Parkinson’s Disease

The National Institute of Environmental Health Sciences (NIEHS) is one of the lead research agencies studying the environmental causes of Parkinson’s disease, a neurodegenerative disease thought to be caused by the interaction of genes and environment. NIEHS works closely with other institutes and centers of the National Institutes of Health (NIH), as well as partners and researchers across the country, to look at every aspect of Parkinson’s.

What is Parkinson’s Disease?

Parkinson’s disease is a progressive neurodegenerative disease, the second most common disorder of this type after Alzheimer’s disease. It progresses slowly as small clusters of dopaminergic neurons in the mid-brain die. The gradual loss of these neurons results in reduction of a critical neurotransmitter called dopamine, a chemical responsible for transmitting messages to parts of the brain that coordinate muscle movement.

Parkinson’s patients have less dopamine

Studies have shown that the symptoms of Parkinson’s usually appear when 50 percent or more of the dopamine neurons in the mid-brain have been lost. Symptoms begin gradually and typically worsen over time.

How many people are affected by Parkinson’s Disease?

It is difficult to know exactly how many people have Parkinson’s disease, since there is no national registry, but it is estimated that at least 500,000 people in the U.S. currently have the disease.  The average age of onset is about 60, and prevalence is increasing as the population ages.

The majority of people diagnosed have late-onset sporadic Parkinson’s, which does not have a clear genetic cause. About 10 percent have early-onset Parkinson’s that often begins before the age of 50. There may be a genetic cause associated with many of these patients. Parkinson’s strikes people of all races, ethnic groups, nationalities, and income levels. Actor Michael J. Fox, singer Linda Ronstadt, former U.S. Attorney General Janet Reno, and boxer Muhammad Ali, are among the celebrities living with Parkinson’s.

What causes Parkinson’s Disease?

The exact cause of Parkinson’s disease is unknown. Most researchers agree that the disease is caused by both genetic and environmental factors, and by interactions among these factors.

A full understanding of Parkinson’s risk requires integrated efforts to study both genetic and environmental factors. If environmental exposures can be identified, it may lead to new targets for prevention and intervention.

What are the symptoms of Parkinson’s Disease?

Common motor symptoms include:

• Tremors or shaking in hands, arms, legs, jaw, and face
• Rigidity or stiffness of limbs and trunk
• Slowness of movement
• Difficulties with balance, speech, and coordination

There are also non-motor symptoms which may develop years before the onset of motor problems. These may include:

• Poor sense of smell
• Constipation
• Depression
• Cognitive impairment
• Fatigue

Accumulating evidence indicates that pesticide exposure is associated with an increased risk for developing Parkinson’s disease. Many animal studies have provided evidence for this, and several human studies are beginning to reveal some specific pesticides and classes of pesticides that may be linked to Parkinson’s.

Organochlorine insecticides comprise the pesticide class most commonly associated with the disease. Most of these chemicals were banned in the 1970s and 1980s, but because their chemical structures resist breakdown, they can remain in the environment and food chain for a long time. The organochlorine class includes pesticides like DDT, used for mosquito control, and dieldrin, used for termites.

A study published in 2011 by NIEHS researchers and collaborators at the Parkinson’s Institute and Clinical Center in Sunnyvale, Calif., showed a link between the occupational use of two pesticides, rotenone and paraquat, and Parkinson’s. People who reported use of either pesticide developed the disease 2.5 times more often than nonusers.

Rotenone directly inhibits the function of mitochondria, the structures that create energy to run the cell, while paraquat increases production within cells of certain damaging oxygen derivatives. People who used other pesticides with a similar mechanism of action were also more likely to develop Parkinson’s.

Researchers are trying to understand which people, exposed to specific pesticides, are most at risk of developing Parkinson’s. For example, a recent study found that Parkinson’s risk from paraquat use was particularly high in individuals lacking a certain metabolic enzyme known as GSTT1. The lack of this enzyme is very common, so more research is needed to determine if these individuals are more susceptible to certain pesticides.

Other researchers are studying the combined effect of environmental exposures, like pesticides, and genetic susceptibility on Parkinson’s risk. Studies conducted by NIEHS-funded scientists at the UCLA School of Public Health have shown that the risk of developing Parkinson’s in pesticide-exposed individuals was greater in those who had a gene variation that affected dopamine transport than in those who did not.

Dietary factors

Both in-house researchers and grantees are continuing to explore the role that diet, and lifestyle play in the onset, progression, and treatment of Parkinson’s disease.

How much fat a person consumes in their diet is one area under study. Unfortunately, the findings over the years have been inconsistent. However, in a new study, NIEHS researchers and their collaborators discovered that some fats in a person’s diet may be associated with lower risk for Parkinson’s.

A 2013 study found that people who ate a diet high in polyunsaturated fatty acids and low in saturated fat had a lower risk of developing the disease. Although the results need to be confirmed, they provide additional evidence that it can be beneficial to eat foods high in polyunsaturated fat.

Researchers are also exploring the role of vitamin D deficiency in the development of Parkinson’s. Vitamin D, which can enter the body through food or sunlight, plays an important role in maintaining good balance and muscle strength, and in protecting the body from infections and diseases. Researchers are looking into the role that working outdoors may play in reducing the risk of Parkinson’s.

Another dietary component under study is the possible role of caffeine in the onset and progression of Parkinson’s. Animal studies have shown that caffeine can protect the brain’s dopaminergic neurons, indicating caffeine may reduce the risk of the disease. Researchers also 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 collaborative study found that coffee consumption may be more protective among individuals with one genotype as compared to individuals with another genotype.

Exercise

NIEHS in-house researchers have shown that there is at least one more reason to exercise on a daily basis it may protect against Parkinson’s disease. In a large population of U.S. older adults, higher levels of moderate to vigorous physical activity in midlife were associated with lower risk of Parkinson’s.

Exercise may also benefit patients with the disease, by improving balance and reducing depression, and increasing overall quality of life. For example, a recent study found that tai chi training in patients with mild to moderate Parkinson’s improved balance and reduced falls.

Nicotine

Despite the numerous adverse health effects of cigarette smoking, a large number of studies have consistently found that smokers have a lower incidence of Parkinson’s disease than nonsmokers.

It is not clear why this occurs but is likely related to the fact that nicotine interacts with receptors to protect dopamine neurons. Nicotine has also been shown to be neuroprotective in animal models.

NIEHS researchers looked at data from a large study to see if they could determine the characteristics of smoking behavior that decreased Parkinson’s risk. They found that more years of smoking, rather than increased number of cigarettes smoked per day, was linked closely to lowering risk of Parkinson’s among smokers. NIEHS researchers are also investigating whether genetic factors modify the associations between smoking and Parkinson’s.

Head injuries

Numerous studies over the years have looked at the role that head injuries may play in Parkinson’s disease. This is a reasonable area to explore, since brain injuries involve inflammation, oxidative stress, and possible disruption of the blood-brain barrier, all of which may play a contributing role in neuronal degeneration and Parkinson’s.

Recent studies involving NIEHS researchers further found that the association between head injury and Parkinson’s may be affected by genetic factors. For example, researchers found that certain variations of a key Parkinson’s gene, SNCA, might modify the association between head injury and Parkinson’s disease risk.

NIEHS is currently funding more than 30 grants focused on neurodegenerative diseases, including Parkinson’s disease. There is also a very strong in-house research community working to understand the role of the environment, genes, and gene-environment interactions in the disease.

The multidisciplinary teams of researchers at NIEHS and across the country are working toward ways to prevent Parkinson’s disease or slow its progression.

Moving forward with promising research areas

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

Identifying premotor symptoms before disease sets in One new area of research that NIEHS is pursuing is the premotor symptoms that may occur years before some of the classic muscular deficits surface. By thinking of Parkinson’s as a systemic illness that takes decades to develop, researchers will be better poised to understand the cause of the disease and its initial progression. Some of the early warning indicators discussed were premotor symptoms, including constipation, loss of smell, excessive daytime sleepiness, mood or anxiety disorders, and sleep disorders. Many of these symptoms may occur years before Parkinson’s disease is diagnosed. Although it is difficult to identify a single early symptom that is specifically tied to the disease, researchers are working to identify whether a combination of symptoms may help characterize high-risk populations

Air pollution

Researchers are beginning to explore the role that air pollution may play in the development and progression of brain diseases, such as Parkinson’s disease. Much of the previous research on air pollution has been focused on heart and lung diseases, rather than neurodegenerative diseases.

NIEHS will also continue to support basic research on Parkinson’s, in order to find new approaches and models to advance our understanding of the disease.

For the past few decades, the development and use of animal models have provided valuable insight into the classical motor symptoms of Parkinson’s. These models will continue to shed new light on the pathophysiology of Parkinson’s. Understanding the mechanisms that account for the selective loss of dopamine neurons may provide important clues to explain how Parkinson’s develops, so that therapies can be developed to slow or reverse disease progression. For example, some researchers are beginning to use stem cells that can be induced to develop into dopamine neurons, in order to test new cell-based therapies for central nervous system disorders such as Parkinson’s. Other researchers are using animal models, such as zebrafish, to look at 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 are providing us with additional insight into the molecular causes of Parkinson’s. Since no one can predict which paths of study will provide major breakthroughs, NIEHS will continue to support diverse research, involving experts from a wide range of disciplines.

The Neuropharmacology Group is involved in a number of projects to elucidate the mechanisms involved in the pathogenesis of Parkinson’s disease (PD) and to develop novel therapeutic agents that target these mechanisms as a means to halt the progress of neurodegenerative diseases.

Jau-Shyong (John) Hong, Ph.D., heads the Neuropharmacology Group and holds a secondary appointment in the NIEHS Immunity, Inflammation, and Disease Laboratory. The Neuropharmacology Group is involved in a number of projects to elucidate the mechanisms involved in the pathogenesis of Parkinson’s disease (PD) and to develop novel therapeutic agents that target these mechanisms as a means to halt the progress of neurodegenerative diseases.  The group’s central hypothesis is that activation of microglia, as induced by xenobiotics and endogenous factors released during cellular injury, may self-perpetuate resulting in a sustained, low-grade neuroinflammation that leads to gradual oxidative neurodegeneration of dopaminergic neurons and thus Parkinson’s Disease.

This figure shows how direct neurotoxic insults or inflammatory triggers (indirect neurotoxic insults) can generate a vicious cycle of cytotoxic and stimulatory factors that leads to low-grade, chronic neuroinflammation and progressive neuronal damage and degeneration over time.

Although their previous work primarily focused on acute neurotoxicants (e.g. MPTP, Rotenone and Paraquat) to induce Acute Parkinsonianism in animal models, they are currently utilizing two lipopolysaccharide-induced chronic neuroinflammation models that better recapitulate the delayed, progressive pathology of idiopathic PD.  By focusing on chronic neuroinflammation as the driving factor in the pathogenesis of PD, these models have allowed the Neuropharmacology Group to study anti-inflammatory therapies that dampen or abolish inflammation-mediated neurodegeneration — a strategy with potential applications to prevent the progression of other neurodegenerative diseases associated with chronic neuroinflammation.

Unlike NSAIDs that primarily inhibit cyclooxygenase (COX) enzyme activities, this group has focused its efforts on developing a new class of anti-inflammatory therapies that selectively inhibit the enzyme activities of NADPH oxidase 2 (NOX2). During inflammation NOX2 on microglia generate extracellular superoxide (that quickly form into neurotoxic intermediates) and is also involved in mediating intercellular ROS that is involved in a variety of cell signaling pathways including the generation and maintenance of the pro-inflammatory cascade. By inhibiting the activity of NOX2, this group has been able to interrupt the sustained, low-grade neuroinflammation (as measured by changes in cytokine production and markers for glial activation) and halt neurodegeneration in its PD models.

Beyond the development of novel therapies for neurodegenerative diseases, this group is also studying the neuropathology of alpha-synuclein aggregation, assessing non-motor pathologies and behavioral deficits, and examining for neurovascular unit dysfunctions in PD using its chronic neuroinflammation models. Since PD is known to be associated with environmental exposures such as infectious agents, pesticides and heavy metals all of which trigger a neuro-inflammatory response our research exploring the etiology, pathogenesis and therapies of PD is highly relevant to the mission of NIEHS.

Mind and Body Approaches

• Tai Chi: There’s limited evidence that tai chi may help to improve balance in some people with Parkinson’s disease, but studies have had mixed results. In a 2012 study of people with mild-to-moderate Parkinson’s, the group assigned to do tai chi twice a week for 24 weeks had greater improvements in their balance, stability, and walking speed compared to the groups who did resistance training or stretching. The tai chi group was also more likely to continue exercising after the 24 weeks, a follow-up study showed. However, two or three tai chi classes a week over 16 weeks wasn’t associated with improvements in walking, a smaller, 2013 study funded by NCCIH showed.
• Massage and Acupuncture: The research on massage and acupuncture for people with Parkinson’s is limited. There’s no strong evidence that either helps to reduce symptoms.
• Dance: Compared to other forms of exercise, taking dance lessons, particularly Argentine tango, appears to help with some symptoms of Parkinson’s for at least the short term, research reviews of multiple, small studies show. In general, participants’ balance, mobility, and quality of life improved. The studies didn’t include participants with advanced Parkinson’s.

Repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS uses magnetic pulses to stimulate targeted areas of the brain. It’s been approved for certain types of depression, and a few (but not all) studies show that it may improve some symptoms of Parkinson’s. rTMS is non-invasive and differs from deep brain stimulation, a surgical procedure used to treat several disabling symptoms of Parkinson’s.

Caregivers: To protect your health and well-being, consider joining a support group, establishing a daily routine for yourself, getting exercise, and seeing your own health care provider as needed. For a list of resources, including adult day care or respite care, check out Eldercare listings or contact the groups.

Dietary Supplements:

• No dietary supplements have been shown to reduce symptoms of Parkinson’s. Large, separate studies of the dietary supplement’s creatine and coenzyme Q10 for Parkinson’s were stopped early because the supplements were clearly not better than the placebo that some study participants received.
• Researchers are studying omega-3 fatty acids and a form of glutathione, an antioxidant that is found in the brain, for Parkinson’s.
• In addition to investigating a variety of complementary health approaches for Parkinson’s, researchers are studying how susceptible symptoms of Parkinson’s are to the placebo effect. For example, a placebo pill caused similar changes in brain activity as a standard Parkinson’s drug, a small NCCIH-funded study found.

Safety:

• Tai chi, acupuncture, massage, and dance appear to be safe for most people with Parkinson’s but check with your health care provider before beginning a new exercise program or complementary health approach.
• rTMS generally appears safe for people with Parkinson’s, but it may pose a risk if you have a pacemaker or experience certain types of seizures.
• Dietary supplements may have side effects and interact with drugs. For example, St. John’s wort, which is used for depression and other conditions, can increase how quickly many drugs break down in your body, making the drugs less effective. Some products may be poor quality and contain contaminants, including drugs, chemicals, or metals. Studies have found significant differences between what’s on the label and what’s in the bottle of some supplements.