Introduction

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-onset forms of PD. The parkin gene is translated into a protein that normally helps cells break down and recycle proteins. DJ-1 normally helps regulate gene activity and protect cells from oxidative stress. PINK1 codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress.

LRRK2, which is translated into a protein called dardarin, was originally identified in several English and Basque families and causes a late-onset form of PD. Subsequent studies have identified this gene in other families with PD as well as in a small percentage of people with apparently sporadic PD.

Researchers are continuing to investigate the normal functions and interactions of these genes in order to find clues about how PD develops. They also have identified a number of other genes and chromosome regions that may play a role in PD, but the nature of these links is not yet clear.

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.