Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't produce enough of a brain chemical called dopamine. Sometimes it is genetic, but most cases do not seem to run in families. Exposure to chemicals in the environment might play a role.

Symptoms begin gradually, often on one side of the body. Later they affect both sides. They include

• Trembling of hands, arms, legs, jaw and face
• Stiffness of the arms, legs and trunk
• Slowness of movement
• Poor balance and coordination

As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple tasks. They may also have problems such as depression, sleep problems, or trouble chewing, swallowing, or speaking.

There is no lab test for PD, so it can be difficult to diagnose. Doctors use a medical history and a neurological examination to diagnose it.

PD usually begins around age 60, but it can start earlier. It is more common in men than in women. There is no cure for PD. A variety of medicines sometimes help symptoms dramatically. Surgery and deep brain stimulation (DBS) can help severe cases. With DBS, electrodes are surgically implanted in the brain. They send electrical pulses to stimulate the parts of the brain that control movement.

Like Alzheimer’s disease, Parkinson’s disease is a neurodegenerative disease. It was first characterized by James Parkinson in 1817. Each year, 50,000-60,000 people in the United States are diagnosed with the disease. Parkinson’s disease causes the loss of dopamine neurons in the substantia nigra, a midbrain structure that regulates movement. Loss of these neurons causes many symptoms including tremor (shaking of fingers or a limb), slowed movement, speech changes, balance and posture problems, and rigid muscles. The combination of these symptoms often causes a characteristic slow hunched shuffling walk, illustrated in the figure below. Patients with Parkinson’s disease can also exhibit psychological symptoms, such as dementia or emotional problems.

Although some patients have a form of the disease known to be caused by a single mutation, for most patients the exact causes of Parkinson’s disease remain unknown: the disease likely results from a combination of genetic and environmental factors (similar to Alzheimer’s disease). Post-mortem analysis of brains from Parkinson’s patients shows the presence of Lewy bodies—abnormal protein clumps—in dopaminergic neurons. The prevalence of these Lewy bodies often correlates with the severity of the disease.

There is no cure for Parkinson’s disease, and treatment is focused on easing symptoms. One of the most commonly prescribed drugs for Parkinson’s is L-DOPA, which is a chemical that is converted into dopamine by neurons in the brain. This conversion increases the overall level of dopamine neurotransmission and can help compensate for the loss of dopaminergic neurons in the substantia nigra. Other drugs work by inhibiting the enzyme that breaks down dopamine.

Parkinson’s patients often have a characteristic hunched walk.

Neurologist

Neurologists are physicians who specialize in disorders of the nervous system. They diagnose and treat disorders such as epilepsy, stroke, dementia, nervous system injuries, Parkinson’s disease, sleep disorders, and multiple sclerosis. Neurologists are medical doctors who have attended college, medical school, and completed three to four years of neurology residency.

When examining a new patient, a neurologist takes a full medical history and performs a complete physical exam. The physical exam contains specific tasks that are used to determine what areas of the brain, spinal cord, or peripheral nervous system may be damaged. For example, to check whether the hypoglossal nerve is functioning correctly, the neurologist will ask the patient to move his or her tongue in different ways. If the patient does not have full control over tongue movements, then the hypoglossal nerve may be damaged or there may be a lesion in the brainstem where the cell bodies of these neurons reside (or there could be damage to the tongue muscle itself).

Neurologists have other tools besides a physical exam they can use to diagnose particular problems in the nervous system. If the patient has had a seizure, for example, the neurologist can use electroencephalography (EEG), which involves taping electrodes to the scalp to record brain activity, to try to determine which brain regions are involved in the seizure. In suspected stroke patients, a neurologist can use a computerized tomography (CT) scan, which is a type of X-ray, to look for bleeding in the brain or a possible brain tumor. To treat patients with neurological problems, neurologists can prescribe medications or refer the patient to a neurosurgeon for surgery.

Parkinson's disease (PD) is 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, tremor, 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 appear in other diseases as well.

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

The four primary symptoms of PD are:

1. 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 a “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 or improves with a purposeful, intended movement.
2. Rigidity—Rigidity (muscle stiffness), 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 individual's arm, which will move only in short, jerky movements known as “cogwheel” rigidity.
3. Bradykinesia—This is a slowing down of spontaneous and automatic movement that 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 "masked face").
4. 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 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).

Other problems may accompany PD, such as:

• Depression—Some people lose their motivation and become dependent on family members.
• Emotional changes—Some people with PD become fearful and insecure, while others may become irritable or uncharacteristically pessimistic.
• 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, which can result in choking or drooling. Getting adequate nutrition may be difficult.
• 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.
• Urinary problems or constipation—Bladder and bowel problems can occur due to the improper functioning of the autonomic nervous system, which is responsible for regulating smooth muscle activity.
• Skin problems—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.
• 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.
• Dementia or other cognitive problems—Some people with PD develop memory problems and slow thinking. Cognitive problems become more severe in the late stages of PD, and some people are diagnosed with Parkinson's disease dementia (PDD). Memory, social judgment, language, reasoning, or other mental 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. 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 functions in the body. The medications used to treat PD may also contribute.
• 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. 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.
• 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 muscle stress or from overdoing activity when the person feels well. Fatigue may also result from akinesia, which is trouble initiating or carrying out movement.
• 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.
• Hallucinations, delusions, and other psychotic symptoms can be caused by the drugs prescribed for PD.

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 percent of people with PD have “early-onset” disease that 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. An estimated 15 to 25 percent of people with PD have a known relative with the disease. Some cases of the disease can be traced to specific genetic mutations.
• Exposure to pesticides—Studies show an increased risk of PD in people who live in rural areas with increased pesticide use.

The precise cause of PD is unknown, although some cases 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 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 next “relay station” of the brain, the corpus striatum, to produce smooth, purposeful movement. Loss of dopamine results impaired movement.

Studies have shown that most people with Parkinson's have lost 60 to 80 percent 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 non-motor features seen in PD, including fatigue and abnormalities of 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 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.

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 that are altered in inherited cases may also be altered 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 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 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.

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 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. Normally, the neurons in this area produce dopamine. Dopamine is the 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 Parkinson’s have lost 60 to 80 percent 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 non-motor features seen in PD, including fatigue and abnormalities of 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 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.

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 that are altered in inherited cases may also be altered 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 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 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.

The most prominent signs and symptoms of Parkinson’s disease occur when nerve cells in the basal ganglia, an area of the brain that controls movement, become impaired and/or die. Normally, these nerve cells, or neurons, produce an important brain chemical known as dopamine. When the neurons die or become impaired, they produce less dopamine, which causes the movement problems associated with the disease. Scientists still do not know what causes the neurons to die.

People with Parkinson’s disease also lose the nerve endings that produce norepinephrine, the main chemical messenger of the sympathetic nervous system, which controls many functions of the body, such as heart rate and blood pressure. The loss of norepinephrine might help explain some of the non-movement features of Parkinson’s, such as fatigue, irregular blood pressure, decreased movement of food through the digestive tract, and sudden drop in blood pressure when a person stands up from a sitting or lying position.

Many brain cells of people with Parkinson’s disease contain Lewy bodies, unusual clumps of the protein alpha-synuclein. Scientists are trying to better understand the normal and abnormal functions of alpha-synuclein and its relationship to genetic variants that impact Parkinson’s and Lewy body dementia.

Some cases of Parkinson’s disease appear to be hereditary, and a few cases can be traced to specific genetic variants. While genetics is thought to play a role in Parkinson’s, in most cases the disease does not seem to run in families. Many researchers now believe that Parkinson’s results from a combination of genetic and environmental factors, such as exposure to toxins.

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 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 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 (such as European Ashkenazi Jewish families) 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.
• DJ-1. This gene normally helps regulate gene activity and protect cells from oxidative stress and can cause rare, early forms of PD.
• PRKN (Parkin). The parkin gene is translated into a protein that normally 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.

What do we know about heredity and Parkinson's disease?

Parkinson's disease (PD) is a neurological condition that typically causes tremor and/or stiffness in movement. The condition affects about 1 to 2 percent of people over the age of 60 years and the chance of developing PD increases as we age. Most people affected with PD are not aware of any relatives with the condition but in a number of families, there is a family history. When three or more people are affected in a family, especially if they are diagnosed at an early age (under 50 years) we suspect that there may be a gene making this family more likely to develop the condition.

Genetics: The Basics

Our genetic material is stored in the center of every cell in our bodies (skin cells, hair cells, blood cells). This genetic material comes in individual units called genes. We all have thousands of genes. Genes carry the information the body needs to make proteins, which are the substances in the body that actually carry out all the functions we need to live and grow. Our genes affect many things about us: our height, eye color, why we respond to some medications better than others and our likelihood of developing certain conditions. We have two copies of every gene: we inherit one copy, one member of each pair, from our mother and the other from our father. We then pass only one copy of a gene from each pair of genes to the next generation. Whether we pass on the gene we got from our father or the one from our mother is purely by chance, like flipping a coin heads or tails.

We all have genes that don't work properly. In most cases the other copy of the gene makes up for the one that does not work properly and we are healthy. A problem only arises if we meet someone else who has a non-working copy of the same gene and we have a child who inherits two non-working copies of that gene. This is called recessive inheritance.

Sometimes if one of our genes is not working properly the other copy of the gene cannot make up for it and that causes a condition or an increased risk of developing a condition. Each time we have a child we randomly pass on one copy of each gene. If the child inherits the copy that doesn't work properly, they too may develop the condition. This is called dominant inheritance.

What genes are linked to Parkinson's disease?

In 1997, we studied a large family that came from a small town in Southern Italy in which PD was inherited from parent to child (dominant inheritance). We found the gene that caused their inherited Parkinson's Disease and it coded for a protein called alpha-synuclein. If one studies the brains of people with PD after they die, one can see tiny little accumulations of protein called Lewy Bodies (named after the doctor who first found them). Research has shown that there is a large amount of alpha-synuclein protein in the Lewy Bodies of people who have non-inherited PD as well as in the brains of people who have inherited PD. This immediately told us that alpha-synuclein played an important role in all forms of PD and we are still doing a lot of research to better understand this role.

Currently, seven genes that cause some form of Parkinson's disease have been identified. Mutations (changes) in three known genes called SNCA (PARK1), UCHL1 (PARK 5), and LRRK2 (PARK8) and another mapped gene (PARK3) have been reported in families with dominant inheritance. Mutations in three known genes, PARK2(PARK2), PARK7 (PARK7), and PINK1 (PARK6) have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson's disease (recessive inheritance). There is some research to suggest that these genes are also involved in early-onset Parkinson's disease (diagnosed before the age of 30) or in dominantly inherited Parkinson's disease but it is too early yet to be certain.

New research studies, called genome-wide association studies (GWAS) are an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. GWAS have been able to identify genetic variations that contribute to common diseases including Parkinson's disease.

What determines who gets Parkinson's disease?

In most cases inheriting a non-working copy of a single gene will not cause someone to develop Parkinson's disease. We believe that many other complicating factors such as additional genes and environmental factors determine who will get the condition, when they get it and how it affects them. In the families we have studied, some people who inherit the gene develop the condition and others live their entire lives without showing any symptoms. There is a lot of research on genes and the environment that is attempting to understand how all these factors interact.

Genetic Testing in Parkinson's Disease

Genetic testing has recently become available for the parkin and PINK1 genes. Parkin is a large gene and testing is difficult. At the current stage of understanding, testing is likely to give a meaningful result only for people who develop the condition before the age of 30 years. PINK1 appears to be a rare cause of inherited Parkinson's disease. A small percentage (~2 percent) of those developing the condition at an early age appear to carry mutations in the PINK1 gene. Genetic testing for the PARK7, SNCA and LRRK2 genes is also available.

Individuals and families who are interested in having genetic testing can learn more about their risk for Parkinson's disease and the availability and accuracy of genetic testing for this disease by setting up an appointment with a genetics health professional. Genetic professionals work as members of health care teams providing information and support to individuals or families who have genetic disorders or may be at risk for inherited conditions. Genetic professionals can discuss the risks, benefits and limitations of available genetic testing for Parkinson's disease.

Parkinson disease (PD) is a neurologic disease that affects the movement. The four main symptoms are tremors of the hands, arms, legs, jaw, or head, specially at rest; rigidity, or stiffness; bradykinesia, or slow movement; and postural instability or inability to find balance. The symptoms start slowly, but progress over time, impairing everyday activities such as walking, talking, or completing simple tasks. Other symptoms may include emotional problems, trouble swallowing and speaking; urinary problems or constipation; skin problems; sleep problems, low blood pressure when standing up from sitting or lying down (postural hypotension), and inexpressive face. Some people will loose their mental abilities (dementia).

Parkinson disease affects several regions of the brain, especially a region known as "substantia nigra" that helps controlling balance and movement. Most cases of PD are sporadic (with no family history), and with onset around 60 years of age; onset before age 20 years is considered to be juvenile-onset Parkinson disease, and after age 50 years is considered late-onset Parkinson disease. However, in some families, there are several cases of Parkinson disease. Familial cases of Parkinson disease, and maybe some sporadic cases, can be caused by changes (mutations) in several genes, such as:

• Mutations in the SNCA (PARK1), LRRK2 (PARK8), and VPS35 (PARK17) genes are inherited in an autosomal dominant manner.
• Mutations in genes PARK2, PARK7, and PINK1 (PARK6) appear to be inherited in a recessive manner.
• Very rare mutations in the TAF1 gene cause Parkinson disease with X-linked inheritance.
• Mutations in some genes, including GBA and UCHL1 (PARK 5), do not seem to cause Parkinson disease, but to increase the risk of developing the disease in some families.

Autosomal recessive PD have earlier onset than autosomal dominant PD. Some studies suggest that these genes are also involved in early-onset or juvenile PD. However, inheriting a mutation does not always mean that a person will have Parkinson's disease, because there may be other genes and environmental factors determining who will develop Parkinson disease.

Treatment is usually based on a medication known as levodopa. Other medication includes bromocriptine, pramipexole, ropinirole, amantadine, rasagiline and safinamide. Deep brain stimulation (DBS) a surgical procedure where electrodes are implanted into the brain may be useful for some people.Prognosis varies, and while some people become disabled, others will have only minor movement problems. Studies have shown that people with PD who have cognitive impairment, postural hypotension, and sleep problems may have a more rapid progression of the disease.

Inheritance

Most cases of Parkinson disease are classified as sporadic and occur in people with no apparent history of the disorder in their family. Although the cause of these cases remains unclear, sporadic cases probably result from a complex interaction of environmental and genetic factors. Additionally, certain drugs may cause Parkinson-like symptoms.

Approximately 15 percent of people with Parkinson disease have a family history of the disorder. These familial cases are caused by mutations in the LRRK2, PARK2, PARK7, PINK1, or SNCA gene, or by alterations in genes that have not yet been identified. Mutations in some of these genes may also play a role in cases that appear to be sporadic.

It is not fully understood how mutations in the LRRK2, PARK2, PARK7, PINK1, or SNCA gene cause Parkinson disease. Some mutations appear to disturb the cell machinery that breaks down (degrades) unwanted proteins. As a result, un-degraded proteins accumulate, leading to the impairment or death of dopamine-producing neurons. Other mutations may involve mitochondria, the energy-producing structures within cells. As a byproduct of energy production, mitochondria make unstable molecules, called free radicals, that can damage the cell. Normally, the cell neutralizes free radicals, but some gene mutations may disrupt this neutralization process. As a result, free radicals may accumulate and impair or kill dopamine-producing neurons.

In some families, alterations in the GBA, SNCAIP, or UCHL1 gene appear to modify the risk of developing Parkinson disease. Researchers have identified some genetic changes that may reduce the risk of developing the disease, while other gene alterations seem to increase the risk.

Normal Function

The PINK1 gene provides instructions for making a protein called PTEN induced putative kinase 1. This protein is found in cells throughout the body, with highest levels in the heart, muscles, and testes. Within cells, the protein is located in the mitochondria, the energy-producing centers that provide power for cellular activities. The function of PTEN induced putative kinase 1 is not fully understood. It appears to help protect mitochondria from malfunctioning during periods of cellular stress, such as unusually high energy demands.

Researchers believe that two specialized regions of PTEN induced putative kinase 1 are essential for the protein to function properly. One region, called the mitochondrial-targeting motif, serves as a delivery address: after the protein is made, this motif helps ensure that it is delivered to the mitochondria. Another region, called the kinase domain, probably carries out the protein's protective function.

Health Conditions Related to Genetic Changes

Parkinson's disease

Researchers have identified more than 70 mutations in the PINK1 gene that can cause Parkinson's disease, a condition characterized by progressive problems with movement and balance. PINK1 gene mutations are associated with the early-onset form of the disorder, which typically begins before age 50.

Many PINK1 gene mutations alter or eliminate the kinase domain, leading to a loss of protein function. At least one mutation affects the mitochondrial-targeting motif and may disrupt delivery of the protein to mitochondria. With reduced or absent PTEN induced putative kinase 1 activity, mitochondria may malfunction, particularly when cells are stressed. Cells can die if energy is not provided for essential activities. It is unclear how PINK1 gene mutations cause the selective death of nerve cells that characterizes Parkinson's disease. The loss of these cells weakens communication between the brain and muscles, and ultimately the brain becomes unable to control muscle movement.

Other Names for This Gene

• BRPK
• PARK6
• PINK1_HUMAN
• PTEN induced putative kinase 1

Genomic Location

Parkinson’s has four main symptoms:

• Tremor in hands, arms, legs, jaw, or head
• Muscle stiffness, where muscle remains contracted for a long time
• Slowness of movement
• Impaired balance and coordination, sometimes leading to falls

Other symptoms may include:

• Depression and other emotional changes
• Difficulty swallowing, chewing, and speaking
• Urinary problems or constipation
• Skin problems

The symptoms of Parkinson’s and the rate of progression differ among individuals. Early symptoms of this disease are subtle and occur gradually. For example, 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. Friends or family members may be the first to notice changes in someone with early Parkinson’s. They may see that the person’s face lacks expression and animation, or that the person does not move an arm or leg normally.

People with Parkinson's disease often develop a parkinsonian gait that includes a tendency to lean forward; take small, quick steps; and reduce swinging their arms. They also may have trouble initiating or continuing movement.

Symptoms often begin on one side of the body or even in one limb on one side of the body. As the disease progresses, it eventually affects both sides. However, the symptoms may still be more severe on one side than on the other.

Many people with Parkinson’s disease note that prior to experiencing stiffness and tremor, they had sleep problems, constipation, loss of smell, and restless legs. While some of these symptoms may also occur with normal aging, talk with your doctor if these symptoms worsen or begin to interfere with daily living.

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.

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. Muscles stiffen and movement may be slower. The person’s face may lack expression and animation (known as “masked face”). People may notice that they speak too softly or with hesitation, 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, symptoms 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).

Other problems may accompany PD, some of which can be treated with medication or different types of therapy (for example, physical therapy to maintain flexibility and help with balance, occupational therapy to learn new ways of handling everyday tasks that may be affected by the disease or its complications, vocational, and speech-language to help with speaking and swallowing).

• Depression. Some people lose their motivation and become dependent on family members.
• Emotional changes. Some people with PD become fearful and insecure, while others may become irritable or uncharacteristically pessimistic.
• 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, which can result in choking or drooling. Getting adequate nutrition may be difficult.
• 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.
• Urinary problems or constipation. Bladder and bowel problems can occur due to the improper functioning of the autonomic nervous system, which is responsible for regulating smooth muscle activity.
• Skin problems. 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.
• 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 of these sleep issues. Many of these problems respond to specific therapies.
• Dementia or other cognitive problems. Some people with PD develop memory problems and slow thinking. Cognitive problems become more severe in late stages of PD, and some people are diagnosed with Parkinson’s disease dementia (PDD). Memory, social judgment, language, reasoning, or other mental 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. 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 may also 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. 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.
• 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 muscle stress or from overdoing activity when the person feels well. Fatigue may also result from akinesia—trouble initiating or carrying out movement.
• 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.
• Hallucinations, delusions, and other psychotic symptoms can be caused by the drugs prescribed for PD.

PD is the most common form of parkinsonism, which describes disorders of other causes 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 (MSA) refers to a set of slowly progressive disorders that affect the central and autonomic nervous systems. The protein alpha-synuclein forms harmful filament-like aggregates in the supporting cells in the brain called oligodendroglia. MSA may have symptoms that resemble PD. It may also take a form that primarily produces poor coordination and slurred speech, or it may involve a combination of these symptoms. MSA with parkinsonian symptoms is sometimes referred to as MSA-P (or striatonigral degeneration).
• Lewy body dementia is associated with the same abnormal protein deposits (Lewy bodies) found in Parkinson's disease but appears in areas throughout the brain. Symptoms may range from primary parkinsonian symptoms such as bradykinesia, rigidity, tremor, and shuffling walk, to symptoms similar to those of Alzheimer's disease (memory loss, poor judgment, and confusion). These symptoms may fluctuate (vary) dramatically. Other symptoms may include visual hallucinations, psychiatric disturbances such as delusions and depression, and problems with cognition.
• Progressive supranuclear palsy (PSP) is a rare, progressive brain disorder caused by a gradual deterioration of cells in the brain stem. Symptoms may include problems with control of gait and balance (people often tend to fall early in the course of PSP), an inability to move the eyes, and alterations of mood and behavior, including depression and apathy as well as mild dementia. PSP is characterized by clumps of a protein called tau.
• Corticobasal degeneration (CBD) results from atrophy of multiple areas of the brain, including the cerebral cortex and the basal ganglia. Initial symptoms may first appear on one side of the body, but eventually affect both sides. Symptoms include rigidity, impaired balance, and problems with coordination. Other symptoms may include dystonia that affects one side of the body, cognitive and visual-spatial impairments, apraxia (loss of the ability to make familiar, purposeful movements), hesitant and halting speech, myoclonus (muscular jerks), and dysphagia (difficulty swallowing). CBD also is characterized by deposits of the tau protein.

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 a clearly inherited form of PD, researchers can test for known gene mutations as a way of determining 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.

There are currently no blood or laboratory tests to diagnose non-genetic cases of Parkinson’s. Doctors usually diagnose the disease by taking a person’s medical history and performing a neurological examination. If symptoms improve after starting to take medication, it’s another indicator that the person has Parkinson’s.

A number of disorders can cause symptoms similar to those of Parkinson’s disease. People with Parkinson’s-like symptoms that result from other causes, such as multiple system atrophy and dementia with Lewy bodies, are sometimes said to have parkinsonism. While these disorders initially may be misdiagnosed as Parkinson’s, certain medical tests, as well as response to drug treatment, may help to better evaluate the cause. Many other diseases have similar features but require different treatments, so it is important to get an accurate diagnosis as soon as possible.

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

Drug Therapy

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.

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

Medications

Levodopa-Carbidopa—The cornerstone of PD therapy is the drug levodopa (also known as L-dopa). 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 pass through the blood-brain barrier, which is a protective lining of cells inside blood vessels that regulate 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 levidopa 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:

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

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

• Hallucinations and psychosis
• Dyskinesia, or involuntary movements such as mild to severe twisting and writhing

Later in the course of the disease, people with PD may begin to 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, 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 longer periods of time. 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.

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 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 appears to enhance and prolong 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.

COMT inhibitors—COMT stands for catechol-O-methyltransferase and is another enzyme that breaks down dopamine. The drugs entacapone, opicapone, and tolcapone 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 certain 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 tremor 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 will assess how much the symptoms disrupt the person's life and then tailor therapy to the person's particular condition. Since no two people will 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

Surgery

Before the discovery of levodopa, surgery was an option for treating PD. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again considered for people with PD for whom drug therapy is no longer sufficient.

Pallidotomy and Thalamotomy

The earliest types of surgery for PD involved selectively destroying specific parts of the brain that contribute to PD symptoms. Surgical techniques have been refined and can be very effective for the motor symptoms of PD. 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 symptoms of tremor, rigidity, and bradykinesia, 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 treatment of PD. However, a method using focused ultrasound from outside the head is being tested because it creates lesions without the need for surgery.

Deep Brain Stimulation

Deep brain stimulation (DBS) uses an electrode surgically implanted into part of the brain, typically the subthalamic nucleus or the globus pallidus. Similar to a cardiac pacemaker, a pulse generator (battery pack) that is 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 using an external wand, 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. (The signal can be turned off using the wand.) Individuals must return to the medical center frequently for several months after DBS surgery in order to have the stimulation adjusted very carefully to give the best results. DBS is approved by the U.S. Food and Drug Administration (FDA) and is widely used as a treatment for PD.

• DBS is primarily used to stimulate one of three brain regions: the subthalamic nucleus, the globus pallidus interna, or the thalamus. Stimulation of either the globus pallidus or the subthalamic nucleus can reduce tremor, bradykinesia, and rigidity. Stimulation of the thalamus is useful primarily for reducing tremor.
• DBS does not stop PD from progressing, and 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 with levodopa-responsive PD who have developed dyskinesias or other disabling “off” symptoms despite drug therapy. DBS has not been demonstrated to be of benefit for “atypical” parkinsonian syndromes such as multiple system atrophy, progressive supranuclear palsy, or post-traumatic parkinsonism, which also do not improve with Parkinson's medications.

Although there is no cure for Parkinson’s disease, medicines, surgical treatment, and other therapies can often relieve some symptoms.

Medicines for Parkinson’s disease

Medicines can help treat the symptoms of Parkinson’s by:

• Increasing the level of dopamine in the brain
• Having an effect on other brain chemicals, such as neurotransmitters, which transfer information between brain cells
• Helping control non-movement symptoms

The main therapy for Parkinson’s is levodopa. Nerve cells use levodopa to make dopamine to replenish the brain’s dwindling supply. Usually, people take levodopa along with another medication called carbidopa. Carbidopa prevents or reduces some of the side effects of levodopa therapy — such as nausea, vomiting, low blood pressure, and restlessness — and reduces the amount of levodopa needed to improve symptoms.

People living with Parkinson’s disease should never stop taking levodopa without telling their doctor. Suddenly stopping the drug may have serious side effects, like being unable to move or having difficulty breathing.

The doctor may prescribe other medicines to treat Parkinson’s symptoms, including:

• Dopamine agonists to stimulate the production of dopamine in the brain
• Enzyme inhibitors (e.g., MAO-B inhibitors, COMT inhibitors) to increase the amount of dopamine by slowing down the enzymes that break down dopamine in the brain
• Amantadine to help reduce involuntary movements
• Anticholinergic drugs to reduce tremors and muscle rigidity

Deep brain stimulation

For people with Parkinson’s disease who do not respond well to medications, the doctor may recommend deep brain stimulation. During a surgical procedure, a doctor implants electrodes into part of the brain and connects them to a small electrical device implanted in the chest. The device and electrodes painlessly stimulate specific areas in the brain that control movement in a way that may help stop many of the movement-related symptoms of Parkinson’s, such as tremor, slowness of movement, and rigidity.

Other therapies

Other therapies that may help manage Parkinson’s symptoms include:

• Physical, occupational, and speech therapies, which may help with gait and voice disorders, tremors and rigidity, and decline in mental functions
• A healthy diet to support overall wellness
• Exercises to strengthen muscles and improve balance, flexibility, and coordination
• Massage therapy to reduce tension
• Yoga and tai chi to increase stretching and flexibility

A wide variety of complementary and supportive therapies 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. 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 else. Eating a fiber-rich diet and drinking plenty of fluids also can help alleviate constipation. A high protein diet, however, may limit levodopa's absorption.

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

Alternative approaches that are used by some individuals with PD include:

• A NINDS-funded clinical trial demonstrated the benefit of tai chi exercise compared to resistance or stretching exercises in people with PD
• Massage therapy to reduce muscle tension

• Yoga to increase stretching and flexibility
• Hypnosis acupuncture
• The Alexander Technique to optimize posture and muscle activity

NIH BRAIN Initiative-funded research a key first step to improving deep brain stimulation

Deep brain stimulation has been used to treat Parkinson’s disease symptoms for 25 years, but limitations have led researchers to look for ways to improve the technique. This study describes the first fully implanted DBS system that uses feedback from the brain itself to fine-tune its signaling. The study was supported by the National Institutes of Health’s Brain Research through Advancing Innovative Technologies (BRAIN) Initiative and the National Institute of Neurological Disorders and Stroke (NINDS).

“The novel approach taken in this small-scale feasibility study may be an important first step in developing a more refined or personalized way for doctors to reduce the problems patients with Parkinson’s disease face every day,” said Nick B. Langhals, Ph.D., program director at NINDS and team lead for the BRAIN Initiative.

Deep brain stimulation is a method of managing Parkinson’s disease symptoms by surgically implanting an electrode, a thin wire, into the brain. Traditional deep brain stimulation delivers constant stimulation to a part of the brain called the basal ganglia to help treat the symptoms of Parkinson’s. However, this approach can lead to unwanted side effects, requiring reprogramming by a trained clinician. The new method described in this study is adaptive, so that the stimulation delivered is responsive in real time to signals received from the patient’s brain.

“This is the first time a fully implanted device has been used for closed-loop, adaptive deep brain stimulation in human Parkinson’s disease patients,” said Philip Starr, M.D., Ph.D., professor of neurological surgery, University of California, San Francisco, and senior author of the study, which was published in the Journal of Neural Engineering.

In a short-term feasibility trial, two patients with Parkinson’s received a fully implanted, adaptive deep brain stimulation device. The device differs from traditional ones in that it can both monitor and modulate brain activity. In this work, sensing was done from an electrode implanted over the primary motor cortex, a part of the brain critical for normal movement. Signals from this electrode are then fed into a computer program embedded in the device, which determines whether to stimulate the brain. For this study the researchers taught the program to recognize a pattern of brain activity associated with dyskinesia, or uncontrolled movements that are a side effect of deep brain stimulation in Parkinson’s disease, as a guide to tailor stimulation. Stimulation was reduced when it identified dyskinesia-related brain activity and increased when brain sensing indicated no dyskinesia to minimize deep brain stimulation-related side effects.

Results of initial, short-term studies aimed at demonstrating feasibility and effectiveness of using adaptive deep brain stimulation to overcome the impediment to movement of Parkinson’s suggested that this adaptive approach was equally effective at controlling symptoms as traditional deep brain stimulation. Doctors saw and patients noticed no differences in the improvement in movement under adaptive stimulation versus constant, open loop stimulation set manually by the researchers. Because adaptive deep brain stimulation did not continuously stimulate the brain, the system saved about 40 percent of the device’s battery energy used during traditional stimulation. The short time periods over which movement was assessed did not permit comparison of the two deep brain stimulation paradigms relative to incidence of dyskinesia, but it is hoped that the variable stimulation will also translate into a reduction in adverse effects when tested over longer time periods.

“Other adaptive deep brain stimulation designs record brain activity from an area adjacent to where the stimulation occurs, in the basal ganglia, which is susceptible to interference from stimulation current” said Dr. Starr. “Instead, our device receives feedback from the motor cortex, far from the stimulation source, providing a more reliable signal.”

Many patients with Parkinson’s disease who would benefit from deep brain stimulation are difficult to treat because too much stimulation can cause dyskinesia. Thus, finding the correct level of stimulation is like trying to hit a constantly moving target. An adaptive system like the one being tested here could offer an effective alternative and may also limit adverse effects of traditional deep brain stimulation, but considerable testing remains to be done.

“Here we have demonstrated the feasibility of adaptive deep brain stimulation,” said Dr. Starr. “We are now planning larger, longer-term trials to determine how effective this system is in managing the symptoms of patients with Parkinson’s disease.”

This study was supported by the NIH’s BRAIN Initiative (NS100544), the NINDS (NS090913), the UC President's Postdoctoral Fellowship, NSF EEC-1028725, and a NDSEG graduate fellowship.

Fully-implanted adaptive DBS system
Stimulating and sensing electrodes are implanted in the brain and connect to small computer under the skin. Data from this computer can be read by an external device. Image courtesy ofKen Probst/Starr lab

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 an individual person.

While PD usually progresses slowly, eventually daily routines may be affected—from socializing with friends to earning a living and taking care of a home. These changes can be difficult 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. A list of national organizations that can help people locate support groups in their communities appears at the end of this information. Individual or family counseling may also help people find ways to cope with PD.

People with PD may also benefit from being proactive and finding out as much as possible about the disease in order to alleviate fear of the unknown and to take a proactive role in maintaining their health. 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.

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use the knowledge to reduce the burden of neurological disease. NINDS, a component of the National Institutes of Health (NIH), conducts and supports research on Parkinson's disease are to better understand and diagnose PD, develop new treatments, and ultimately, prevent PD. NINDS also supports training for the next generation of PD researchers and clinicians and serves as an important source of information for people with PD and their families.

Establishing PD research priorities

The NINDS-organized Parkinson's Disease 2014: Advancing Research, Improving Lives conference brought together researchers, clinicians, patients, caregivers, and nonprofit organizations to develop 31 prioritized recommendations for research on PD. These recommendations are being implemented through investigator-initiated grants and several NINDS programs. NINDS and the NIH's National Institute of Environmental Health Sciences held the Parkinson's Disease: Understanding the Environment and Gene Connection workshop to identify priorities for advancing research on environmental contributors to PD.

Key programs and resources

• The Parkinson's Disease Biomarkers Programs (PDBP), a major NINDS initiative, is aimed at discovering ways to identify individuals at risk for developing PD and Lewy Body Dementia and to track the progression of the diseases. It funds research and collects human biological samples and clinical data to identify biomarkers (signs that may indicate risk of a disease and improve diagnosis) that will speed the development of novel therapeutics for PD. Goals are improving clinical trials and earlier diagnosis and treatment. Projects are actively recruiting volunteers at sites across the U.S. NINDS also collaborates with the Michael J. Fox Foundation for Parkinson's Research (MJFF) on BioFIND, a project collecting biological samples and clinical data from healthy volunteers and those with PD.
• 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 Accelerating Medicines Partnership^® for Parkinson's Disease (AMP^® -PD) program is a partnership between the NIH, multiple biopharmaceutical and life sciences communities, and nonprofit advocacy organizations to identify and validate biomarkers that can track the progression of PD. It allows scientists to perform large-scale genetic analyses and share data to more quickly bring new medicines to people either with or at risk of PD.
• The NINDS Intramural Research Program conducts clinical studies to better understand PD mechanisms and develop novel and improve treatments.
• The NINDS Biospecimens Repositories store and distribute DNA, cells, blood samples, cerebrospinal fluid, and autopsy tissue to PD researchers around the world.

Disease research

NINDS research looks at all aspects of the mechanisms of PD, identifying clues to PD development and its processes, and improving current therapies and testing new ones. Research efforts include:

Cellular Processes—Mutations in alpha-synuclein and dozens of genes (some of which were discovered at NIH) are known to either cause PD or modify a person's risk of developing it. Researchers are investigating how the cellular processes controlled by these genes contribute to neurodegeneration, including the toxic accumulation of alpha-synuclein and how the loss of dopamine impairs communication between nerve cells.

Deep Brain Stimulation (DBS)—NINDS has been a pioneer in the study and development of DBS, which is now considered a standard treatment response to PD medications. Current NINDS-funded projects include research to fine-tune the optimal site within the brain to implant the DBS electrode, studies to better understand the therapeutic effect of DBS on neural circuitry and brain regions affected by PD, and different forms of brain stimulation on different areas of the brain.

Environmental studies—Risk factors such as repeated occupational exposure to certain pesticides and chemical solvents may influence who develops PD. A NINDS-funded research consortium is hunting for environmental risk factors that increase susceptibility to developing PD.

Genetic studies—A better understanding of genetic risk factors is playing a critical role in revealing PD disease mechanisms. A NINDS workshop contributed to the development of NeuroX, the first DNA chip that can identify genetic changes in persons at risk for a number of late-onset neurodegenerative diseases, including PD. Another NINDS collaborative, the Consortium On Risk for Early-onset Parkinson's Disease (CORE PD), is trying to identify the genetic factors that contribute to the development of early-onset PD. Current clinical studies include the genetic connection to memory and motor behavior, the search for genes that may increase the risk of PD and related neurodegenerative disorders, and identifying biomarkers for PD.

Motor complications—NINDS scientists have studied the safety and effectiveness of drugs and interventions in alleviating motor symptoms in people with PD. For example, basic research using adenosine found it could improve motor complications associated with PD. A current NINDS clinical study of motor complications is testing an at-home device to evaluate PD movement symptoms while performing different tasks.

Exercise—Exercise routines are often recommended to help individuals with PD maintain movement and balance necessary for everyday living. Research continues on the role of exercise in slowing the decline of motor function and modifying the course of PD.

Neuroprotective Drugs—NINDS supports basic, clinical, and translational research aimed at protecting nerve cells from the damage caused by PD. The NINDS-funded NeuroNext Network is designed to test new therapies and to validate biomarkers in a number of neurological disorders, including Parkinson's disease.

At a Glance

• Researchers were able to track the spread of the protein thought to cause Parkinson’s disease from the gut to the brain by way of the vagus nerve in mice.
• Results from the study suggest that finding a way to stop the spread of this protein from gut to brain might help prevent Parkinson’s disease in people.

The brains of people with Parkinson’s disease contain abnormal clumps of proteins called Lewy bodies. These clumps are largely made up of the protein alpha-synuclein, which plays a role in crosstalk between brain cells. Lewy bodies interrupt this communication and are thought to be toxic to certain neurons in the brain.

These neurons produce a chemical called dopamine, which is vital for normal brain functioning. When dopamine-producing neurons start to die, the symptoms of Parkinson’s disease emerge. These include shaking, stiffness, and difficulty with walking, balance, and coordination. Some people also experience depression, anxiety, and memory loss. There is no cure for Parkinson’s disease, but treatments can provide relief from its symptoms for some time.

Abnormal clusters of alpha-synuclein have also been found in the guts of people with Parkinson’s disease. Researchers have proposed that alpha-synuclein may actually first misfold and accumulate in the gut. Recent studies showed that alpha-synuclein clumps can cause nearby normal alpha-synuclein proteins to misfold and form more clumps. These findings suggest that a chain reaction started by misfolded alpha-synuclein could travel from the gut all the way up the vagus nerve, which connects directly to the brain.

To further test this idea, researchers led by Drs. Ted Dawson and Hanseok Ko from Johns Hopkins University injected misfolded alpha-synuclein into a thin layer of muscle in the guts of mice and tracked whether it progressed to the brain. The research was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA). Results were published on June 26, 2019, in Neuron.

The researchers found that misfolded alpha-synuclein slowly spread to regions of the mouse brain associated with Parkinson’s disease, and dopamine-producing neurons started to die. The injected mice performed worse on tests of movement, dexterity, strength, memory, and mental health than mice that hadn’t received misfolded alpha-synuclein.

The scientists also found that interfering with the chain reaction caused by the misfolded protein stopped the spread of alpha-synuclein from gut to brain. Mice that had their vagus nerve cut before injection of the misfolded alpha-synuclein into their guts did not have the protein spread to their brains. Mice engineered not to produce any normal alpha-synuclein of their own also had no signs of the misfolded protein in their brains. Both these sets of mice performed similarly on all the tests to mice that didn’t receive any misfolded alpha-synuclein.

“These findings provide further proof of the gut’s role in Parkinson’s disease, and give us a model to study the disease’s progression from the start,” Dawson says. Blocking the transmission of alpha-synuclein from gut to brain “presents a target for early intervention in the disease.”

In addition to providing further insights into Parkinson’s disease, this mouse system could allow researchers to test treatments that might prevent or halt disease progression.

Brain images of dopamine neurons in mice injected in the gut with misfolded alpha-synuclein (right) and control injected animals (left). Ted Dawson et al. / Neuron, 2019

Introduction

NIEHS is one of the lead research agencies studying environmental links to Parkinson’s disease. The institute works closely with other research programs within the National Institutes of Health (NIH), as well as partners and scientists across the country, to look at every aspect of this disease.

What is Parkinson's Disease?

Parkinson's disease is neurodegenerative, the second most common disorder of this type after Alzheimer's disease.

Within your body, nerves transmit information to and from the brain or spinal cord, which affects muscles and organs. Neurodegeneration means that your nerves are not functioning normally. Parkinson’s disease is a progressive and unending movement disorder.

What is NIEHS Doing?

NIEHS supports diverse research, involving experts from many disciplines, to uncover what may cause or help prevent Parkinson’s disease. Varied methods are important because no one can predict which paths of study will provide major breakthroughs. Basic research on Parkinson's will continue to help us advance our understanding of the disease. Highlights from NIEHS research are described below, grouped by environmental factors that may affect Parkinson’s and by research approaches.

Pesticides

Mounting evidence, from animal and human studies, suggests that exposure to certain types of pesticides can increase a person’s risk of developing Parkinson's disease.

• A 17-year long, NIEHS-funded study of the links among Parkinson’s disease, environment, and genes shows that some pesticides, including paraquat, maneb, ziram, benomyl, and several organophosphate pesticides, including diazinon and chlorpyrifos, contribute to Parkinson’s disease onset and progression.
• Other NIEHS research found that people who occupationally used two pesticides, rotenone or paraquat, developed Parkinson’s disease 2.5 times more often than nonusers.
• In addition, people exposed to pesticides in the home or garden may face a greater chance of developing Parkinson’s disease.
• Pesticides may directly or indirectly disrupt the biological pathways that normally protect dopaminergic neurons, the brain cells selectively attacked by the disease.
• Some pesticides, like rotenone, can directly block the function of mitochondria, the structures that create energy to run the cell. NIEHS researchers showed in mice that disrupting mitochondria through exposure to rotenone early in development changed the epigenome – the chemical tags that turn genes on and off – in ways that persisted throughout life.
• Other pesticides, like paraquat, have been found to increase production of free radicals that can damage cells.

Some people are more vulnerable to the harmful effects of pesticides because of their age or genetic makeup.

• Many studies identified genetic variations that provide insight into why certain people appear to be at higher risk of developing Parkinson’s.
• Using data from the NIEHS-conducted Agricultural Health Study, researchers found that Parkinson's risk from paraquat use was particularly high in people with a particular variant of a gene known as GSTT1.
• Similarly, other research has indicated that people with lower levels of the PON1 gene, which is important for the metabolism of organophosphate pesticides, showed faster progression of the disease.

Further research into links between preventable exposures and Parkinson’s disease, as well as preventative therapies, could help reduce the incidence of the disease. For example, using protective gloves and other hygiene practices reduced the risk of Parkinson’s disease among farmers using paraquat, permethrin, and trifluralin.⁷

Trichloroethylene (TCE)

TCE is a chemical compound used in industrial degreasing, dry cleaning, and some household cleaning products. It can be released into the environment from industrial sites, contaminating air, water, and soil.

The National Toxicology Program states TCE is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans. It has been linked to kidney, liver, and blood cancers.

NIEHS-funded researchers show exposure to TCE may affect protein kinase LRRK2, a gene that is active in the brain and other body tissues, and elevate the risk of Parkinson's.

Head Injuries

Numerous studies over the years suggest that head injuries could contribute to Parkinson's disease through the death of dopaminergic neurons. Head injuries can be particularly damaging for people exposed to pesticides such as paraquat⁸ as well as those who carry a genetic risk factor in the alpha-synuclein gene.⁹ Individuals with head injuries who lived or worked near areas where paraquat had been applied were several times more likely to develop Parkinson’s disease.

Air Pollution

Air pollution is a mixture of hazardous substances from both human-made and natural sources. The harmful effects of air pollution on the heart and lungs are well-documented, although effects on the brain are less understood. Recent studies suggest that air pollution might act on the biological pathways that are involved in Parkinson’s disease. For example, one study found that exposure to high air pollution levels caused neuroinflammation, an altered brain immune response, and an accumulation of toxic alpha-synuclein deposits starting in childhood.

When looking at the general population, a study by NIEHS researchers and their collaborators found limited evidence of an association between air quality and Parkinson’s disease risk. However, the study showed that gender and smoking status made a difference. The findings indicated that female nonsmokers exposed to high levels of particulate matter in air pollution had an increased risk of developing the disease. The research suggests further work is needed to study the impact of air pollution on this potentially vulnerable population.

Diet and Lifestyle

Diet and lifestyle factors may contribute to the development and progression of Parkinson's disease. Understanding the role that these factors could play in the disease could inform future prevention and treatment.

Caffeine. Caffeine may reduce the chance of developing the disease. NIEHS researchers looked at data from a large sample of older Americans, and found that higher caffeine intake was associated with lower risk of Parkinson's in both men and women. A separate study found that Parkinson’s disease patients who were lifelong coffee drinkers had slower progression, less cognitive decline, and reduced mortality.Animal studies have also shown that caffeine can protect the brain's dopaminergic neurons.

Cooking meat. Heterocyclic amines (HCAs) are chemicals that are produced during high temperature meat cooking. These compounds have been investigated for their role in cancer, but not as much for their effect on neurodegenerative diseases. Working in animal models, NIEHS grantees showed that a variety of different HCAs were selectively toxic to the dopaminergic neurons affected in Parkinson’s disease. The findings are important because HCAs are a commonly consumed dietary component.

Vitamin D. Several studies suggest vitamin D deficiency may be involved in the development of Parkinson's. Vitamin D, obtained through food or sunlight, plays an important role in regulating the normal function of brain cells, as well as in maintaining good balance and muscle strength. NIEHS-funded scientists at the UCLA School of Public Health found genetic variants that affect the body’s ability to respond to vitamin D may influence a person’s susceptibility to cognitive decline in Parkinson’s disease. Additional studies are needed to further clarify this association.

Exercise. Regular exercise can improve a person’s quality of life and can influence many chronic diseases, including cardiovascular disease and cancer. Several studies suggest that those benefits may extend to protecting against Parkinson's disease. In older U.S. adults, higher levels of moderate to vigorous physical activity during middle age were associated with lower risk of Parkinson's. Exercise may also benefit patients with the disease, by improving balance and reducing depression. For example, some work has suggested that tai chi training in patients with mild to moderate Parkinson's improved balance and reduced falls. A recent study showed that a history of competitive sports and more lifelong physical exercise also predicted slower motor and cognitive decline in patients with Parkinson’s disease.

Heavy metals and the workplace. Welders exposed to the heavy metal manganese may develop symptoms associated with Parkinson’s disease, including slowness of movement in the arms and hands, speech problems, and reduced facial expressions. These symptoms may get worse the more workers are exposed, even when the concentrations of manganese are below the regulatory limit. NIEHS grantees discovered how manganese exposure can lead to aggregation and spread of toxic clumps of alpha-synuclein proteins. This study provides new information about the biological processes that link manganese exposure and the onset of Parkinson’s-like symptoms.

Predicting Disease

Some of the risk factors and premotor symptoms that may be involved in Parkinson's.

Premotor symptoms of Parkinson’s disease may occur years before some muscular problems surface. By thinking of Parkinson's as a systemic illness that takes decades to develop, researchers may better understand the causes of the disease and its progression. Some early warning indicators include premotor symptoms, including constipation, loss of smell, fatigue, and mood or anxiety disorders.

NIEHS-funded researchers developed a mathematical algorithm that could provide an early indicator to physicians that patients may need to be evaluated for the disease. The predictive model relies on demographic data, as well as medical tests and diagnoses available in Medicare claims data, to identify people with a high probability of being diagnosed with Parkinson’s disease. This method may also be used to identify other factors, such as environmental hazards, that may be associated with a higher or lower risk of the disease.

Other work by NIEHS-funded scientists identified a chemical signature, or biomarker, in blood that predicts the rapid progression of the disease’s motor progression. The scientists also identified biomarkers that suggest the immune system of Parkinson’s disease patients ages faster. The findings represent an important step forward in understanding how the illness evolves over time.

Understanding Disease Progression

Over the past few decades, the development and use of animal models have provided valuable insight into the symptoms of Parkinson's and how the disease progresses. Learning what causes the selective loss of dopamine neurons may inform development of new therapies that slow or reverse disease progression.

Other researchers are using nematodes and zebrafish to test the role that some chemicals may play in the brain, and to better understand how neurodegeneration occurs.

Brain imaging techniques and genome-wide association studies provide additional insight into the molecular causes of Parkinson's.

Grant-funded Research at NIEHS

Beyond the above-mentioned research findings, NIEHS is funding more than 45 grant projects related to Parkinson's disease.

One way that the institute supports Parkinson’s research is through its Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program. This program provides long-term funding for researchers tackling challenging, but potentially revolutionary, lines of research.

For example, in 2019 Kim Tieu, Ph.D., of the Stemple College of Public Health and Social Work in Miami, Florida, is investigating environmental factors that may trigger the death of brain cells in Parkinson’s disease. A goal is to develop therapies that prevent their loss. Specifically, Tieu plans to study how manganese and pesticides promote the accumulation and spread of toxic proteins in the brain.

In-house Research at NIEHS

At NIEHS, multidisciplinary teams of distinguished researchers work in our labs to understand the role of the environment, genes, and gene-environment interactions in Parkinson’s disease.

• The Ion Channel Physiology Group studies the structure, function and regulation of the Cys-loop ligand-gated ion channel superfamily, with a particular focus on the nicotinic acetylcholine receptor channels and their role in neurological disorders.
• The Neuropharmacology Group has several projects to explain mechanisms involved in the pathogenesis of Parkinson's disease and to develop novel therapeutic agents that target these mechanisms as a means to halt disease progress.