help to distinguish them from Parkinson's disease.
MSA, corticobasal degeneration, and progressive supranuclear palsy are sometimes referred to as "Parkinson's-plus" diseases because they have the symptoms of Parkinson's disease plus additional features.
How is Parkinson's Disease Diagnosed?
There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic Parkinson's disease. 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 Parkinson's disease 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 Parkinson's disease 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.
What is the Prognosis for Parkinson's disease?
Parkinson's disease is not by itself a fatal disease, but it does get worse with time. The average life expectancy of a Parkinson's disease patient is generally the same as for people who do not have the disease. However, in the late stages of the disease, Parkinson's disease may cause complications such as choking, pneumonia, and falls that can lead to death. Fortunately, there are many treatment options available for people with Parkinson's disease.
The progression of symptoms in Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease can live productive lives for many years after diagnosis.
How is the Parkinson's Disease Treated?
At present, there is no cure for Parkinson's disease. But medications or surgery can sometimes provide dramatic relief from the symptoms.
Medications for Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease-related depression may be prescribed antidepressants.
- Levodopa. The cornerstone of therapy for Parkinson's disease is the
drug levodopa (Sinemet) (also called L-dopa). Levodopa (from the full name
L-3,4-dihydroxyphenylalanine) is a simple chemical found naturally in plants and
animals. Levodopa is the generic name used for this chemical when it is
formulated for drug use in patients. Nerve cells can use levodopa to make
dopamine and replenish the brain's dwindling supply. People cannot simply take
dopamine pills because dopamine does not easily pass through the blood-brain
barrier, a lining of cells inside blood vessels that regulates the transport of
oxygen, glucose, and other substances
into the brain. Usually, patients are given levodopa combined with another
substance called carbidopa. When added to levodopa, carbidopa delays the
conversion of levodopa into dopamine until it reaches the brain, preventing or
diminishing some of the side effects that often accompany levodopa therapy.
Carbidopa also reduces the amount of levodopa needed.
Levodopa is very successful at reducing the tremors and other symptoms of Parkinson's disease during the early stages of the disease. It allows the majority of people with Parkinson's disease to extend the period of time in which they can lead relatively normal, productive lives.
Although levodopa helps most people with Parkinson's disease, 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 Parkinson's disease during the early stages of the disease. But levodopa is not a cure. Although it can reduce the symptoms of Parkinson's disease, 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease. These therapies include the following:
- Dopamine agonists. These drugs, which include
bromocriptine, apomorphine, pramipexole, and ropinirole, mimic the role of
dopamine in the brain. They can be given alone or in conjunction with levodopa.
They may be used in the early stages of the disease, or later on in order to
lengthen the duration of response to levodopa in patients who experience wearing
off or on-off effects. They are generally less effective than levodopa in
controlling rigidity and bradykinesia. Many of the potential side effects are
similar to those associated with the use of levodopa, including drowsiness,
sudden sleep onset, hallucinations,
edema (swelling due to excess fluid in body tissues),
nightmares, and vomiting. In rare cases, they can cause compulsive behavior,
such as an uncontrollable desire to gamble, hypersexuality, or compulsive
shopping. Bromocriptine can also cause fibrosis, or a buildup of fibrous tissue,
in the heart valves or the
chest cavity. Fibrosis usually goes away once the
drugs are stopped.
- MAO-B inhibitors. These drugs inhibit the enzyme
monoamine oxidase B, or MAO-B, which breaks down dopamine in the brain. MAO-B
inhibitors cause dopamine to accumulate in surviving nerve cells and reduce the
symptoms of Parkinson's disease. Selegiline, also called deprenyl, is an MAO-B inhibitor that is
commonly used to treat Parkinson's disease. Studies supported by the NINDS have shown that
selegiline can delay the need for levodopa therapy by up to a year or more. When
selegiline is given with levodopa, it appears to enhance and prolong the
response to levodopa and thus may reduce wearing-off fluctuations. Selegiline is
usually well-tolerated, although side effects may include nausea, orthostatic
hypotension, or insomnia. It should not be taken with the antidepressant
Serafem) or the sedative
meperidine, because combining selegiline with these
drugs can be harmful. An NINDS-sponsored study of selegiline in the late 1980s
suggested that it might help to slow the loss of nerve cells in Parkinson's
follow-up studies cast doubt on this finding. Another MAO-B inhibitor,
rasagiline, (Azilect) was approved by the FDA in May 2006 for use in treating
- COMT inhibitors. COMT stands for
another enzyme that helps to break down dopamine. Two COMT inhibitors are
approved to treat Parkinson's disease in the United States: entacapone and tolcapone. These drugs
prolong the effects of levodopa by preventing the breakdown of dopamine. COMT
inhibitors can decrease the duration of "off" periods, and they usually make it
possible to reduce the person's dose of levodopa. The most common side effect is
diarrhea. The drugs may also cause nausea, sleep disturbances, dizziness, urine
discoloration, abdominal pain, low blood pressure, or hallucinations. In a few
rare cases, tolcapone has caused severe
liver disease. Because
of this, patients taking tolcapone need regular monitoring of their liver
- Amantadine. An antiviral drug,
amantadine (Symmetrel), can help reduce symptoms of
and levodopa-induced dyskinesia. It is often used alone in the early stages of
the disease. It also may be used with an anticholinergic drug or levodopa. After
several months, amantadine's effectiveness wears off in up to half of the
patients taking it. Amantadine's side effects may include insomnia, mottled
skin, edema, agitation, or hallucinations. Researchers are not certain how
amantadine works in Parkinson's disease, but it may increase the effects of dopamine.
- Anticholinergics. These drugs, which include trihexyphenidyl, benztropine (Cogentin), and ethopropazine, decrease the activity of the neurotransmitter acetylcholine and help to reduce tremors and muscle rigidity. Only about half the patients who receive anticholinergics are helped by it, usually for a brief period and with only a 30 percent improvement. Side effects may include dry mouth, constipation, urinary retention, hallucinations, memory loss, blurred vision, and confusion.
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)
- Selegiline (deprenyl)
Drugs that inhibit dopamine breakdown (COMT inhibitors)
Drugs that decrease the action of acetylcholine anticholinergics)
Drugs with an unknown mechanism of action for Parkinson's disease
Medications for Non-Motor Symptoms. Doctors may prescribe a variety of medications to treat the non-motor symptoms of Parkinson's disease, such as depression and anxiety. For example, depression can be treated with standard anti-depressant drugs such as amitriptyline (Elavil, Endep) 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 Parkinson's disease. Therefore reducing or stopping Parkinson's disease medications may alleviate psychosis. If such measures are not effective, doctors sometimes prescribe drugs called atypical antipsychotics, which include clozapine (Clozaril) and quetiapine (Seroquel). 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 Parkinson's disease 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 Parkinson's disease for whom drug therapy is no longer sufficient.
Pallidotomy and Thalamotomy. The earliest types of surgery for Parkinson's disease 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 Parkinson's disease.
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 Parkinson's disease. DBS has now been approved by the U.S. Food and Drug Administration, and it is widely used as a treatment for Parkinson's disease.
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 Parkinson's disease 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 Parkinson's disease 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.
Complementary and Supportive Therapies
A wide variety of complementary and supportive therapies may be used for Parkinson's disease. 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 Parkinson's disease. Some early reports have suggested that dietary supplements might be protective in Parkinson's disease. 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 Parkinson's disease. 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 Parkinson's disease. While there is currently no proof that any specific dietary factor is beneficial, a normal, healthy diet can promote overall well-being for Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease, 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 Parkinson's disease should always check with their doctors before beginning a new exercise program.
Other complementary therapies that are used by some individuals with Parkinson's disease 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 Parkinson's disease and there is no convincing evidence that they are beneficial.
How Can People Cope with Parkinson's Disease?
While Parkinson's disease 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 Parkinson's disease, 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 Parkinson's disease.
People with Parkinson's disease 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 Parkinson's disease 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.
Can Scientists Predict or Prevent Parkinson's Disease?
In most cases, there is no way to predict or prevent sporadic Parkinson's disease. However, researchers are looking for a biomarker — a biochemical abnormality that all patients with Parkinson's disease 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 Parkinson's disease. 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 Parkinson's disease, 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.
What Research is Being Done on Parkinson's Disease?
In recent years, Parkinson's research has advanced to the point that halting the progression of Parkinson's disease, restoring lost function, and even preventing the disease are all considered realistic goals. While the ultimate goal of preventing Parkinson's disease may take years to achieve, researchers are making great progress in understanding and treating Parkinson's disease.
One of the most exciting areas of Parkinson's disease 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 Parkinson's disease occurs, develop animal models that accurately mimic the neuronal death in human Parkinson's disease, 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 Parkinson's disease 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 Parkinson's disease in some families. Researchers hope to identify the genes located in these chromosomal regions and to determine which of them may play roles in Parkinson's disease.
Researchers funded by NINDS are gathering information and DNA samples from hundreds of families with Parkinson's disease and are conducting large-scale gene expression studies to identify genes that are abnormally active or inactive in Parkinson's disease. They also are comparing gene activity in Parkinson's disease 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 Parkinson's disease, while other variations are associated with a lowered risk of the disorder. They also have found that Parkinson's disease 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 Parkinson's disease.
In addition to identifying new genes for Parkinson's disease, researchers are trying to learn how known Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease. Other studies have suggested that prenatal exposure to certain toxins can increase susceptibility to Parkinson's disease 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 Parkinson's disease.
Another major area of Parkinson's disease 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 Parkinson's disease.
Other studies focus on how Lewy bodies form and what role they play in Parkinson's disease. 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease. Inflammation is common to a variety of neurodegenerative diseases, including Parkinson's disease, 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 Parkinson's disease have higher levels of an inflammatory enzyme called COX-2 than those of people without Parkinson's disease. Inhibiting COX-2 doubled the number of neurons that survived in a mouse model for Parkinson's disease.
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 Parkinson's disease.
Biomarkers for Parkinson's disease – 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 Parkinson's disease 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 Parkinson's disease and to determine how these changes relate to disease symptoms. Other potential biomarkers for Parkinson's disease include alterations in gene expression.
Researchers also are conducting many studies of new or improved therapies for Parkinson's disease. While deep brain stimulation (DBS) is now FDA-approved and has been used in thousands of people with Parkinson's disease, 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 Parkinson's disease. 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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease.
A variety of new drug treatments are in clinical trials for Parkinson's disease. 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 Parkinson's disease patients. Other studies are testing whether a drug called istradefylline can improve motor function in Parkinson's disease, 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 Parkinson's disease patients. Other topics of research include controlled-release formulas of Parkinson's disease 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 Parkinson's disease. One study, called NET-Parkinson's disease (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-Parkinson's disease 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 Parkinson's disease.
Nerve growth factors, or neurotrophic factors, which support survival, growth, and development of brain cells, are another type of potential therapy for Parkinson's disease. 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 Parkinson's disease. This drug has been tested in several clinical trials for people with Parkinson's disease, 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 Parkinson's disease 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 Parkinson's disease, 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 Parkinson's disease. The study also suggested that dietary restriction affected dopamine activity in the brain. Another study showed that dietary restriction before the onset of Parkinson's disease 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 Parkinson's disease, such as depression and swallowing disorders. One clinical trial is investigating whether a drug called quetiapine can reduce psychosis or agitation in Parkinson's disease 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 Parkinson's disease, and whether levetiracetam, a drug approved to treat epilepsy, can reduce dyskinesias in Parkinson's patients without interfering with other Parkinson's disease drugs.
Another approach to treating Parkinson's disease 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 Parkinson's disease. 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 Parkinson's disease. 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 Parkinson's disease. 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 Parkinson's disease. 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 Parkinson's disease. A study of gene therapy in non-human primate models of Parkinson's disease 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 Parkinson's disease. 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 Parkinson's disease 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 Parkinson's disease. 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 Parkinson's disease 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.
What is the Role of the NINDS?
As a world leader in research on neurological disorders, including Parkinson's disease, the NINDS supports a wide range of basic laboratory studies and clinical trials at its Bethesda, Maryland , location and at grantee institutions around the world. Through these and other research projects, scientists are moving ever closer to unraveling the mysteries of Parkinson's disease. For patients and their families, this research should offer encouragement and hope for the future.
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 Parkinson's disease 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 Parkinson's disease. They also study the brain using PET brain scans and test potential Parkinson's disease treatments in animals. The NINDS hopes that research at these Centers of Excellence will lead to clinical trials of new therapies in humans with Parkinson's disease.
What Can I Do to Help?
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 Parkinson's disease 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
Philadelphia, PA 19103
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 Parkinson's disease 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 Parkinson's disease is eligible to take part in this registry. For more information, contact:
Parkinson's Disease Registry
500 W. Thomas Rd., Suite 720
Phoenix, Arizona 85013
877-287-7122 (toll free)
Some states, including California and Nebraska, also have registries of people with Parkinson's disease.
People with Parkinson's disease 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 Parkinson's disease is the www.Parkinson's diseasetrials.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)
Where can I get more information?
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
Church Street Station
P.O. Box 780
New York, NY 10008-0780
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.