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 PD, although some estimates are much higher. Society pays an enormous price for PD. The total cost to the nation is estimated to exceed $6 billion annually. The risk of PD 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 PD, as the symptoms sometimes appear in other diseases as well.
PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. It is not contagious. Although some PD cases appear to be hereditary, and a few can be traced to specific genetic mutations, most cases are sporadic - that is, the disease does not seem to run in families. Many researchers now believe that PD results from a combination of genetic susceptibility and exposure to one or more environmental factors that trigger the disease.
PD is the most common form of parkinsonism, the name for a group of disorders with similar features and symptoms. PD is also called primary parkinsonism or idiopathic PD. The term idiopathic means a disorder for which no cause has yet been found. While most forms of parkinsonism are idiopathic, there are some cases where the cause is known or suspected or where the symptoms result from another disorder. For example, parkinsonism may result from changes in the brain's blood vessels.
What Causes the 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 PD also have loss of the nerve endings that produce the neurotransmitter norepinephrine. Norepinephrine, which is closely related to dopamine, is the main chemical messenger of the sympathetic nervous system, the part of the nervous system that controls many automatic functions of the body, such as pulse and blood pressure. The loss of norepinephrine might help explain several of the non-motor features seen in PD, including fatigue and abnormalities of blood pressure regulation.
Many brain cells of people with PD contain Lewy bodies - unusual deposits or clumps of the protein alpha-synuclein, along with other proteins. Researchers do not yet know why Lewy bodies form or what role they play in development of the disease. The clumps may prevent the cell from functioning normally, or they may actually be helpful, perhaps by keeping harmful proteins "locked up" so that the cells can function.
Scientists have identified several genetic mutations associated with PD, and many more genes have been tentatively linked to the disorder. Studying the genes responsible for inherited cases of PD can help researchers understand both inherited and sporadic cases. The same genes and proteins that are altered in inherited cases may also be altered in sporadic cases by environmental toxins or other factors. Researchers also hope that discovering genes will help identify new ways of treating PD.
Although the importance of genetics in PD is increasingly recognized, most researchers believe environmental exposures increase a person's risk of developing the disease. Even in familial cases, exposure to toxins or other environmental factors may influence when symptoms of the disease appear or how the disease progresses. There are a number of toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or MPTP (found in some kinds of synthetic heroin), that can cause parkinsonian symptoms in humans. Other, still-unidentified environmental factors also may cause PD in genetically susceptible individuals.
Viruses are another possible environmental trigger for PD. People who developed encephalopathy after a 1918 influenza epidemic were later stricken with severe, progressive Parkinson's-like symptoms. A group of Taiwanese women developed similar symptoms after contracting herpes virus infections. In these women, the symptoms, which later disappeared, were linked to a temporary inflammation of the substantia nigra.
Several lines of research suggest that mitochondria may play a role in the development of PD. Mitochondria are the energy-producing components of the cell and are major sources of free radicals - molecules that damage membranes, proteins, DNA, and other parts of the cell. This damage is often referred to as oxidative stress. Oxidative stress-related changes, including free radical damage to DNA, proteins, and fats, have been detected in brains of PD patients.
Other research suggests that the cell's protein disposal system may fail in people with PD, causing proteins to build up to harmful levels and trigger cell death. Additional studies have found evidence that clumps of protein that develop inside brain cells of people with PD may contribute to the death of neurons, and that inflammation or overstimulation of cells (because of toxins or other factors) may play a role in the disease. However, the precise role of the protein deposits remains unknown. Some researchers even speculate that the protein buildup is part of an unsuccessful attempt to protect the cell. While mitochondrial dysfunction, oxidative stress, inflammation, and many other cellular processes may contribute to PD, the actual cause of the dopamine cell death is still undetermined.
What Genes are Linked to Parkinson's Disease?
Several genes have now been definitively linked to PD. 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 PD 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 PD. These findings prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies from people with the sporadic form of PD 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 PD discovered that the disease in one large family was caused by a triplication of the normal alpha-synuclein gene on one copy of chromosome 4. This triplication caused people in the affected family to produce too much of the normal alpha-synuclein. This study showed that an excess of the normal form of the protein could result in PD, just as the abnormal form does.
Other genes linked to PD include parkin, DJ-1, PINK1,and LRRK2. Parkin, DJ-1, and PINK-1 cause rare, early-onsetforms of PD. The parkin gene is translated intoa protein that normally helps cells break down andrecycle proteins. DJ-1 normally helps regulategene activity and protect cells from oxidative stress. PINK1codes for a protein active in mitochondria. Mutationsin this gene appear to increase susceptibility to cellularstress.
LRRK2, which is translated into a protein called dardarin,was originally identified in several English and Basquefamilies and causes a late-onset form of PD. Subsequentstudies have identified this gene in other familieswith PD as well as in a small percentage of peoplewith apparently sporadic PD.
Researchers are continuing to investigate the normalfunctions and interactions of these genes in orderto find clues about how PD develops. They alsohave identified a number of other genes and chromosomeregions that may play a role in PD, but the natureof these links is not yet clear.
Who Gets Parkinson's Disease?
About 50,000 Americans are diagnosed with PD each year, but getting an accurate count of the number of cases may be impossible because many people in the early stages of the disease assume their symptoms are the result of normal aging and do not seek help from a physician. Also, diagnosis is sometimes difficult and uncertain because other conditions may produce symptoms of PD and there is no definitive test for the disease. People with PD may sometimes be told by their doctors that they have other disorders, and people with PD-like diseases may be incorrectly diagnosed as having PD.
PD strikes about 50 percent more men than women, but the reasons for this discrepancy are unclear. While it occurs in people throughout the world, a number of studies have found a higher incidence in developed countries, possibly because of increased exposure to pesticides or other toxins in those countries. Other studies have found an increased risk in people who live in rural areas and in those who work in certain professions, although the studies to date are not conclusive and the reasons for the apparent risks are not clear.
One clear risk factor for PD is age. The average age of onset is 60 years, and the incidence rises significantly with increasing age. However, about 5 to 10 percent of people with PD have "early-onset" disease that begins before the age of 50. Early-onset forms of the disease are often inherited, though not always, and some have been linked to specific gene mutations. People with one or more close relatives who have PD have an increased risk of developing the disease themselves, but the total risk is still just 2 to 5 percent unless the family has a known gene mutation for the disease. An estimated 15 to 25 percent of people with PD have a known relative with the disease.
In very rare cases, parkinsonian symptoms may appear in people before the age of 20. This condition is called juvenile parkinsonism. It is most commonly seen in 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 the Disease?
Early symptoms of PD are subtle and occur gradually. Affected people may feel mild tremors or have difficulty getting out of a chair. They may notice that they speak too softly or that their handwriting is slow and looks cramped or small. They may lose track of a word or thought, or they may feel tired, irritable, or depressed for no apparent reason. This very early period may last a long time before the more classic and obvious symptoms appear.
Friends or family members may be the first to notice changes in someone with early PD. They may see that the person's face lacks expression and animation (known as "masked face") or that the person does not move an arm or leg normally. They also may notice that the person seems stiff, unsteady, or unusually slow.
As the disease progresses, the shaking or tremor that affects the majority of Parkinson's patients may begin to interfere with daily activities. Patients may not be able to hold utensils steady or they may find that the shaking makes reading a newspaper difficult. Tremor is usually the symptom that causes people to seek medical help.
People with PD often develop a so-called parkinsoniangait that includes a tendency to lean forward,small quick steps as if hurrying forward (called festination), and reduced swinging of the arms.They also may have trouble initiating movement (start hesitation), and they may stop suddenly as they walk (freezing).
PD does not affect everyone the same way, and the rate of progression differs among patients. Tremor is the major symptom for some patients, while for others, tremor is nonexistent or very minor.
PD symptoms often begin on one side of the body. However, as it progresses, the disease eventually affects both sides. Even after the disease involves both sides of the body, the symptoms are often less severe on one side than on the other. The four primary symptoms of PD are:
- Tremor. The tremor associated with PD 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 PD. 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 PD, 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 PD. Some are minor; others are not. Many can be treated with medication or physical therapy. No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms varies from person to person.
- 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 medications.
- Emotional changes. Some people with PD 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 pessimistic.
- 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 nutrition. Speech-language therapists, occupational therapists, and dieticians can often help with these problems.
- Speech changes. About half of all PD 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 ofthe 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 PD 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 PD, 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 PD.
- Sleep problems. Sleep problems common in PD include difficulty staying asleep at night, restless sleep, nightmares and emotional dreams, and drowsiness or sudden sleep onset during the day. Patients with PD should never take over-the-counter sleep aids without consulting their physicians.
- Dementia or other cognitive problems. Some, but not all, people with PD may develop memory problems and slow thinking. In some of these cases, cognitive problems become more severe, leading to a condition called Parkinson's dementia late in the course of the disease. There is currently no way to halt PD dementia, but studies have shown that a drug called rivastigmine may slightly reduce the symptoms. The drug donepezil also can reduce behavioral symptoms in some people with PD-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 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 that controls heart rate, blood pressure, and other automatic functions in the body. The medications used to treat PD also may contribute to this symptom.
- Muscle cramps and dystonia. The rigidity and lack of normal movement associated with PD often causes muscle cramps, especially in the legs and toes. Massage, stretching, and applying heat may help with these cramps. PD also can 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. It can usually be relieved or reduced by adjusting the person's medications.
- Pain. Many people with PD develop aching muscles and joints because of the rigidity and abnormal postures often associated with the disease. Treatment with levodopa and other dopaminergic drugs often alleviates these pains to some extent. Certain exercises also may help. People with PD also may develop pain due to compression of nerve roots or dystonia-related muscle spasms. In rare cases, people with PD may develop unexplained burning, stabbing sensations. This typeof pain, called "central pain," originates inthe 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 PD 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. PD often causes erectile dysfunction because of its effects on nerve signals from the brain orbecause of poor blood circulation. PD-related depression or use of anti depressant medication also may cause decreased sex drive and other problems. These problems are often treatable.