Parkinson's Disease

What is Parkinson’s disease?

Parkinson's disease is a progressive movement disorder of the nervous system. It causes nerve cells (neurons) in parts of the brain to weaken, become damaged, and die, leading to symptoms that include problems with movement, tremor, stiffness, and impaired balance. As symptoms progress, people with Parkinson’s disease (PD) may have difficulty walking, talking, or completing other simple tasks. 

Parkinson’s and the brain

Although many brain areas are affected in Parkinson’s disease, the most common symptoms result from the loss of neurons in an area near the base of the brain called the substantia nigra. The neurons in this area produce dopamine. Dopamine is the chemical messenger that transmits  signals in the brain to produce smooth, purposeful movement. Studies have shown that most people with PD have lost 60 to 80% or more of the dopamine-producing cells in the substantia nigra by the time symptoms appear. 

People with PD also lose the nerve endings that produce the neurotransmitter norepinephrine—the main chemical messenger to 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 explain several of the symptoms of Parkinson’s that are not related to movement, such as fatigue and blood pressure changes. 

The affected brain cells of people with PD contain Lewy bodies—deposits of the protein alpha-synuclein. Researchers do not yet know why Lewy bodies form or their role  in the disease. Some 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 the brain cells of people with PD may contribute to the death of neurons.

Symptoms of Parkinson’s disease

PD affects different people in different ways. The rate of progression and the particular symptoms differ among individuals. PD symptoms typically begin on one side of the body. However, the disease eventually affects both sides, although symptoms are often less severe on one side than on the other. The four primary symptoms of PD are:

1. Tremor (shaking) often begins in a person’s hand, although sometimes the person’s foot or jaw is affected first. The particular tremor associated with PD has a rhythmic back-and-forth motion. Often, the tremor will cause the person to rub their thumb and forefinger together, which may appear as  “pill rolling.” It is most obvious when the hand is at rest or when a person is under stress. This tremor usually disappears during sleep and may improve when the person makes a purposeful, intended movement.
    
2. Rigidity (muscle stiffness), or resistance to movement, affects most people with PD. The muscles stay tense and tight so the person aches or feels stiff. If another person tries to move the individual's arm, it will move only in short, jerky movements ( known as “cogwheel” rigidity).
    
3. Bradykinesia is a slowing down of spontaneous and some automatic movement. It can make simple tasks more difficult, and activities the person could once perform quickly and easily—such as washing or dressing—may take much longer. The person’s face may be less expressive ( known as "masked face").
    
4. Postural instability, such as balance problems and changes in posture, can increase the risk of falls.

People with PD often develop a “parkinsonian gait.” This includes a tendency to lean forward, taking small, quick steps as if hurrying (called festination), and reduced swinging in one or both arms. They may have trouble initiating movement (called “start hesitation”) and stop suddenly as they walk, freezing in place.

In addition to the characteristic symptoms noted above, people with PD may experience other problems related to the disease. These may include:

• Mental and emotional health problems, including depression or anxiety, may occur during the early stage of the disease, even before  the onset of movement issues. 
   
• Difficulty with swallowing and chewing. Problems with swallowing and chewing may occur in later stages of the disease. Food and saliva may collect in the mouth and back of the throat, resulting in choking or drooling. It can be difficult for people in the later stages of PD to get enough nutrients. 
   
• Speech changes. Most individuals with PD have speech difficulties, which may include speaking quietly or in a monotone. Some people may hesitate before speaking. They may also slur or speak too quickly.
   
• Urinary problems or constipation. In PD, the autonomic nervous system, which controls movements and functions we don’t have to think about, doesn’t function normally. This can cause bladder and bowel problems.
   
• Skin problems. People with Parkinson’s may have increased  facial oils, 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, or the person may experience excessive sweating. 
   
• Sleep problems. Common sleep problems in PD include difficulty staying asleep at night, restless sleep, nightmares and emotional dreams, and drowsiness or suddenly falling asleep during the day. Another common problem is REM sleep behavior disorder, in which people act out their dreams. This may result in injury to themselves or their bed partners. Medications used to treat PD may contribute to some sleep issues. 
   
• Dementia or other cognitive problems. Some people with PD develop memory problems and slowed thinking. Cognitive problems become more severe in the late stages of PD, and some people are diagnosed with Parkinson's disease dementia. Memory, visuospatial skills, attention, language, reasoning, or other mental and cognitive skills may be affected.
   
• Orthostatic hypotension. Orthostatic hypotension is a sudden drop in blood pressure when a person stands up from a lying down or seated position. This may cause dizziness, lightheadedness, and, in extreme cases, loss of balance or fainting. 
   
• Muscle cramps and dystonia. The rigidity and lack of normal movement associated with PD often causes muscle cramps, especially in the legs and toes. PD can also be associated with dystonia—sustained muscle contractions that cause forced or twisted positions. 
   
• Pain. People with PD may have aches and pains in their muscles and joints because of the rigidity and abnormal postures with the disease.
   
• Fatigue and loss of energy. Many people with PD often have fatigue, especially late in the day. Fatigue may be associated with depression or sleep disorders, but it may also result from motor control issues such as trouble initiating or carrying out movement, tremors or stiffness. 
   
• Sexual dysfunction. Because it affects nerve signals from the brain, PD can cause sexual dysfunction. PD-related depression or use of certain medications may also cause decreased sex drive and other problems.

PD is the most common form of parkinsonism, which describes disorders that produce features and symptoms that closely resemble Parkinson's disease. Many disorders can cause symptoms similar to those of PD, including multiple system atrophy, Lewy body dementia, progressive supranuclear palsy, and corticobasal degeneration. These disorders are sometimes referred to as “Parkinson's-plus syndrome” or “atypical Parkinsonism” because they have the symptoms of PD plus additional features. These disorders often do not respond to levodopa treatment like PD does.

In very rare cases, parkinsonian symptoms may appear in people before the age of 20. This condition is called juvenile parkinsonism. It often begins with dystonia and bradykinesia, and the symptoms often improve with levodopa medication.

Who is more likely to get Parkinson’s disease?

Risk factors for PD include:

• Age. The average age of onset is in a person’s early to mid-60s, and the incidence rises significantly with older age. However, a small percent of people with PD have “early-onset” Parkinson’s disease, which begins before the age of 50.
   
• Biological sex. PD affects more men than women.
   
• Heredity. People with one or more close relatives who have PD have an increased risk of developing the disease themselves. 
   
• Environmental exposure. Studies show an increased risk of PD in people who live in rural areas where exposure to pesticides is common. Exposure to certain toxins has caused parkinsonian symptoms in rare circumstances (such as exposure to MPTP, an illicit drug—or exposure to the metal manganese in welders).

While the exact cause of PD is unknown, some cases are hereditary and can be traced to specific genetic mutations. . Most cases are sporadic, meaning they arise with no known cause. Researchers think  that PD likely results from a combination of genetics and exposure to one or more (mostly unknown) environmental factors that trigger the disease.

Several genetic mutations are associated with PD, including the alpha-synuclein gene, and many more genes have been linked to the disorder. The same genes and proteins that are altered in inherited cases may also be altered in sporadic cases by environmental toxins or other factors, including inflammation.

Researchers have detected damage from oxidative stress in the brains of people with PD. . Oxidative stress refers to damage caused by free radicals—molecules that result from abnormalities in mitochondria, the energy-producing components of the cell.  Researchers have also identified some gene mutations that affect mitochondrial function as causes of PD. .

Genes linked to PD

Several genes have been definitively linked to PD:

• SNCA—This gene, which makes the protein alpha-synuclein, was the first gene identified to be associated with Parkinson's disease. Research findings by the National Institutes of Health (NIH) and other institutions prompted studies of the role of alpha-synuclein in PD. This  led to the discovery that Lewy bodies seen in all cases of PD contain clumps of abnormal alpha-synuclein. This discovery revealed the link between hereditary and sporadic forms of the disease.
   
• LRRK2—LRRK2 codes for a complex protein called dardarin that plays a role in many cellular functions. Research has shown that LRRK2 mutations affect how cells metabolize alpha-synuclein. . These changes may lead to the formation of Lewy bodies. Studies suggest that the activity of this protein may increase in sporadic PD.
   
• DJ-1—This gene helps protect cells from oxidative stress, and mutations in this gene can cause rare, early-onset forms of PD.
   
• PRKN (Parkin)—The parkin gene makes a protein that helps cells break down and recycle proteins. Mutations in this gene can cause early-onset PD.
   
• PINK1—PINK1 codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress. PINK1 has been linked to early-onset forms of PD.
   
• GBA (glucocerebrosidase-beta)—Mutations in GBA cause Gaucher disease, a type of lipid storage disorder. Different changes in this gene are associated with an increased risk for Parkinson's disease and faster progression of symptoms in people who have PD.

How is Parkinson’s disease diagnosed and treated?

Diagnosing PD

There are currently no specific tests that diagnose PD. The diagnosis is typically made based on:

• The person’s medical history and a neurological examination. PD has many characteristic movement problems and other symptoms that can aid in diagnosis. 
   
• Blood and other laboratory tests to rule out other disorders that may be causing the symptoms.
   
• Brain imaging such as SPECT (Single-photon emission computed tomography) and MRI (magnetic resonance imaging) to rule out other disorders. A Dopamine Active Transporter (DaT) scan is a type of SPECT that can help diagnose PD. However, it cannot differentiate the diagnosis of PD from Parkinson’s-plus syndrome. 

In rare cases where people have an inherited form of PD, researchers can test for known gene mutations to determine  an individual's risk of developing the disease. However, this genetic testing can have far-reaching implications, and people should carefully consider how to use the results of such tests if they decide to take them. 

A lab test recently developed by NIH-funded researchers called the alpha-synuclein seeding amplification assay (SAA) can detect abnormal alpha-synuclein in the spinal fluid of persons with PD. Studies suggest that this test may also detect PD in people who have not yet been diagnosed. Researchers are working to adapt this test to blood samples and make it more widely available.

Treating PD

Currently, there is no cure for PD, but medications or surgery can improve many of the movement symptoms in Parkinson’s disease.

Medications to treat Parkinson’s disease

Medications for PD fall into three categories:

1. Drugs that increase the level of dopamine in the brain. The most common drugs for PD are dopamine precursors—substances like levodopa that cross the blood-brain barrier and are then changed into dopamine. Other drugs mimic dopamine or prevent or slow its breakdown.
    
2. Drugs that affect other neurotransmitters in the body to ease some of the symptoms of the disease. For example, anticholinergic drugs interfere with production or uptake of the neurotransmitter acetylcholine. These can be effective in reducing tremors.
    
3. Medications that help control the non-motor symptoms of the disease, or the symptoms that don't affect movement. For example, people with PD-related depression may be prescribed antidepressants.

Motor symptoms may significantly improve at first with medication, but can reappear over time as PD worsens and the medications become less effective. When recommending a course of treatment, a doctor will assess how much the symptoms disrupt the person's daily activities and then tailor therapy to the person's condition. Since no two people will react the same way to a given drug, it may take time and patience to get the dose and combination of medications right. Even then, symptoms may not completely disappear.

A doctor should monitor the person for any side effects of Parkinson's disease medications. For example, some medications prescribed for PD can cause obsessive- compulsive disorder, hallucinations, or delusions, in some people. 

Carbidopa-Levodopa. The cornerstone of PD therapy is a medication called levodopa (also known as L-dopa). Levodopa can reduce the movement-related symptoms of PD, but it does not replace lost nerve cells or stop its progression. Nerve cells can use levodopa to make dopamine and replenish the brain's reduced supply. People cannot simply take dopamine pills because dopamine does not easily cross the blood-brain barrier, a protective lining of cells inside blood vessels that regulate the transport of oxygen, glucose, medications, and other substances in the brain. People with PD are given levodopa combined with another substance called carbidopa. When added to levodopa, carbidopa prevents the conversion of levodopa into dopamine except for in the brain. This stops or diminishes the side effects of  excess dopamine in the bloodstream, such as nausea. Carbidopa-levodopa is often very successful at reducing or eliminating the tremors and other motor symptoms of PD during the early stages of the disease. People may need to increase their dose of levodopa gradually for maximum benefit.

Initial side effects of carbidopa-levodopa may include nausea, low blood pressure, restlessness, and drowsiness. Over long-term use of carbidopa-levodopa, a person may experience dyskinesia (involuntary movements such as twisting and writhing), hallucinations, or psychosis.

Later in the course of the disease, people with PD may notice more pronounced symptoms before their first dose of medication in the morning and between doses as the period of effectiveness after each dose begins to shorten. People may experience sudden, unpredictable “off periods” where the medications do not seem to be working. Taking levodopa more often and in smaller amounts can help with this. People with PD should never stop taking levodopa without consulting their doctor because rapidly withdrawing the drug can have potentially serious side effects.

Dopamine agonists. These mimic the role of dopamine in the brain and can be given alone or with levodopa. They are used most often in early-stage PD or in conjunction with levodopa in later stages. Many of the potential side effects are similar to those associated with the use of levodopa, including drowsiness, sudden falling asleep, hallucinations, confusion, dyskinesia, edema (swelling due to excess fluid in body tissues), nightmares, and vomiting. In rare cases, they can cause an uncontrollable desire to gamble, hypersexuality, or compulsive shopping. Dopamine agonist drugs include apomorphine, pramipexole, ropinirole, and rotigotine. 

MAO-B inhibitors. These drugs block or reduce the activity of 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 PD. These medications include selegiline and rasagiline. Studies supported by NINDS have shown that selegiline (also called deprenyl) 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. Selegiline is usually well-tolerated, although side effects may include nausea, orthostatic hypotension, and insomnia. The drug rasagiline is used to treat the motor symptoms of PD (with or without levodopa).

COMT inhibitors. COMT stands for catechol-O-methyltransferase and is another enzyme that breaks down dopamine. The COMT inhibitor drugs entacapone, opicapone, and tolcapone prolong the effects of levodopa by preventing the breakdown of dopamine. They can decrease the duration of “off periods” of one's dose of levodopa. Side effects may include diarrhea, nausea, sleep disturbances, dizziness, urine discoloration, abdominal pain, low blood pressure, or hallucinations. In a few rare cases, tolcapone has caused severe liver disease, and people taking tolcapone should have their liver function monitored regularly.

Anticholinergics. These drugs, which include trihexyphenidyl, benztropine, and ethopropazine, decrease the activity of the neurotransmitter acetylcholine and can be particularly effective for PD tremor. Side effects may include dry mouth, constipation, urinary retention, hallucinations, memory loss, blurred vision, and confusion.

Amantadine. This antiviral drug can help reduce symptoms of PD and levodopa-induced dyskinesia. It can be prescribed alone in the early stages of the disease, and can be used with an anticholinergic drug or levodopa. After several months, amantadine's effectiveness wears off in up to half of the people taking it. Amantadine's side effects may include insomnia, mottled skin, edema, agitation, or hallucinations. Researchers are not certain how amantadine works in PD, but it may increase the effects of dopamine.

Medications to treat motor symptoms of PD

Surgery

Surgery may be considered for people with PD when  drug therapy is no longer sufficient to manage symptoms. Studies in the past few decades have led to great improvements in surgical techniques. 

One type of surgery for PD, called lesion surgery, involves selectively destroying specific parts of the brain that contribute to PD symptoms. The most common lesion surgery is called pallidotomy. In this procedure, a surgeon selectively destroys a portion of the brain called the globus pallidus. Pallidotomy can improve tremor, rigidity, and bradykinesia symptoms, 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 people require, thus reducing drug-induced dyskinesias. Another procedure, called thalamotomy, involves surgically destroying part of the thalamus; this approach is useful primarily to reduce tremor.

Because these procedures cause permanent destruction of small amounts of brain tissue, they have largely been replaced by deep brain stimulation for the treatment of PD. Additionally, a method that uses focused ultrasound from outside the head can now create brain lesions without surgery.

Deep Brain Stimulation

Deep brain stimulation (DBS) uses an electrode surgically implanted into the brain, typically in the subthalamic nucleus or the globus pallidus. Similar to a cardiac pacemaker, a pulse generator (battery pack)  implanted in the chest area under the collarbone sends finely controlled electrical signals to the electrode(s) via a wire placed under the skin. When turned on, the pulse generator and electrodes painlessly stimulate the brain in a way that helps to block signals that cause many of the motor symptoms of PD. DBS is approved by the U.S. Food and Drug Administration (FDA) and is widely used as a treatment for PD.

DBS does not stop PD from progressing; some problems may gradually return. While the motor function benefits of DBS can be substantial, it usually does not help with speech problems, “freezing,” posture, balance, anxiety, depression, or dementia.

DBS is generally appropriate for people whose PD responds to levodopa and who have developed dyskinesias or other symptoms despite drug therapy. 

Lifestyle changes and complementary and supportive therapies

A wide variety of complementary and supportive therapies and lifestyle changes may be used for PD, including:

• A healthy diet. At this time, there are no specific vitamins, minerals, or other nutrients that have any proven therapeutic value in PD. However, a healthy diet can promote overall well-being for people with PD just as it would for anyone else. Eating a fiber-rich diet and drinking plenty of fluids can help alleviate constipation. A high-protein diet, however, may limit levodopa's absorption. NINDS and other components of the NIH are funding research to determine if caffeine, antioxidants, and other dietary factors may be beneficial for preventing or treating PD.
• Exercise. Physical activity, such as walking, yoga, cycling, swimming, and other activities can help people with PD. Exercise can improve mobility, flexibility, balance, and strength. People with PD should always check with their doctors before beginning a new exercise program. Researchers supported by NINDS are conducting clinical trials to test whether high-intensity exercise can slow the progression of PD. 

Other approaches that some people use to help manage PD symptoms include:

• Physical, occupational, and speech therapies to help with gait and voice disorders, tremor and rigidity, and adapting to decline in mental functions
   
• Vocal exercises to improve speech and swallowing
   
• Complementary health approaches, such as hypnosis, massage therapy, or acupuncture

Coping with PD

PD usually progresses slowly. Over time, a person’s day-to-day life will be affected, from socializing with friends to earning a living and caring for   the home. These changes can be difficult to accept. Support groups can help people cope with the disease's emotional impact and provide valuable information, advice, and experience. They can 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. Individual or family counseling may also help people find ways to cope with PD.

Outlook for people with Parkinson’s disease

The average life expectancy of a person with PD is generally the same as the average for a person who does not have the disease. PD is a slow, progressive disorder, and it is not possible to predict what course the disease will take for an individual person. Many people with PD continue to work either full- or part-time, although they may need to adjust their schedule and working environment to accommodate their symptoms. Fortunately, there are many treatment options available for people with PD. However, in the late stages, PD may no longer respond to medications and can lead to serious complications such as choking, pneumonia, and falls.

What are the latest updates on Parkinson’s disease?

NINDS, a component of the National Institutes of Health (NIH), conducts and supports research to better understand and diagnose PD, develop new treatments, and, ultimately, prevent Parkinson’s disease. NINDS is the primary NIH institute supporting PD research. NINDS research looks at all aspects of PD—from identifying clues to the development of the disorder and its processes to improving current therapies and testing new ones. Learn more about NINDS’ research focus on Parkinson’s disease. 

One promising research advance is a new way to detect the disorder early. Scientists have developed a test called the alpha-synuclein seed amplification assay, which detects misfolded alpha-synuclein protein in the fluid that surrounds the brain. Additional research is needed, but current data suggest that the test shows good accuracy in diagnosing a specific form of Parkinson’s disease and can do so years before motor symptoms begin. This offers the possibility of diagnosing and treating PD early enough to minimize or prevent the development of disabling symptoms. The test requires a lumbar puncture (also called a spinal tap) and is not yet widely available. However, NINDS-supported scientists are working on less invasive assay applications, such as those that would test blood, saliva, or skin.

Key NINDS programs and resources for PD research include:

• The NINDS Intramural Research Program conducts clinical studies to understand PD mechanisms better and develop novel and improve treatments.
   
• The NINDS Morris K. Udall Centers of Excellence for Parkinson's Disease Research program supports research centers across the country that work collaboratively to study PD disease mechanisms, the genetic contributions to PD, and potential therapeutic targets and treatment strategies.
   
• The Parkinson's Disease Biomarkers Program (PDBP) aims to discover ways to identify individuals at risk for developing PD and to track the disease progression. It funds research and collects human biological samples and clinical data to identify biomarkers (signs that may indicate risk of a disease) that will speed the development of novel therapeutics for PD. NINDS has expanded the scope of PDBP to include diseases related to PD, like progressive supranuclear palsy, multiple system atrophy, and Lewy body dementia (including Parkinson’s disease dementia). As part of the PDBP, the NINDS Data Management Resource (DMR) advances PD research through the support of electronic data capture, clinical site management, data quality assessment, and data access. This resource provides researchers with tools that allow for data  collection and quality assurance in a standardized format.
   
• The Accelerating Medicines Partnership^® for Parkinson's Disease (AMP^® PD) program is a public-private partnership between the NIH, multiple biopharmaceutical and life sciences communities, and nonprofit organizations to identify and validate biomarkers that can diagnose and track the progression of PD. It allows scientists to perform large-scale genetic analyses and share data through a centralized web portal to accelerate research and quickly bring new medicines to people with Parkinson’s or at risk of PD. 
   
• NINDS Biospecimen Exchange for Neurological Disorders (BioSEND) houses biospecimens collected through NINDS-supported studies including phase 2 and 3 clinical trials along with an array of studies focused on biomarkers of disease susceptibility, onset, and progression. The primary goal of the BioSEND repository is standardize biospecimen collection and distribution to facilitate research on PD and neurological disorders.
   
• NINDS Human Cell and Data Repository (NHCDR) provides cell sources to academic and industry investigators to advance the study of neurological disorders, including PD. Cell sources currently include fibroblasts and/or induced pluripotent stem cells. NHCDR also provides new tools for analytics, searching, and ordering for all components of the repository.
   
• NINDS Common Data Elements (CDEs) are standards that enable clinical investigators to systematically collect, analyze, and share harmonized data across the research community. NINDS strongly encourages researchers who receive funding from the Institute to ensure their data collection is compatible with these CDEs.
   
• NIH NeuroBioBank (NBB) is a national resource and repository for human post-mortem brain tissue and related biospecimens that are crucial to understanding healthy brain function and nervous system dysfunction in nervous system disorders, including PD. 

How can I or a loved one help improve care for people with Parkinson's disease?

Consider participating in a clinical trial, so clinicians and scientists can learn more about PD and related disorders. Clinical research with human study participants helps researchers learn more about a disorder and perhaps find better ways to detect, treat, or prevent disease safely.

All types of participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research, visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with PD at Clinicaltrials.gov.

Learn about related topics

• Corticobasal Degeneration
• Dementias
• Lewy Body Dementia
• Multiple System Atrophy
• Progressive Supranuclear Palsy 
• Tremor