Parkinson’s Disease

Parkinson’s disease (PD) is a movement disorder of the nervous system that gets worse over time. As nerve cells (neurons) in parts of the brain weaken, are damaged or die, people may begin to notice problems with movement, tremors, stiffness in the limbs or the trunk of the body or impaired balance. As symptoms progress, people may have difficulty walking, talking or completing other simple tasks. Not everyone with one or more of these symptoms has PD, as the symptoms also appear in other diseases.

The cause of PD is unknown, although some cases are hereditary and can be traced to specific genetic mutations. Most cases are sporadic, and the disease does not typically run in families. PD likely results from a combination of genetics and exposure to one or more unknown environmental factors that trigger the disease.

Parkinson’s disease occurs when nerve cells, or neurons, in the brain die or become impaired. Although many brain areas are affected, 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 responsible for transmitting signals between the substantia nigra and the subsequent “relay station” of the brain, the corpus striatum, to produce smooth, purposeful movement. Loss of dopamine results in impaired movement.

Studies have shown that most people with Parkinson’s have lost 60–80% 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 primary chemical messenger to the part of the nervous system that controls many autonomic functions of the body, such as pulse and blood pressure. The loss of norepinephrine might explain several non-motor features seen in PD, including fatigue and abnormalities in blood pressure regulation.

The protein alpha-synuclein: 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 what their role is 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.

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

Environment: Exposure to certain toxins has caused parkinsonian symptoms in rare circumstances (such as exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine—MPTP—an illicit drug, or in miners exposed to the metal manganese). Other still-unidentified environmental factors may also cause PD in genetically susceptible individuals.

Mitochondria: Mitochondria are the energy-producing components of the cell, and abnormalities in them are significant 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 the brains of individuals with PD. Some mutations that affect mitochondrial function have been identified as causes of PD.

Genes Linked to Parkison’s Disease

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. Research findings by the National Institutes of Health (NIH) and other institutions prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies seen in all cases of PD contain clumps of alpha-synuclein. This discovery revealed the link between hereditary and sporadic forms of the disease.
• LRRK2: Mutations in LRRK2 were initially identified as a cause of late-onset Parkinson’s disease (PD) in several English and Basque families. Subsequent studies have identified mutations in this gene in other families with PD (such as European Ashkenazi Jewish families) and a small percentage of people with apparently sporadic PD. LRRK2 mutations significantly cause PD in North Africa and the Middle East.
• DJ-1: This gene helps regulate gene activity and protects cells from oxidative stress. It can also cause rare, early forms of PD.
• PRKN (Parkin): The parkin gene is translated into a protein that helps cells break down and recycle proteins.
• 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 forms of PD.
• GBA (glucocerebrosidase-beta): Mutations in GBA cause Gaucher disease (in which fatty acids, oils, waxes and steroids accumulate in the brain), but different changes in this gene are associated with an increased risk for Parkinson’s disease as well.

Risk factors for PD include:

• Age: The average age of onset is about 70 years, and the incidence rises significantly with older age. However, a small percentage of people with PD have early-onset disease that begins before the age of 50.
• Biological sex: PD affects more men than women.
• Exposure to pesticides: Studies show an increased risk of Parkinson’s disease in people who live in rural areas with high pesticide use.
• Heredity: People with one or more close relatives who have PD have an increased risk of developing the disease themselves. An estimated 15–25% of people with PD have a known relative with the disease. Some cases of the disease can be traced to specific genetic mutations.

There are currently no specific tests to diagnose PD. The diagnosis is based on:

• Medical history and a neurological examination
• Blood and laboratory tests to rule out other disorders that may be causing the symptoms
• Brain scans to rule out other disorders; computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear “normal” or “unremarkable.”

In rare cases where people have an inherited form of Parkinson’s disease, 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 whether they want to know the results of such tests.

No specific vitamins, minerals or other nutritional supplements have proven therapeutic value in PD. The National Institute of Neurological Disorders and Stroke (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. A healthy diet can promote overall well-being for people with PD just as it would for anyone. Eating a fiber-rich diet and drinking plenty of fluids can help alleviate constipation. A high-protein diet, however, may limit the absorption of the drug levodopa.

Exercise can help people with Parkinson’s disease improve their mobility, flexibility and body strength. It can also improve well-being and balance, minimize gait problems and strengthen certain muscles so people can speak and swallow better. General physical activity, such as walking, gardening, swimming, calisthenics and exercise machines, can have other benefits. People with Parkinson’s disease should always check with their doctors before beginning a new exercise program.

The four primary symptoms of PD are:

• Tremor: Tremor (shaking) often begins in a hand, although sometimes a foot or the jaw is affected first. The tremor associated with PD has a characteristic rhythmic back-and-forth motion that may involve the thumb and forefinger and appear as “pill-rolling.” It is most apparent when the hand is at rest or when a person is under stress. This tremor usually disappears during sleep or improves with a purposeful, intended movement.
• Rigidity: Rigidity (muscle stiffness), or resistance to movement, affects most people with PD. The muscles remain constantly tense and contracted, causing the person to ache or feel stiff. The rigidity becomes obvious when another person tries to move the individual’s arm, which moves only in short, jerky movements, known as “cogwheel” rigidity.
• Bradykinesia: This slowing down of spontaneous and automatic movement can be particularly frustrating because it may make simple tasks difficult. Activities, once performed quickly and easily, such as washing or dressing, may take much longer. There is often a decrease in facial expressions (also known as the “masked face”).
• Postural instability: Impaired balance and changes in posture can increase the risk of falls.

PD does not affect everyone the same way. 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.

People with PD often develop a so-called parkinsonian gait, which includes a tendency to lean forward, take small, quick steps as if hurrying (called festination) and reduce swinging in one or both arms. They may also have trouble initiating movement (start hesitation) and stop suddenly as they walk (freeze).

Other problems may accompany PD, such as:

• Dementia or other cognitive problems: Some people with Parkinson’s disease develop memory problems and slow thinking. Cognitive issues become more severe in the late stages of PD, and some are diagnosed with Parkinson’s disease dementia (PDD). Memory, social judgment, language, reasoning or other mental skills may be affected.
• Depression: Some people lose their motivation and become dependent on family members.
• Difficulty 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. Getting adequate nutrition may be difficult.
• Emotional changes: Some people with PD become fearful and insecure, while others may become irritable or uncharacteristically pessimistic.
• Fatigue and loss of energy: Many people with PD experience fatigue, especially late in the day. Fatigue may be associated with depression or sleep disorders, but it may also result from muscle stress or from overdoing activity when the person feels well. It may also result from akinesia, which is trouble initiating or carrying out movement.
• Hallucinations, delusions and other psychotic symptoms: These can be caused by the drugs prescribed for PD.
• Orthostatic hypotension: This is a sudden drop in blood pressure when a person stands up from lying down or seated. It may cause dizziness, lightheadedness and, in extreme cases, loss of balance or fainting. Studies have suggested that, in PD, this problem results from a loss of nerve endings in the sympathetic nervous system, which controls heart rate, blood pressure and other automatic bodily functions. The medications used to treat PD may also contribute.
• Muscle cramps and dystonia: The rigidity and lack of normal movement associated with PD often cause muscle cramps, especially in the legs and toes. PD can also be associated with dystonia—sustained muscle contractions that cause forced or twisted positions. Dystonia in PD is often caused by fluctuations in the body’s level of dopamine (a chemical in the brain that helps nerve cells communicate and is involved with movement).
• Pain: Muscles and joints may ache because of the rigidity and abnormal postures often associated with the disease.
• Sexual dysfunction: Because of its effects on nerve signals from the brain, PD may cause sexual dysfunction. PD-related depression or use of certain medications may also cause decreased sex drive and other problems.
• Skin problems: The skin on the face may become oily, particularly on the forehead and at the sides of the nose. The scalp may also become oily, resulting in dandruff. In other cases, the skin can become very dry.
• Sleep problems: Common sleep problems in PD include difficulty staying asleep at night, restless sleep, nightmares and emotional dreams and drowsiness or sudden sleep onset during the day. Another common problem is REM behavior disorder, in which people act out their dreams, potentially resulting in injury to themselves or their bed partners. The medications used to treat PD may contribute to some sleep issues. Many of these problems respond to specific therapies.
• Speech changes: About half of all individuals with PD have speech difficulties, such as speaking too softly or in a monotone. Some may hesitate before speaking, slur or speak too fast.
• Urinary problems or constipation: Bladder and bowel problems can occur when the autonomic nervous system, which regulates smooth muscle activity, improperly functions.

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

• Medical history and a neurological examination
• Blood and laboratory tests to rule out other disorders that may be causing the symptoms
• Brain scans to rule out other disorders. However, computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear “normal” or “unremarkable.”

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 whether they want to know the results of such tests.

Drug therapy is the primary method for treating PD. Medications for PD fall into three categories:

• Drugs that increase the level of dopamine in the brain. The most common medications 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.
• Drugs that affect other neurotransmitters in the body ease some of the symptoms of the disease. For example, anticholinergic drugs interfere with the production or uptake of the neurotransmitter acetylcholine. These can be effective in reducing tremors.
• 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.

Symptoms may significantly improve at first with medication but can reappear over time as PD worsens and drugs become less effective.

Currently, there is no cure for PD, but medications or surgery can often provide improvement in the motor symptoms.

Medications

Levodopa-carbidopa: The drug levodopa (also known as L-dopa) is the cornerstone of PD therapy. Nerve cells can use levodopa to make dopamine and replenish the brain’s reduced supply. However, people cannot take dopamine pills because dopamine does not easily pass through the blood-brain barrier, a protective lining of cells inside blood vessels that regulates the transport of oxygen, glucose and other substances in the brain.

People 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 due to dopamine in the bloodstream. Levodopa-carbidopa 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. Levodopa can reduce the symptoms of PD, but it does not replace lost nerve cells or stop its progression.

Initial side effects of levodopa-carbidopa may include:

• Drowsiness or sudden sleep
• Low blood pressure
• Nausea
• Restlessness

Side effects of long-term or extended use of levodopa may include:

• Dyskinesia, or involuntary movements such as mild to severe twisting and writhing
• Hallucinations and 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, which is called the wearing-off effect. People experience sudden, unpredictable “off periods” where the medications do not seem to be working. One approach to alleviating this is to take levodopa more often and in smaller amounts. People with PD should never stop taking levodopa without their physician’s input 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 somewhat less effective than levodopa in treating PD symptoms but work for more extended periods. Many of the potential side effects are similar to those associated with the use of levodopa, including drowsiness, sudden sleep onset, hallucinations, confusion, dyskinesias, 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.

Monoamine oxidase B (MAO-B) inhibitors: These drugs block or reduce the activity of the enzyme monoamine oxidase B (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 the 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 enhances and prolongs the response to levodopa and thus may reduce wearing-off. Selegiline is usually well tolerated, although side effects may include nausea, orthostatic hypotension or insomnia. The drug rasagiline is used in treating the motor symptoms of PD with or without levodopa.

Catechol-O-methyltransferase (COMT) inhibitors: COMT is another enzyme that breaks down dopamine. entacapone, opicapone and tolcapone are drugs that prolong the effects of levodopa by preventing the breakdown of dopamine. COMT inhibitors 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 need regular monitoring of their liver function.

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 sure how amantadine works in PD, but it may increase the effects of dopamine.

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

When recommending a course of treatment, a doctor assesses how much the symptoms disrupt the person’s life and then tailors therapy to the person’s particular condition. Since no two people react the same way to a given drug, it may take time and patience to get the dose right. Even then, symptoms may not be completely alleviated.

Medications to Treat Motor Symptoms of PD:

While PD usually progresses slowly, daily routines may eventually be affected—from socializing with friends to earning a living and caring for a home. These changes can be challenging to accept. Support groups can help people cope with the disease’s emotional impact. These groups can provide valuable information, advice and experience to help people with PD, their families and their caregivers deal with a wide range of issues, including locating doctors familiar with the disease and coping with physical limitations. Individual or family counseling may also help people find ways to cope with PD.

People with PD may also benefit from being proactive and learning as much as possible about the disease. This can alleviate their fear of the unknown and allow them to maintain their health proactively. Many people with PD continue to work full- or part-time, although they may need to adjust their schedule and working environment to accommodate their symptoms.

The average life expectancy of a person with PD is generally the same as for people who do not have the disease. 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 become associated with serious complications such as choking, pneumonia and falls.

Because PD is a slow, progressive disorder, it is not possible to predict what course the disease will take for each individual.