Friday, November 18, 2016

NINDS Parkinsons Disease Hope Through Research

NINDS | Parkinsons Disease | Hope Through Research

Parkinsons Disease: Hope Through Research

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Enfermedad de Parkinson: Esperanza en la Investigación
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Table of Contents (click to jump to sections)

What is Parkinsons disease?
What causes the disease?
What genes are linked to Parkinsons disease?
Who gets Parkinsons disease?
What are the symptoms of the disease?
What other diseases and conditions resemble Parkinsons disease?
Parkinsonism resulting from neurological disorders
Environmental causes
How is Parkinsons disease diagnosed?
What is the prognosis?
How is the disease treated?
Drug TherapySurgeryComplementary and Supportive TherapiesHow can people cope with Parkinsons disease?
Can scientists predict or prevent Parkinsons disease?
What research is being done?
Where can I get more information?
Glossary

What is Parkinsons disease?

Parkinsons disease (PD) is a degenerative disorder of the central nervous system that belongs to a group of conditions called movement disorders. It is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. As nerve cells (neurons) in parts of the brain become impaired or die, people may begin to notice problems with movement, tremor, stiffness in the limbs or the trunk of the body, or impaired balance. As these symptoms become more pronounced, 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 appear in other diseases as well.

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

PD is the most common form of parkinsonism^[1], in which disorders of other causes produce features and symptoms that closely resemble Parkinson’s disease. While most forms of parkinsonism have no known cause, there are cases in which the cause is known or suspected or where the symptoms result from another disorder.

No cure for PD exists today, but research is ongoing and medications or surgery can often provide substantial improvement with motor symptoms.

[1] Words in italics appear in a Glossary at the end of this information.

What causes the disease?

Parkinsons 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 thesubstantia nigra. Normally, the neurons in this area 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 people with Parkinsons have lost 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra by the time symptoms appear, and 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 explain several of the non-motor features seen in PD, including fatigue and abnormalities of blood pressure regulation.

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 role they play 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 brain cells of people with PD may contribute to the death of neurons. Some researchers speculate that the protein buildup in Lewy bodies is part of an unsuccessful attempt to protect the cell from the toxicity of smaller aggregates, or collections, of synuclein.

Genetics. Scientists have identified several genetic mutations associated with PD, including the alpha-synuclein gene, 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.

Environment. Exposure to certain toxins has caused parkinsonian symptoms in rare circumstances (such as exposure to 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. 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 abnormalities in the mitochondria 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 the brains of individuals with PD. Some mutations that affect mitochondrial function have been identified as causes of PD.

While mitochondrial dysfunction, oxidative stress, inflammation, toxins, and many other cellular processes may contribute to PD, the actual cause of the cell loss death in PD is still undetermined.

What genes are linked to Parkinsons disease?

Several genes have been definitively linked to PD. The first to be identified was alpha-synuclein. In the 1990s, researchers at National Institutes of Health 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 seen in all cases of PD contain alpha-synuclein protein. This discovery revealed the 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 (a chromosome is a threadlike structure of a protein and the genetic material DNA). 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 synuclein could result in PD, just as the abnormal form does.

Other genes linked to PD include parkin, DJ-1, PINK1, and LRRK2. DJ-1 and PINK1 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.

Mutations in LRRK2 were originally identified in several English and Basque families as a cause of a late-onset PD. Subsequent studies have identified mutations of this gene in other families with PD as well as in a small percentage of people with apparently sporadic PD. LRRK2 mutations are a major cause of PD in North Africa and the Middle East.

Another interesting association is with the GBA gene, which makes the enzyme glucocerebrosidase. Mutations in both GBA genes 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. Investigators seek to understand what this association can tell us about PD risk factors and potential treatments.

Who gets Parkinsons disease?

Estimates suggest that about 50,000 Americans are diagnosed with PD each year, although some estimates are much higher. Getting an accurate count of the number of cases is difficult because many people in the early stages of the disease may assume their symptoms are the result of normal aging and do not seek medical attention. Diagnosis is sometimes complicated by the fact that 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 affects about 50 percent more men than women, and the reasons for this discrepancy are unclear. While PD occurs in people throughout the world, a number of studies have found a higher incidence in developed countries. Other studies have found an increased risk in people who live in rural areas with increased pesticide use. However, those apparent risks are not fully characterized.

One clear risk factor for PD is age. The average age of onset is 60 years, and the incidence rises significantly with advancing age. However, about 5 to 10 percent of people with PD have "early-onset" disease that begins before the age of 50. Some early-onset cases are linked to specific gene mutations such as parkin. 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 about 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 often begins with dystonia and bradykinesia, and the symptoms often improve with levodopa medication.

What are the symptoms of the disease?

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. Tremor usually disappears during sleep or improves with intentional movement. It is usually the first symptom that causes people to seek medical attention.
Rigidity. Rigidity, or a resistance to movement, affects most people with PD. The muscles remain constantly tense and contracted so that the person aches or feels stiff. The rigidity becomes obvious when another person tries to move the individuals arm, which will move only in ratchet-like or short, jerky movements known as "cogwheel" rigidity.
Bradykinesia. This slowing down of spontaneous and automatic movement is particularly frustrating because it may make simple tasks difficult. The person cannot rapidly perform routine movements. Activities once performed quickly and easily—such as washing or dressing—may take much longer. There is often a decrease in facial expressions.
Postural instability. Postural instability, or impaired balance, causes affected individuals to fall easily.

PD does not affect everyone the same way, and 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. Even after the disease involves both sides of the body, the symptoms are often less severe on one side than on the other.

Friends or family members may be the first to notice changes in someone with early PD. They may see that the persons face lacks expression and animation (known as "masked face") or that the person moves more slowly.

Early symptoms of PD may be subtle and occur gradually. Affected people may feel mild tremors or have difficulty getting out of a chair. Activities may take longer to complete than in the past and individuals may note some stiffness in addition to slowness. They may notice that they speak too softly or that their handwriting is slow and looks cramped or small. This very early period may last a long time before the more classical and obvious motor (movement) symptoms appear.

As the disease progresses, the symptoms of Parkinsons disease may begin to interfere with daily activities. Affected individuals may not be able to hold utensils steady or they may find that the shaking makes reading a newspaper difficult. People with PD often develop a so-called parkinsonian gait that 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 (start hesitation), and they may stop suddenly as they walk (freezing).

A number of other symptoms may accompany PD, and some can be treated with medication or physical therapy.

Depression. This common disorder may appear early in the course of the disease, even before other symptoms are noticed. Some people lose their motivation and become dependent on family members. Fortunately, depression typically can be treated successfully with antidepressant medications such as amytriptyline or fluoxetine.
Emotional changes. Some people with PD become fearful and insecure, while 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. Food and saliva may collect in the mouth and back of the throat, which can result in choking or drooling. These problems may also make it difficult to get adequate nutrition. Speech-language therapists, occupational therapists (who help people learn new ways to perform activities of daily living), and dieticians can often help with these problems.
Speech changes. About half of all individuals with PD have speech difficulties that may be characterized as speaking too softly or in a monotone. Some may hesitate before speaking, slur, or speak too fast. A speech therapist may be able to help these individuals reduce some of these problems.
Urinary problems or constipation. In some people with PD, bladder and bowel problems can occur due to the improper functioning of the autonomic nervous system, which is responsible for regulating smooth muscle activity. Medications can effectively treat some of these symptoms.
Skin problems. In PD, the skin on the face may become 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. Standard treatments for skin problems can help.
Sleep problems. Sleep problems are common in PD and 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 of these sleep issues. Many of these problems respond to specific therapies.
Dementia or other cognitive problems. Some people with PD may develop memory problems and slow thinking. Cognitive problems become more severe in late stages of PD, and a diagnosis of Parkinson’s disease dementia (PDD) may be given. Memory, social judgment, language, reasoning, or other mental skills may be affected. There is currently no way to halt PD dementia, but drugs such as rivastigmine, donepezil, or memantine may help. The medications used to treat the motor symptoms of PD may cause confusion and hallucinations.
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
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