What Is Parkinson

What is Parkinsons Disease?
Parkinson's disease (PD) is a chronic and progressive movement disorder, meaning that symptoms continue and worsen over time. Nearly one million people in the US are living with Parkinson's disease. The cause is unknown, and although there is presently no cure, there are treatment options such as medication and surgery to manage its symptoms. Parkinsons involves the malfunction and death of vital nerve cells in the brain, called neurons. Parkinson's primarily affec ts neurons in the area of the brain called the substantia nigra. Some of these dying neurons produce dopamine, a chemical that sends messages to the part of the brain that controls movement and coordination. As PD progresses, the amount of dopamine produced in the brain decreases, leaving a person unable to control movement normally. The specific group of symptoms that an individual experiences varies from person to person. Primary motor signs of Parkinson s disease include the following.
tremor of the hands, arms, legs, jaw and face bradykinesia or slowness of movement rigidity or stiffness of the limbs and trunk postural instability or impaired balance and coordination
Scientists are also exploring the idea that loss of cells in other areas of the brain and body cont ribute to Parkinsons. For example, researchers have discovered that the hallmark sign of Parkinsons disease clumps of a protein alpha-synuclein, which are also called Lewy Bodies are found not only in the mid-brain but also in the brain stem and the olfactory bulb.
These areas of the brain correlate to nonmotor functions such as sense of smell and sleep regulation. The presence of Lewy bodies in these areas could explain the nonmotor symptoms experienced by some people with PD before any motor sign of the disease appears. The intestines also have dopamine cells that degenerate in Parkinsons, and this may be important in the gastrointes tinal symptoms that are part of the disease.
Diagnosis
Making an accurate diagnosis of Parkinsons particularly in its early stages is difficult, but a skilled practitioner can come to a reasoned conclusion that it is PD. You may have experienced this frustration. Perhaps it took years for you to receive a diagnose. Perhaps you have been diagnosed, but with Parkinsonism, not Parkinson's, and are confused about the implications.
How is Parkinsons Diagnosed?

Often, the diagnosis of Parkinsons is first made by an internist or family physician. Many people seek an additional opinion from a neurologist with experience and specific training in the assessment and treatment of Parkinsons disease referred to as a movement disorder specialist.
To diagnose Parkinsons, the physician takes a careful neurological history and performs an examination. There are no standar d diagnostic tests for Parkinsons, so the diagnosis rests on the clinical information provided by the person with Parkinsons and t he findings of the neurological exam.
The doctor looks to see if your expression is animated. Your arms are observed for tremor, which is present either when they are at rest, or extended. Is there stiffness in your limbs or neck? Can you rise from a chair easily? Do you walk normally or with short steps, and do your arms swing symmetrically? The doctor will pull you backwards. How quickly are you able to regain your balance?
The main role of any additional testing is to exclude other diseases that imitate Parkinsons disease, such as stroke or hydrocephalus. Very mild cases of PD can be difficult to confirm, even by an experienced neurologist. This is in part because there are many neurological conditions that mimic the appearance of Parkinsons. A persons good response to levodopa (which temporarily restores dopamine action in the brain) may support the diagnosis. But this is not relevant if your doctor thinks you do not need any medication at this time. If you are in doubt of your diagnosis or if you need further information, you may want to seek a second opinion.
PDF recommends that a person with symptoms resembling those of PD consider making an appointment with a movement disorder specialist. To find a specialist in your community, call PDF's HelpLine at (800) 457-6676 from Monday to Friday, 9 AM EDT to 5 PM EDT and our staff can help you locate one.
Why Arent There Tests to Diagnose Parkinsons?

There is no standard diagnostic test for Parkinsons. Researchers are working to develop an accurate biological marker, suc h as a blood test or an imaging scan. To date, the best objective testing for PD consists of specialized brain scanning techniques that can measure the dopamine system and brain metabolism. But these tests are performed only in specialized imaging centers and can be very expensive.
Parkinsonisms and Parkinson's Plus Syndromes

If you have been diagnosed, but with Parkinsonism, not Parkinson's, you may be confused about the implications. Because there are no definitive diagnostic tests for Parkinsons, the diagnosis can sometimes be unclear. The term parkinsonism is a generic descriptive term that refers to the wh ole category of neurological diseases that causes slowness of movement. The category includes the classic form of Parkinsons disease, many atypical variants, sometimes called Parkinsons Plus Syndromes, and any other brain disease that resembles Parkinsons, such as hydrocephalus or drug-induced parkinsonism.
In all cases of parkinsonism, no matter the cause, there is a disturbance in the dopamine systems of the basal ganglia a part of the brain that controls movement. In all cases, this dopamine deficiency leads to the characteristic combination of tremor, slowness, rigidity and postural instability. Classic (idiopathic) Parkinsons is the most common and most treatable form of parkinsonism. For a significant minority, abou t 15 percent of all persons with parkinsonism, one of the atypical variants may be present. These conditions aremore serious and less treatable than classic PD, and include diseases such as:
multiple system atrophy (MSA) progressive supranuclear palsy (PSP) corticobasal degeneration (CBD) Lewy body dementia (LBD)
Symptoms
The diagnosis of PD depends upon the presence of one or more of the four most common motor symptoms of the disease. In addition, there are other secondary and nonmotor symptoms that affect many people and are increasingly recognized by doctors as important to treating Parkinsons.
Each person with Parkinson's will experience symptoms differently. For example, many people experience tremor as their primary symptom, while others may not have tremors, but may have problems with balance. Also, for some people the disease progresses quickly, and in others it does not. By definition, Parkinsons is a progressive disease. Although some people with Parkinsons only have symptoms on one side of the body for many years, eventually the symptoms begin on the other side. Symptoms on the other side of the body often do not become as severe as symptoms on the initial side.
Find out more by reading detailed descriptions of Parkinson's symptoms below:
Primary Motor Symptoms Secondary Motor Symptoms Nonmotor Symptoms Coping with Symptoms
Primary Motor Symptoms

Almost 200 years after Parkinson's was first discovered and after many new discoveries about the biology of the disease, a diagnosis still depends on identifying the core features tremor, slowness and stiffness described by James Parkinson. The diagnosis of Parkinsons does not come from a test, but instead requires a careful medical history and a physical examination to detect the cardinal signs of the disease, including:
Resting Tremor: In the early stages of the disease, about 70 percent of people experience a slight tremor in the hand or foot on one side of the body, or less commonly in the jaw or face. A typical onset is tremor in one finger. The tremor consists of a shaking or oscillating movement, and usually appears when a person's muscles are relaxed, or at rest, hence the term "resting tremor." The affected body part trembles when it is not performing an action. Typically, the fingers or hand will tremble when folded in the lap, or when the arm is held loosely at the side, i.e., when the limb is at rest. The tremor usually ceases when a person begins an action. Some people with PD have noticed that they can stop a hand tremor by keeping the hand in motion or in a flexed grip. The tremor of PD can be exacerbated by stress or excitement, sometimes attracting unwanted notice. The tremor often spreads to the other side of the body as the disease progresses, but usually remains most apparent on the initially affected side. Although tremor is the most noticeable outward sign of the disease, not all people with PD will develop tremor.
Bradykinesia: Bradykinesia means slow movement. A defining feature of Parkinsons, bradykinesia also describes a general reduction of spontaneous movement, which can give the appearance of abnormal stillness and a decrease in facial expressivity. Bradykinesia causes difficulty with repetitive movements, such as finger tapping. Due to bradykinesia, a person with Parkinsons may have difficulty performing everyday functions,such as buttoning a shirt, cutting food or brushing his or her teeth. People who experience bradykinesia may walk with short, shuffling steps. The reduction in movement and the limited range of movement caused by bradykinesia can affect a persons speech, which may become quieter and less distinct as Parkinsons progresses.
Rigidity: Rigidity causes stiffness and inflexibility of the limbs, neck and trunk. Muscles normally stretch when they move, and then relax when they are at rest. In Parkinsons rigidity, the muscle tone of an affected limb is always stiff and does not relax, sometimes contributing to a decreased range of motion. People with PD most commonly experience tightness of the neck, shoulder and leg. A person with rigidity and bradykinesia tends to not swing his or her arms when walking. Rigidity can be uncomfortable or even painful.
Postural Instability: One of the most important signs of Parkinsons is postural instability, a tendency to be unstable when standing upright. A person with posturalinstability has lost some of the reflexes needed for maintaining an upright posture, and may topple backwards if jostled even slightly. Some develop a dangerous tendency to sway backwards when rising from a chair, standing or turning. This problem is called retropulsion and may result in a backwards fall. People with balance problems may have particular difficulty when pivoting or making turns or quick movements. Doctors test postural stability by using the pull test. During this test, the neurologist gives a moderately forceful backwards tug on the standing individual and observes how well the person recovers. The normal response is a quick backwards step to prevent a fall; but many people with Parkinsons are unable to recover, and would tumble backwards if the neurolo gist were not right there to catch him or her.
Secondary Motor Symptoms

In addition to the cardinal signs of Parkinsons, there are many other motor symptoms associated with the disease.
Freezing: Freezing of gait is an important sign of PD that is not explained by rigidity or bradykinesia. People who experience freezing will normally hesitate before stepping forward. They feel as if their feet are glued to the floor. Often, freezing is temporary, and a person can enter a normal stride once he or she gets past the first step. Freezing can occur in very specific situations, such as when starting to walk, when pivoting, when crossing a threshold or doorway, and when approaching a
chair. For reasons unknown, freezing rarely happens on stairs. Various types of cues, such as an exaggerated first step, can help with freezing. Some individuals have severe freezing, in which they simply cannot take a step. Freezing is a potentially serious problem in Parkinsons disease, as it may increase a persons risk of falling forward.
Micrographia: This term is the name for a shrinkage in handwriting that progresses the more a person with Parkinsons writes. This occurs as a result of bradykinesia, which causes difficulty with repetitive actions. Drooling and excess saliva result from reduced swallowing movements.
Mask-like Expression: This expression, found in Parkinsons, meaning a persons face may appear less expressive than usual, can occur because of decreased unconscious facial movements. The flexed posture of PD may result from a combination of rigidity and bradykinesia.
Unwanted Accelerations: It is worth noting that some people with Parkinsons experience movements that are too quick, not too slow. These unwanted accelerations are especially troublesome in speech and movement. People with excessively fast speech, tachyphemia, produce a rapid stammering that is hard to understand. Those who experience festination, an uncontrollable acceleration in gait, may be at increased risk for falls.
Additional secondary motor symptoms include those below, but not all people with Parkinsons will experience all of these.
Stooped posture, a tendency to lean forward Dystonia Impaired fine motor dexterity and motor coordination Impaired gross motor coordination Poverty of movement (decreased arm swing) Akathisia Speech problems, such as softness of voice or slurred speech caused by lack of muscle control Difficulty swallowing Sexual dysfunction Cramping Drooling
Nonmotor Symptoms
Most people with Parkinsons experience nonmotor symptoms, those that do not involve movement, coordination, physical tasks o r mobility. While a persons family and friends may not be able to see them, these invisible symptoms can actually be m ore troublesome for some people than the motor impairments of PD.
Early Symptoms Many researchers believe that nonmotor symptoms may precede motor symptoms and a Parkinsons diagnosis by years. The most recognizable early symptoms include:
loss of sense of smell, constipation
REM behavior disorder (a sleep disorder) mood disorders orthostatic hypotension (low blood pressure when standing up).
If a person has one or more of these symptoms, it does not necessarily mean that individual will develop Park insons, but these markers are helping scientists to better understand the disease process.
Other Nonmotor Symptoms
Some of these important and distressing symptoms include:
sleep disturbances constipation bladder problems sexual problems excessive saliva weight loss or gain vision and dental problems fatigue and loss of energy. depression fear and anxiety skin problems cognitive issues, such as memory difficulties, slowed thinking, confusion and in some cases, dementia medication side effects, such as impulsive behaviors
What Causes Parkinson's?

To date, despite decades of intensive study, the causes of Parkinsons remain unknown. Many experts think that the disease is caused by a combination of genetic and environmental factors, which may vary from person to person.
In some people, genetic factors may play a role; in others, illness, an environmental toxin or other event may contribute to PD. Scientists have identified aging as an important risk factor; there is a two to four percent riskfor Parkinsons among people over age 60, compared with one to two percent in the general population.
The chemical or genetic trigger that starts the cell death process in dopamine neurons is the subject of intense scientific study. Many believe that by understanding the sequence of events that leads to the loss of dopamine cells, scientists will be able to develop treatments to stop or reverse the disease
Read more below about each of these:
Genetic Factors Environmental Factors
Genetic Factors The vast majority of Parkinson's cases are not directly inherited. About 15 to 25 percent of people with Parkinsons report h aving a relative with the disease. In large population studies, researchers have found that people with an affected first-degree relative, such as a parent or sibling, have a four to nine percent higher chance of developing PD, as compared to the general population. This means that if a persons parent has PD, his or her chances of developing the disease are slightly higher than the r isk among the general population.
Researchers have discovered several gene mutations that can cause the disease directly, but these affect only a small number of families. Some of these mutations involve genes that play a role in dopamine cell functions. P arkinsons has developed at an early age in individuals with mutations in genes for parkin, PINK1, LRRK2, DJ-1, and glucocerebrosidase, among others.
Because genetic forms of a disease can be studied in great detail in the laboratory, and because understanding the rare genetic forms of Parkinson's may help us to understand more common forms of the disease, genetics is currently the subject of intense research.
Environmental Factors
Some scientists have suggested that Parkinson's disease may result from exposure to an environmental toxin or injury. Epidemiological research has identified several factors that may be linked to Parkinsons, including rural living, well water , manganese and pesticides.
Some studies have demonstrated that prolonged occupational exposure to certain chemicals is associated with an elevated risk of PD. These include the insecticides permethrin and beta-hexachlorocyclohexane (beta-HCH), the herbicides paraquat and 2,4dichlorophenoxyacetic acid and the fungicide maneb. In 2009, the US Department of Veterans Affairs added Parkinsons to a list of diseases possibly associated with exposure to Agent Orange.
A synthetic neurotoxin agent called MPTP can also cause immediate and permanent parkinsonism. The compound was discovered in the 1980s in individuals who injected themselves with a synthetic form of heroin contaminated with MPTP. Cases of MPTPinduced Parkinsons in the general population are exceedingly rare. It is noted that a simple exposure to an environmental toxin is never enough to cause Parkinsons. Most people exposed to a toxin do not develop the disease. In fact, there is no conclusive evidence that any environmental factor, alone, can be considered a cause of the disease.
However, environmental factors have been helpful in studying laboratory models of Parkinson's. Scientists continue to pursue these clues to understand why Parkinsons disease occurs.
Genetics and Parkinson's Disease: What Have We Learned?

By Katrina Gwinn, M.D. Originally published in the Winter 2009 issue of PDF's Newsletter, News & Review.
You may have noticed a surge in stories about genetic testing and about specific genes that have been discovered to play a role in diseases. These discoveries, made mostly in the decade since the human genome was successfully sequenced, include 13 gene mutations that are associated with Parkinsons disease (PD). Whether it is you or your loved one who is living with Parkinsons, you may be wondering how the new genetic discoveries will affect you and what they mean for your own risk or that of your children. In the long run, scientists hope that the knowledge provided by genetics will help us both to diagnose Parkinsons earlier and to slow or stop its progression. They also hope that genetic studies will help us better predict who is at risk for Parkinsons disease, so that interventions can take place before someone develops its symptoms but we arent there yet.
Understanding Two Categories of Genes To understand how genes are linked to Parkinsons, begin by thinking of them in two categories. The first, causal genes, actually cause the disease. A causal gene alone, without the influence of other genes or environmental factors, guarantees that a person who inherits it will develop PD. This kind of genetic Parkinsons is very rare, accounting for perhaps one to two percent of people with PD. The second category of genes, associated genes, do not cause Parkinsons on their own, but increase the risk of developing it. A person may have these genes and never develop PD, while people who do not have these genes can still end up being diagnosed with Parkinsons. However, those who have the gene are more likely to develop PD then those without it. In order for associated genes to trigger PD, they probably need to be combined with other genes or environmental factors. For example, having genes for fair skin increases your risk of developing skin cancer, but whether you actually develop cancer will depend upon other factors, such as whether or not you spend a lot of time in the sun. Scientists discovered both kinds of genes by studying families in which many members have developed Parkinsons. It may be helpful to look at some of these families and how they have been affected by genetics.
Causal Genes: Alpha-synuclein
The Iowa kindred or Spellman-Muenter kindred, as it is known to PD researchers, is a large family in Iowa in which a specific gene for Parkinsons was found. My colleagues and I traced 200 members of the family, including those who developed PD, back to the 1800s and we reviewed medical records dating back to about 1914. Then, taking DNA from blood samples provided by members of the current generation, we tested the entire genome to figure out which genes are associated with PD in this family.
We discovered that the culprit gene in the Iowa kindred was one known as alpha-synuclein, which is located on chromosome 4. Normally, the chromosome carries only a single copy of the alpha-synuclein gene, but members of this family with Parkinsons carried three copies of the gene. This extra dose of alpha-synuclein caused certain family members to develop Parkinsons at a young age.
Even within a family whose members have the same disease-causing gene, individuals may have very different experiences with the disease. In the Iowa kindred, the member of the family who was oldest upon diagnosis was a 51-year-old woman with a form of Parkinsons called Lewy body dementia (LBD). Her cousin, however, was just 24 years old when typical Parkinsons symptoms emerged. Comparing these two people who share the same Parkinsons genes, but who experience it differently, can give us clues about t he disease. We can hypothesize that the woman who developed LBD at 51 had a genetic or environmental factor that protected her for 20 or 30 years. If we can understand how she was protected from PD, this knowledge could provide valuable insights into how to slow the progress of PD.
Associated Genes: LRRK2 While the gene for alpha-synuclein actually caused Parkinsons in members of the Iowa kindred, another gene called LRRK2 the gene for the protein Dardarin is only associated with PD. Mutations in the LRRK2 gene that lead to PD are most common in people of North African, Basque, Portuguese and Ashkenazi Jewish descent, but occur in almost all ethnic groups.
For LRRK2, there is great variability in the mutations that occur in the gene, as well as in their effects. Some people with LRRK2 mutations develop PD in their 30s or 40s, while others develop the disease in their 80s, and others never develop PD at all. In some cases, people with LRRK2 gene mutations develop dementia, while others develop a form of Parkinsons that shares feature s with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs diseas e. Understanding this variability why some people develop certain disease features and others are protected gives scientists clues about how PD starts and progresses.
Using Genetics to Diagnose and Treat Parkinsons Disease By discovering genes linked to Parkinsons, scientists can develop tests to find out who is at risk of developing Parkinsons and can begin to diagnose it early, even before symptoms are obvious. Once we find a treatment that can slow down Parkinsons, as opposed to simply easing its symptoms, it will become important to assess genetic risk, and to make a diagnosis as early as possible in order to begin treatment. Genetic research can also provide clues to identifying new therapeutic targets for Parkinsons disease.
Already, the identification of genes associated with PD has allowed scientists to better understand the disease. For example, the first gene mutation identified to cause Parkinsons was the gene for alpha-synuclein, now known as Park 1. After its discovery, scientists began looking for the alpha-synuclein protein in the brains of people who had died with PD. They learned that Lewy bodies, the protein clumps that accumulate in dying brain cells, are full of alpha-synuclein. This insight into the basic biological cause of PD has led to ideas for treatments.
The Iowa family studies mentioned above demonstrated that three copies of a normal gene can cause PD. Once this was discovered, the original mutations were re-evaluated, and it was found that both genetic causes increased the amount of synuclein in the cell. Scientists realized that it was the amount of synuclein, not just the type, which led to disease. That understanding, in turn, is leading to strategies which may lessen the amount of synuclein in the cells of people with Parkinsons. It is it hoped that someday in the future, this method may help lessen, or hopefully even reverse PD.
Assessing Your Genetic Risk
Am I at risk? Should I get tested? If you or your parent or sibling is living with PD, you have probably asked these questions. You may wonder whether you have passed on risk factors to your children or whether you yourself have inherited any risk. I can relate to this because my own father has Parkinsons. Statistically, my risk is between four and nine percent higher than it would be for a person with no family history of disease. What does that really mean for me? What does it mean for my niece and nephew? The truth is, we dont yet know. Plus, because we lack treatments to slow the development and progression of Parkinsons, genetic testing is not part of routine clinical practice, but is restricted as a research tool. However, ongoing research will refine our knowledge and perhaps provide better answers to these important questions.
Looking Forward The next time you see genetics and Parkinsons in the news, I hope that you will better understand why this field is so excit ing. Discovering Parkinsons genes both those that cause disease on their own and those that contribute to risk is helping doctors to better understand PD, to identify the risk of Parkinsons earlier and to treat it more effectively.
Katrina Gwinn, M.D., is Vice Chair of Research Development in the Department of Molecular and Human Genetics at Baylor College of Medicine. This article was adapted from Dr. Gwinns presentation at a recent PDF symposium and webcast, which is now available for you to view at www.pdf.org/en/edu_events_carolinas.
This article was originally published in the Winter 2009 issue of PDF's newsletter, News & Review.
Environmental Factors and Parkinson's: What Have We Learned?

By Caroline M. Tanner, M.D., Ph.D. Originally published in the Spring 2011 issue of PDF's Newsletter, News & Review.
Scientists generally agree that most cases of Parkinsons disease (PD) result from some combination of nature and nurture the interaction between a persons underlying genetic make-up and his or her life activities and environmental exposures. A simple way to describe this is that genetics loads the gun and environment pulls the trigger. In this formulation, environment has a very broad meaning that is, it refers to any and all possible causes other than those that are genetic in origin.
The interactions between genes and environment can be quite complex. Some environmental exposures may lower the risk of PD, while others may increase it. Similarly, some people have inherited a genetic makeup that makes them more or less susceptible to the effects of toxicants, or poisonous agents, than others. The effect of a combined exposure can be greater or lower than a single exposure. All of this means that the particular combination of factors leading to PD is likely to be unique for each person. These combinations, in different ways, may trigger a common series of biological changes that will ultimately lead to the disease.
Scientists are beginning to tease apart the non-genetic factors that influence PD risk. In particular, epidemiologists are working to identify differences in the experiences of people who develop PD, compared to those who do not. But identifying these risk factors can be difficult. And when we do identify them, they serve only as clues. They do not provide a direct explanation for the cause of Parkinsons, so scientists must supplement these population studies with laboratory experiments.
The following is a list of some of the risk factors for which we have found some evidence of an association with PD. For the most part, it is too soon to make recommendations for how to prevent Parkinsons based on this research. However, these results may help us to understand the causes of PD, and provide direction for future research and therapy development.
Potential Risk Factors

Age. About one percent of people over age 60 have Parkinson's disease, compared with just 0.001 percent of people 45 or younger.
Gender. Parkinsons is more common in men than in women. It is not known whether this is due to genetic factors, hormones or differences in behavior.
Head Injury. Traumatic brain injury injury that results in amnesia or loss of consciousness has been associated with an increased risk of developing Parkinsons years after the injury. Laboratory studies suggest that such injury may provoke inflammation in the brain, which could lead to the development of PD.
Area of Residence. There are differences in the geographic distribution of PD. These could be due to differences in environmental factors, some of which are referenced below, and differences in genetic risk factors. Alternatively, they could be traced to differences in the methods that are used to count people with PD. While studies are too few to provide definitive patterns, some have been suggested. For example, Parkinsons prevalence is higher in the Inuit population in Denmark than it is among other Danes, possibly reflecting a greater dietary intake among the Inuits of persistent organic pollutants such as polychlorinated biphenyls, or PCBs (see page 7). In the agricultural California central valley, living in a home near to fields where the pesticides paraquat and maneb were used was associated with PD in one report. Another study reported greater incidence of PD in urban areas with high levels of industrial emissions of the metal manganese, and possibly copper (see more on page 7).
Occupation. Certain occupational categories or job titles have been associated with a higher incidence of PD, but results have been inconsistent. The relationship between welding (the process of fusing substances, usually metals) and PD has been a recent focus of controversy. In some reports for example, studies of people who are referred for medicolegal evaluation (an examination to determine the legal aspects of a workplace) welding has been suggested to cause Parkinsons symptoms or earlier onset of PD.
However, in most other studies, including several in large national occupational and disease registries, welding has not been associated with PD risk.
A higher frequency of PD has been associated with many other occupations, but only a few occupations have been associated with PD in multiple studies, including agricultural and industrial workers. By contrast, lower rates of Parkinsons are associated with shift work and jobs involving vigorous physical work. While we can hypothesize that the agricultural or industrial jobs may involve greater exposure to toxicant chemicals, further study in other populations is needed to understand if certain occupations are actually associated with a higher risk of PD. Some of the studies investigating specific toxicant exposures are described in the next sections.
Pesticide Exposure. Of all the chemical exposures that have been linked to Parkinsons, pest icides have been reported the most consistently. Recent research has shown higher rates of Parkinsons among people who were exposed to pesticides over a long period of time as part of their work. Investigating other types of pesticide exposure, such as home use, is more challenging. However, hobby gardening and home pesticide use have each been associated with PD in one report. Although few studies have identified specific pesticides as leading to PD, those that have been so identified include the insecticides rotenone and permethrin (used in clothing and mosquito netting to kill mosquitos); organochlorines such as beta-hexachlorocyclohexane (beta-HCH used in the United States from the 1950s to the 1970s); and the herbicides paraquat and 2,4- dichlorophenoxyacetic acid (2,4-D). It is important to note that most people who are exposed to these pesticides do not go on to develop Parkinsons. The herbicide 2,4-D is one of the chemicals making up Agent Orange, used as a defoliant during the Vietnam war era. Although Agent Orange has not been proven to cause PD, the US Department of Veterans Affairs has ruled that veterans with PD who served in Vietnam between January 9, 1962 and May 7, 1975 are eligible to receive disability compensation from the Veterans Administration.
Exposure to Metals. Occupational exposures to various metals have been suggested to be related to the development of PD. But long-term exposure to metals is not easily measured, and the results of studies measuring PD risk and specific metals have been inconsistent. For example, high dose manganese exposure, a metal mentioned earlier, is known to cause a form of parkinsonism called manganism. Whether there is a relationship between manganese exposure and PD has been a point of interest, with focus on welders who may be exposed to it. A recent review concluded that manganese is an unlikely cause of Parkinsonism in the US population of welders. Direct measurement of lead levels in bone and blood serum suggests a link between PD and lead exposure, with greater risk associated with greater lifetime exposure.
Solvents and Polychlorinated Biphenyls (PCBs). Trichloroethylene (TCE) is a solvent used in many industries and is the most common organic contaminant in groundwater. Occupational exposure to TCE was found to be associated with Parkinsons among workers whose factory jobs resulted in long-term (eight to 33 years) exposure to the solvent. In a study of discordant twins (that is, twin pairs in which just one of the members had PD), the twin who had been occupationally exposed to TCE was more likely to
develop Parkinsons than the one who had not. This link has also been observed in experiments in the laboratory.
Polychlorinated biphenyls (PCBs), mentioned earlier, are persistent organic pollutants that were used in industrial processes until the late 1970s. PCBs have been found in relatively high concentrations in the brains of people who had PD. Occupational exposure to PCBs has been associated with greater risk of Parkinsons in women, but not in men, and those women who were exposed have shown evidence of injury to their dopamine systems (the systems disrupted in PD).
Genetic Predisposition. Often, a persons genetic makeup will help to determine the effect of an environmental exposure. For example, agricultural workers exposed to pesticides were at an increased risk of PD only if they also had inherited a reduced ability to metabolize toxicants. In another study, head injury was associated with a higher risk of Parkinsons o nly in people with one form of a particular gene; in people without this particular gene variant, head injury was not associated with a higher risk of PD. Increasingly, epidemiologists and geneticists are working together to identify combinations of genes and environmental exposures that are related to PD.
Potential Protective Factors

Scientists have also found certain factors that may actually reduce the risk of developing Parkinsons. As with risk factors, not enough is known about these and they should not be tried without the counsel of a doctor.
Coffee and tea. Drinking coffee or tea has been associated with a lower risk of Parkinsons, most markedly so in men. Caffeine has direct effects on the brain, and some of these effects may help to cause a lower risk of PD.
Uric acid or urate. This chemical occurs naturally in blood. High levels, associated with diets high in certain foods, such as meats, can cause gout and kidney stones. However, researchers have found that men with uric acid levels in the high end of the normal range have a lower incidence of Parkinsons. Men with PD who have uric acid in the high normal range have a slower rate of PD progression. In women, who typically have lower urate levels, the same effects are not established. A drug that increases blood urate is being studied in a clinical trial in PD.
Anti-inflammatory drugs. Several studies have shown that people who regularly take anti-inflammatory drugs such as ibuprofen have a lower risk of Parkinsons. Inflammation is thought to play a role in causing Parkinsons, and reducing inflammation may explain the reduced PD risk.
Smoking. Many studies have associated cigarette smoking with a decreased risk of PD. Researchers hypothesize that nicotine may block the damaging processes causing PD, but the exact effects are not known. A clinical trial to study nicotine in PD is planned.
Cholesterol levels. Some studies have suggested that the use of statins drugs that are used to lower cholesterol levels is associated with reduced PD risk. However, in other studies an association was also found between low blood cholesterol levels and
increased PD risk. Understanding cholesterol metabolism may provide clues to the molecular mechanisms that cause PD.
Body mass. People with higher vitamin D levels were at lower risk of PD in one study. Vitamin D has many beneficial effects that, theoretically, could help to prevent PD, and Vitamin D receptors (recognition sites) are found in the brain areas damaged in PD.
Exercise. Greater physical activity has been associated with lower risk of Parkinsons. Studies in animals also support this.
The Search for Proof
Observational studies cannot prove that an association is truly a cause of PD. This is because the kinds of studies that could pin down exact answers cannot be carried out on people. Instead, we must conduct experiments in the laboratory and then project the results of these tests as best we can to what happens in people. However, laboratory experiments can never give us the full picture of PD risk in humans. The final test can only be done through an iterative process, taking the clues gained from observations of human populations into the laboratory, and then bringing the laboratory results back again to the human population. Plausibility in the human framework provides the ultimate test for results from laboratory research. Our hope is that understanding environmental risk factors will lead to a better understanding not only of the causes of PD, but of other neurodegenerative disorders as well.
Dr. Tanner is the Director of Clinical Research at the Parkinson's Institute and Clinical Center.
Progression
The progression of Parkinsons disease varies among different individuals. Parkinson's is chronic and slowly progressive, meaning that symptoms continue and worsen over a period of years. Parkinson's is not considered a fatal disease. And the way that it progresses it different for everyone:
Movement symptoms vary from person to person, and so does the rate at which they progress. Some are more bothersome than others depending on what a person normally does during the day. Some people with Parkinson's live with mild symptoms for many years, whereas others develop movement difficulties more quickly. Nonmotor symptoms also are very individualized, and they affect most people with Parkinson's at all stages of disease. Some people with Parkinson's find that symptoms such as depression or fatigue interfere more with daily life than do problems with movement.
Rating Scales
That said, there are tools that your doctor may use understand the progression of your Parkinson's. The stages of Parkinson's correspond both to the severity of movement symptoms and to how much the disease affects a persons daily activities. The most commonly used rating scales are focused on the motor symptoms, but new scales include information on non-motor symptoms (such as problems with sense of smell).
1.
The first, known as Hoehn and Yahr, will rate your symptoms on a scale of 1 to 5. On this scale, depending on a persons difficulties, 1 and 2 represent early-stage, 2 and 3 mid-stage, and 4 and 5 advanced-stage Parkinson's.
2.
Another scale commonly used to assess the progression of Parkinson's is the United Parkinsons Disease Rating Scale (UPDRS). It is more comprehensive than the Hoehn and Yahr scale, which focuses on movement symptoms. In addition to these, the UPDRS takes into account cognitive difficulties, ability to carry out daily activities, and treatment complications.
Severity of Parkinson's
Below are some descriptions of mild, moderate and advanced Parkinson's. As disease progresses differently in different people, many do not progress to the advanced stage.
Mild Parkinsons
Movement symptoms may be inconvenient, but do not affect daily activities Movement symptoms, often tremor, occur on one side of the body Friends may notice changes in a persons posture, walking ability or facial expression Parkinson's medications suppress movement symptoms effectively Regular exercise improves and maintains mobility, flexibility, range of motion and balance, and also reduces depression and constipation
Moderate Parkinsons
Movement symptoms occur on both sides of the body The body moves more slowly Trouble with balance and coordination may develop Freezing episodes when the feet feel stuck to the ground may occur Parkinson's medications may wear off between doses Parkinson's medications may cause side effects, including dyskinesias (involuntary movements) Regular exercise, perhaps with physical therapy, continues to be important for good mobility and balance Occupational therapy may provide strategies for maintaining independence
Advanced Parkinsons
Great difficulty walking; in wheelchair or bed most of the day Not able to live alone Assistance needed with all daily activities Cognitive problems may be prominent, including hallucinations and delusions Balancing the benefits of medications with their side effects becomes more challenging
At all stages of Parkinson's, effective therapies are available to ease symptoms and make it possible for people with Parkinson's to live well.
Medications & Treatments

There are many medications available to treat the symptoms of Parkinsons, although none yet that actually reverse the effect s of the disease. It is common for people with PD to take a variety of these medications all at different doses and at different times of day - in order to manage the symptoms of the disease.
While keeping track of medications can be a challenging task, understanding your medications and sticking to a schedule will provide the greatest benefit from the drugs and avoid unpleasant off periods due to missed doses.
Prescription Medications
Although there are general guidelines that doctors use to choose a treatment regimen, each person with PD must be individually evaluated to determine which drug or combination of drugs is best for them. For some, a first choice drug might be one of t he levodopa preparations, and for others, an initial prescription may be given for one of the agonists, an MAO inhibitor or an anticholinergic.
The choice of drug treatment depends on many variables including symptom presentation, other concurrent health issues (and the medications being used to treat them) and a persons age. And whil e the suggested starting dosages (as indicated by the package insert) are listed here, remember that they too can vary greatly depending on a persons needs and metabolism. Below, we summarize types (classes) of medications available to treat Parkinsons on the market, along with each specific medication. If you would like to print an overview of what appears here, please click here to download our two-page fact sheet. For more detailed information, please scroll below.
Carbidopa/Levodopa therapy Dopamine Agonists Anticholinergics MAO-B Inhibitors COMT Inhibitors Other medications
Carbidopa/Levodopa (Sinemet)The most potent medication for Parkinsons is levodopa. Its development in the late 1960s represents one of the most important breakthroughs in the history of medicine. Plain levodopa produces nausea and vomiting. It is now combined with carbidopa to prevent this side effect. The well-known combined carbidopa/levodopa formulation is called Sinemet
There are many different preparations and strengths of carbidopa/levodopa, including longacting forms and a formulation that dissolves in the mouth without water, called Parcopa. There is also a combined formulation that includes the COMT inhibitor entacapone, called Stalevo.
It is important that people with Parkinsons are aware which levodopa preparation they are taking because there are so many different pill sizes, strengths and manufacturers. Be careful when renewing prescriptions at the pharmacy because the accidental substitute of a different formulation may lead to an overdosage or underdosage.
Carbidopa/levodopa remains the most effective drug for treating Parkinsons. The addition of carbidopa prevents levodopa from being converted into dopamine in the bloodstream, allowing more of it to get to the brain. Therefore, a smaller dose of levodopa is needed to treat symptoms.
Some people with PD have been reluctant to take it, believing it to be a last resort. But most neurologists agree that delaying treatment too long is unwise, and may put a person with PD at risk for falling. The decision about when to start carbidopa/levodopa is different for every person with Parkinsons, and requires consideration of potential benefits, risks and the availability of alternatives.
Unfortunately, with increased dosing and prolonged use of levodopa, patients experience other side effects including dyskinesias (spontaneous, involuntary movements) and "on-off" periods when the medication will suddenly and unpredictably start or stop working. Check with a doctor before taking any of the following to avoid possible interactions: antacids, anti-seizure drugs, antihypertensives, anti-depressants and high protein food. The same drugs that interact with carbidopa/levodopa and entacapone interact with Stalevo.
AVAILABLE DOSES INITIAL DOSING
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Carbidopa/
10/100 mg
25/100 mg 2-3X/day
Low blood pressure, nausea, confusion,
First course of treatment; converts to dopamine to manage major
Antacids, antiseizure drugs, antihypertensives, anti-depressants, high protein food
Levodopa
25/100 mg
(Sinemet)
50/200 mg dyskinesia, dry mouth, dizziness symptoms
Carbidopa/
10/100 mg
50/200 mg 2X/day
Levodopa
25/100 mg
controlled release
50/200 mg dyskinesia, dry mouth, dizziness symptoms and
(Sinemet CR)
may prolong effectiveness
MEDICATION
AVAILABLE DOSES
INITIAL DOSING
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Carbidopa/
12.5/50/200 mg
12.5/50/200 Dyskinesia, mg nausea, diarrhea,
Secondary course of treatment; combines entacapone with levodopa/ carbidopa to block COMT enzyme and prolong levodopas
Same as levodopa/ carbidopa, MAO inhibitors, Comtan, Sinemet, high doses (10 mg or more) of selegiline
Levodopa/ 25/100/200 Entacapone mg
hyperkinesia, abdominal pain, dizziness,
(Stalevo)
18.75/75/200 harmless mg discoloration of 31.25/125/200 mg urine, saliva and/ or sweat
37.5/150/200 mg
effectiveness
50/200/200 mg
Carbidopa/
10/100 mg
25/100 mg 2-3X/day
Levodopa
25/100 mg
Orally disintegrating
25/250 mg dyskinesia, dry mouth, dizziness symptoms; also
tablet for patients with (Parcopa) swallowing difficulties
Dopamine agonists are drugs that stimulate the parts of the human brain influenced by dopamine. In effect, the brain is tricked into thinking it is receiving the dopamine it needs. In general, dopamine agonists are not as potent as carbidopa/levodopa, and therefore are less likely to cause dyskinesias. Dopamine agonists can be taken alone or in combination with medications containing levodopa. The two most commonly prescribed oral pill agonists in the US are pramipexole (Mirapex) and ropinirole (Requip). A third, rotigotine transdermal system (Neupro), was recently re-approved after several years of being off the market. Bromocriptine (Parlodel ) is available, but is less commonly used.
As a class, dopamine agonists may cause nausea, hallucinations, sedation (including sudden sleepiness, called sleep attacks) and lightheadedness due to low blood pressure, so it is important to start at a low dose, increase gradually and be alert for side effects. In some people (in a recent study up to 14 percent), these medications have also been linked with compulsive behaviors, such as gambling and shopping.
One dopamine agonist, apomorphine (Apokyn), is a powerful and fast-acting injectable medication that promptly relieves symptoms of PD within minutes, but only provides 30 to 60 minutes of benefit. With training provided by the Parkinsons specialist, pe ople with PD, spouses and family members can be taught to administer the agent, using a pre-filled syringe system. Its main advantage is its rapid effect. It is used for people who experience sudden wearing-off spells when their Parkinsons medication abruptly stops working, leaving them unexpectedly immobile. Apomorphine may cause severe nausea, and so people using this agent must take an antiemetic agent. In addition, apomorphine can provoke dyskinesias and other side effects associated with dopamine drugs.
Consult a doctor before taking any of the following to avoid possible interactions: alcohol, anti-psychotics, medications that lower blood pressure, Navane (thiothixene), Taractan (chlorprothixene), Haldol (haloperidol), Reglan (metoclopramide), phenothiazines, thiozanthenes, cimetidine, phenothiazines, butyrophenones, Cipro and benzodiazepines.
AVAILABLE INITIAL DOSING DOSES
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
APOKYN injection (apomorphine hydrochloride)
.02 mL
.02 mL during off periods
Nausea, vomiting, low blood pressure, sleepiness, dyskinesias, hallucinations, chest pain
Adjunct levodopa therapy to treat off periods
5HT3 agonists (for example, Zofran, Kytril) antihypertensives (for example Norvasc and Zestril)
.06 mL
Bromocriptine
2.5 mg
2.5 mg 3X/day
Low blood pressure,
First course of treatment alone or with levodopa;
Alcohol, antipsychotics, blood pressure lowering medications
(Parlodel)
5 mg
nausea, edema, confusion, dry mouth, depression, headaches
mimics dopamine to manage major symptoms
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Rotigotine Transdermal System (Neupro)
2mg/24hrs
One 2 mg
Nausea, application site reactions, somnolence, dizziness, headache, vomiting, sleep attacks, insomnia.
First course of treatment alone or with levodopa in early-stage idiopathic Parkinsons disease; for advanced stage idiopathic Parkinson's; mimics dopamine to manage major symptoms
May cause allergic-type reactions including anaphylactic symptoms especially in people sensitive to sulfites, including those with asthma.
4 mg/24hrs patch a day 6 mg/24hrs 8 mg/24hrs
Pramipexole
.125 mg
.125 mg 3X/day
Arthritis, chest
First course
Sedatives and tranquilizers; metocipramide, thiozanthenes, cimetidine,
pain, nausea, low of treatment blood pressure, sleep alone or with levodopa;
(Mirapex)
.25 mg
.5 mg disturbances, 1 mg sedation mimics dopamine to 1.5 mg manage major symptoms phenothiazines, butyrophenones
Pramipexole dihydrochloride extendedrelease
.375 mg
.375 mg 1x/day Somnolence (sleepiness),
For the treatment of the signs and symptoms of early Parkinsons
Dopamine antagonists
.75 mg
Dose may be increased
nausea, constipation, dizziness, fatigue,
1.5 mg
gradually, not more
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
(Mirapex ER) 3 mg
frequently than every 5 to 7
hallucinations, dry mouth, muscle spasms, and peripheral edema
disease
4.5 mg
days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day.
Ropinirole
.25 mg
.25 mg 2X/day
Abdominal pain, sleep
Alcohol, antidepressants, Cipro, antipsychotics, benzodiazipines
(Requip)
.5 mg
disturbances, nausea, low
1 mg blood pressure, 2 mg sedation mimics dopamine to 3 mg manage major 4 mg symptoms
5mg
Ropinirole extendedrelease tablets
(All doses
2 mg taken
Nausea, dizziness, drowsiness, or sleepiness, headache,
Inhibitors (e.g., ciprofloxacin, fluvoxamine) or inducers
taken once once a day for a day) 1 to 2 weeks, followed by
(Requip XL)
2 mg increases of 2 4 mg mg/day at 1 week or longer 6 mg intervals as 8 mg appropriate
sudden uncontrolled movements (dyskinesia), abdominal
mimics dopamine to manage major symptoms.
(e.g., omeprazole or smoking) of CYP1A2
higher doses of estrogen, usually
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
10 mg
pain/discomfort, hallucination,
24-hours continuous delivery of the medicine
associated with hormone replacement
12 mg
constipation and increase or
14 mg decrease in blood to provide 16 mg pressure and heart rate. 18 mg Patients should also tell their 20 mg doctor if they experience new smooth blood levels
therapy (HRT), dopamine antagonists, such as neuroleptics (e.g., phenothiazines,
22 mg
butyrophenones, or increased thioxanthenes) or gambling, sexual, metoclopramide. or other intense urges while taking Requip XL. Requip XL may increase the side effects of levodopa.
24 mg
Anticholinergics Anticholinergics can be helpful for tremor and may ease dystonia associated with wearing-off or peak-dose effect. They have little effect on other symptoms of Parkinsons. The drugs in this class include trihexyphenidyl (Artane), benztrop ine mesylate (Cogentin) and procyclidine (no longer available in the US), among others. They do not act directly on the dopaminergic system. Instead, they decrease the activity of acetylcholine, a neurotransmitter that regulates movement. Potential adverse effects include blurred vision, dry mouth, constipation and urinary retention.
Older individuals are susceptible to confusion and hallucinations on anticholinergics, so these agents should be avoided in individuals over the age of 70. Adverse effects of these drugs include blurred vision, dry mouth and urinary retention.
Check with a doctor before using anticholinergics with anti-histamines, Haldol, Thorazine, Symmetrel, Clozaril and alcohol.
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Benzotropine mesylate
.5 mg
.5 mg 2X/day
Confusion, hallucinations, nausea, blurred
Secondary medication; tremor; attempts
Anti-histamines, Propulside, Haldol,
MEDICATION
AVAILABLE DOSES
INITIAL DOSING
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
(Cogentin)
vision, dry mouth, urinary retention, nervousness; not
to restore balance Thorazine, by inhibiting other enzymes and Symmetrel, Clozaril, alcohol
used long-term due nerve cells that to side effects may attack dopamine
Trihexyphenidyl 1 mg HCL 2 mg (Artane)
1-2 mg 2X/day
Confusion, hallucinations, nausea, blurred vision, dry mouth, urinary retention, nervousness; not
Secondary medication; tremor; attempts to restore balance by inhibiting other enzymes and
Anti-histamines
used long-term due nerve cells that to side effects may attack dopamine
MAO-B inhibitors selegiline (also called deprenyl, with trade names Eldepryland Zelapar) and rasagiline (Azilect) block an enzyme in the brain that breaks down levodopa. These drugs have a modest effect in suppressing the symptoms of Parkinsons . They have been shown to delay the need for Sinemet when prescribed in the earliest stage of Pa rkinsons, and have been approved for use in later stages of PD to boost the effects of Sinemet. Eldepryl may interact with anti-depressants, narcotic pain killers and decongestants. Check with a doctor before taking any new medications.
AVAILABLE INITIAL DOSES DOSING
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Selegiline
5 mg
5 mg 2X/day
Agitation, insomnia, hallucinations
Tertiary medication; controls brains metabolism of dopamine
Anti-depressants, narcotic painkillers, decongestants
(Eldepryl, Carbex) (max dose)
Selegiline HCI Orally
1.25mg
1.25mg Dizziness, 1X daily nausea, pain, headache,
Adjunct to levodopa in patients with
Anti-depressants, narcotic painkillers, decongestants
MEDICATION
AVAILABLE INITIAL DOSES DOSING
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
disintegrating tablet (Zelapar)
insomnia, rhinitis, dyskinesias, back pain, stomatitis, dyspepsia
significant "off" periods
Rasagiline (Azilect)
0.5mg 1mg
0.5mg
Increased
Signs and symptoms of PD as initial monotherapy and adjunct to levodopa
Narcotic painkillers, antidepressants and decongestants. Diets or meals very high in tyramine-rich foods (e.g., draft beer, red wine, aged cheeses, and other products) are not recommended(diets or meals with moderate amounts of these foods are not seen as a problem).
1X daily dyskinesias, postural hypotension, headaches, joint pain, indigestion
COMT inhibitors such as entacapone (Comtan) and tolcapone (Tasmar) represent the newest class of Parkinson's medications. These agents have no direct effect on PD symptoms, but instead are used to prolong the effect of levodopa by blocking its metabolism. COMT inhibitors are used primarily to help with the problem of wearing-off, in which the effect of levodopa becomes short-lived. People who take Tasmar must have regular liver function blood tests. Entacapone is not only a COMT inhibitor, but is also one of the main ingredients in Stalevo.
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Entacapone 200 mg
200 mg with Abdominal pain, levodopa; back pain, constipation, nausea, diarrhea, blood in urine
Secondary medication; delays wearing off by prolonging effectiveness of levodopa
MAO inhibitors
(Comtan)
max 8 per day
MEDICATION
AVAILABLE DOSES
INITIAL DOSING
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Tolcapone
100 mg
100 mg 3X/day
Abdominal pain, back pain, constipation, nausea, diarrhea,
Tertiary medication for motor fluctuations; limited in use to those who have exhausted
MAO inhibitors
(Tasmar)
200 mg
blood in urine, liver other treatment failure options
Other medications such as amantadine (Symmetrel) is a mild agent that is used in early Parkinsons disease to help tremor. In recent years, amantadine has also been found useful in reducing dyskinesias that occur with dopamine medication. Amantadine is a well-tolerated drug, but its potential side effects include dry mouth, constipation, bladder problems, ankle swelling and skin rash. Rivastigmine (Exelon) is the only medication approved by the US Food and Drug Administration for the treatment of dementia in PD.
MEDICATION
SIDE EFFECTS*
INDICATIONS
INTERACTIONS
Amantadine
100 mg
100 mg 2-3
Dizziness, weakness, dry mouth, constipation, skin blotches
Secondary medication for tremor and muscle rigidity
Cogentin (benztropine), Disipal (orphenadrine), Sinemet (levodopa), Artane (trihexyphenidyl), amphetamines, alcohol
(Symmetrel)
X/day
Rivastigmine tartrate
1.5mg 3mg 4.5mg
1.5mg 2X per day
Nausea,
Dementia
No known drug-drug
vomiting, loss of associated with interactions appetite, weight PD loss
(Exelon)
6mg Patch 10 (9.5 mg/24 hrs) Patch 20 (17.4 mg/24 hrs)
* Please note that the side effects listed in the tables that accompany each class of medication are the mostcommonly experienced. Not all individuals will experience such side effects. For many people who do experience side effects, they can often be effectively limited or eliminated with careful adjustments to dosage or the timing of the individual doses. If any side effects are experienced, speak to the treating physician immediately. For a complete description of each drug and its possible side effects, please request a package insert from your pharmacist for each drug being used. It is recommended that all prescriptions be filled at the same pharmacy to avoid interactions between medications. Interactions can be dangerous and even life-threatening, so make sure the pharmacist knows of all medications and supplements being taken including over-the-counter medications and supplements.
Over-the-Counter Medications
Although there is little conclusive scientific information on natural supplements, researchers are examining several substances to evaluate their effectiveness on slowing Parkinson's disease progression and managing its symptoms.
Nutritional supplements are not regulated with the same approval method for prescription drugs, and people with Parkinson's should discuss any medications (prescription or over-the-counter) with a doctor before taking them to avoid potentially dangerous interactions.
Since there is evidence relating oxidative damage of nerve cells to PD, some researchers are studying antioxidants:
A 2002 study focused on the potential antioxidant Coenzyme Q10 (CoQ10), which is believed to play an important role in mitochondria health. Mitochondria are the "powerhouses" of a cell, and some scientists think that abnormalities of mitochondrial function may play a role in Parkinson's. In 2011, a large clinical trial studying the potential beneficial effects of CoQ10 on reducing the progression of early PD was stopped because a mid-study analysis suggested that there was no improvement in the CoQ10-treated individuals in comparison to those receiving placebo (empty tablet) treatment and that continuing the program would have a very low likelihood of demonstrating any benefit from CoQ10 usage in delaying the progression of early PD.
Scientists have also examined Vitamin E, Vitamin C and health foods to evaluate their oxidative properties. Vitamin E can fight damage in the brain caused by free radicals, and has been suggested to lower the risk of PD. However, researchers conducted an extensive and thorough study over 10 years ago (the DATATOP trial) and failed to find any evidence that Vitamin E slows the progression of Parkinson's or manages symptoms. Since Vitamin E has very few side effects, many Parkinson's patients continue to take it in high doses of 400 IU or more. Researchers are also examining health foods, such as fermented papaya and blueberries, to determine their role in slowing nerve cell death. Scientists are optimistic about the research but do not have enough conclusive data to recommend these supplements to treat Parkinson's disease.
Creatine is another compound of scientific interest. It increases levels of phosphocreatine (an energy source in muscle and the brain). The National Institute of Neurological Disorders and Stroke (NINDS) is conducting a multi-center clinical trial to determine if creatine protects against nerve cell damage. Researchers have also studied a compound called glutathione to determine its effect on nerve cell metabolism and its power as an antioxidant. Both compounds show promise, but the appropriate dosing is unclear, as are the most effective method of administration, side effects and long-term dosing risks.
Although nutritional supplements have shown some promising results in preliminary studies, it is important to remember that there is not sufficient scientific data to recommend them for Parkinson's disease. Over-the-counter medications can and do have side effects and interactions with other drugs. They tend to be expensive and they vary with different manufacturers. Before taking any over-thecounter medication, it is very important that a person with Parkinson's discuss the addition of these supplements with their doctor.
Surgical Treatments
Surgery for Parkinson's disease has come a long way since it was first developed more than 50 years ago. The newest version of this surgery, deep brain stimulation (DBS), was developed in the 1990s and is now a standard treatment. Worldwide, about 30,000 people have had deep brain stimulation.
What is DBS?
During deep brain stimulation surgery, electrodes are inserted into the targeted brain region using MRI and neurophysiological mapping to ensure that they are implanted in the right place. A device called an impulse generator or IPG (similar to a pacemaker) is implanted under the collarbone to provide an electrical impulse to a part of the brain involved in motor function. Those who undergo the surgery are given a controller, which allows them to check the battery and to turn the device on or off. An IPG battery lasts for about three to five years and is relatively easy to replace under local anesthesia.
Is DBS Right for Me?

Although DBS is certainly the most important therapeutic advance since the development of levodopa, it is not for every person with Parkinson's. It is most effective - sometimes, dramatically so - for individuals who experience disabling tremors, wearing-off spells and medication-induced dyskinesias. Deep brain stimulation is not a cure for Parkinsons, and it does not slow disease progression. Like all brain surgery, deep brain stimulation surgery carries a small risk of infection, stroke, or bleeding. A small number of people with Parkinsons have experienced cognitive decline after this surgery. That said, for many people, it can dramatically relieve some symptoms and improve quality of life. Studies show benefits lasting at least five years.
It is very important that a person with Parkinson's who is thinking of surgery be well informed about the procedures and realistic in his or her expectations.
The Parkinson's Pipeline

Researchers are working to development new and improved therapies for people living with Parkinson's. Each year, PDF asks a leading researcher to tell us about the current "pipeline" of medications being tested.
The latest, written by David G. Standaert, M.D., Ph.D., appears below.
What's in the Parkinson's Pipeline?

By David G. Standaert, M.D., Ph.D.
If you are a person living with Parkinsons disease (PD), you may be wondering if new and better medications will be availabl e in the near future and how they may help you.
It is difficult to predict which treatments in trials will be approved for the market, but we can assess the possibilities by looking at the pipeline the process by which we find new treatments for Parkinsons. Currently, there are two categories of therapies, symptomatic and neuroprotective, which are making their way through the PD pipeline.
The first category, symptomatic drugs, treats both the motor and nonmotor effects of Parkinsons. There are already several treatments for Parkinsons symptoms and these have made a tremendous difference in the lives of many who live with PD. However, these medications have side effects and do not address certain symptoms for example, none of them help with the common problems of fatigue, constipation or balance. So, one goal is to find better symptomatic drugs.
Second, there is excitement about the possibility of developing neuroprotective treatments, those that would slow or prevent the progression of Parkinsons disease. So far, no therapies have been proven to be neuroprotective and most of the candidates are in the early stages of the development process, years away from approval.
The Drug Development Process
Scientists find new medications in one of two ways. One way is to test the efficacy of compounds that have already been approved by the US Food and Drug Administration (FDA) for other diseases. The other is to theorize a new pathway that may affect PD, and then to find a new compound to target it. Under both approaches, the therapy must travel through a multi-step process before it can be approved for the market.
The first phase of this process is called preclinical research. During this stage, a new compound is discovered and tested on model systems (meaning systems other than humans) that replicate some aspect of PD from simple systems, using a Petri dish or test tube; to more complex models, like yeast and fruit flies; and eventually to very complex systems, such as mice and nonhuman primates.
Once a potential new drug has been validated through animal testing, it may move to the phase where it needs to be tested on humans, called clinical trials. Clinical trials typically proceed through four phases. In a Phase I trial, a drug is tested for safety only, among a small group of 20 to 80 people. A Phase II trial enrolls between 100 and 300 people and while continuing to assess the safety of a medication, now tries to get some idea of whether it is likely to be effective in treating Parkinsons. A Phase III trial typically enrolls between 300 to 3,000 participants at multiple sites. Phase III is the definitive study in which a potential drug is proven safe and effective and therefore eligible for approval by the FDA or it falls by the wayside. After a drug is approved and is used by people with PD, a Phase IV post market trial may be conducted to find out more about how it works in large populations, how it interacts with other drugs, or if it has additional uses.
The Current Pipeline
The following is an assessment of the state of the current Parkinsons pipeline. It includes potential treatments, beginning at the end of the pipeline (Phase IV), and traveling back to the earliest studies (preclinical). Most of the information is drawn from www.PDtrials.org. Please note that each PD medication listed below may be referred to by one or more of its three names. When a drug is in the early stages of development, it has only a chemical name, consisting of letters and numbers. Later on, the medication will be given a generic name. And once it is approved, it will acquire a brand name. For example, a current Parkinsons medication was first referred to by its chemical name, TVP-1012. It then developed the generic name rasagiline, and is now known primarily by its brand name, Azilect.
Phase IV: Post Market Studies
Some drugs that have already been approved by the FDA, either for use in Parkinsons or for another condition, are now being studied to see if they might work for additional Parkinsons symptoms. For example, the drug rasagiline was originally approved to treat Parkinsons both in the early stages (used alone) and in the later stages (as an adjunct to levodopa and other therapies). Today, it is being studied for its effects when given in combination with dopamine agonists.
Then there is naltrexone (brand names ReVia, VivitrolTM and Depade), which is currently used to treat addictions, but which scientists suspect may be useful for treating impulse-control disorders in PD, such as compulsive gambling or shopping. Rivastigmine (Exelon), a drug approved for the treatment of PD dementia, is being studied for treatment of additional cognitive symptoms. Lubiprostone (Amitiza), a gastrointestinal medication, is being evaluated for its efficacy in alleviating constipation. Finally, donepezil (Aricept), originally indicated for the treatment of Alzheimers, is under investigation for the treatment of dementia in Parkinsons.
Phase III: Pivotal Studies
In Phase III trials, the make-or-break stage of the clinical research process, most of the candidate treatments are symptomatic. Few of the neuroprotective therapies have made it this far. The symptomatic therapies being studied include several reformulations of levodopa, which aim to address problems associated with current formulations, such as wearing-off that is, when the time
during which the drug is effective becomes shorter. The newer medications are designed to provide more on-time for people with PD and simplify a persons medication schedule by requiring less frequent dosages throughout the day.
One example is IPX066, which comes in pill formulation. It is an extended-release medication that is, it has a mechanism that releases the compound slowly in the bloodstream throughout the day rather than all at one time, thus requiring a person to take fewer pills. Another therapy under study is intraduodenal levodopa (Duodopa), which is a gel form of levodopa that is pumped directly into the intestines. Its goal is to provide continuous amounts of levodopa to avoid wearing-off. A third medication, safinamide, which is in the class of medications called MAO inhibitors, is also designed to increase on -time and decrease off-time associated with levodopa in the middle and late stages of PD. This drug is being studied as an adjunct treatment, meaning it would be taken in addition to levodopa and other existing PD medications. Also in Phase III is a medication called istradefylline (KW-6002), an adenosine (A2A) agonist. Investigators hope that this drug will suppress dyskinesia, the involuntary movements caused by PD medications, as well as ease the motor symptoms of Parkinsons itself.
Finally, there are two symptomatic drugs under study in Phase III trials that address nonmotor PD issues: pimavanserin (ACP-103), which may suppress psychosis and hallucinations, and pitolisant (BF2.649) which addresses the excessive sleepiness that is experienced by many people with PD.
In the neuroprotective category, two medications have reached Phase III, both of them sponsored by the National Institutes of Health. One is Coenzyme Q10(CoQ10), and the other is creatine. Both are substances that occur naturally in the body. They are being given in much higher amounts than are normally present.
Phases II and I: Safety and Efficacy Studies
Earlier in the pipeline, we find four symptomatic therapies and four neuroprotective drugs under study. Three of the symptomatic therapies AFQ056, pardoprunox (SLV-308) and fipamezole (JP-1730) target particular kinds of receptors in the brain with the hope of easing the movement symptoms of PD. They are all taken as pills. The fourth, Prosavin, is a gene therapy that is administered surgically into the brain. It consists of a genetically engineered virus that expresses enzymes in the brain that help levodopa to be converted into dopamine. The hope is that boosting dopamine will alleviate the symptoms of PD.
Also in the neuroprotective category is a second gene therapy approach calledCERE-120 (AAV neurturin), which uses a growth factor that makes the protein neurturin. The hope is that neurturin will help regenerate the dopaminergic system and turn the clock back on PD.
Another interesting neuroprotective candidate being studied in Phase I and II clinical trials is isradipine (DynaCirc CR). Isradipine is one in a class of medications called calcium channel blockers that is already used to treat high blood pressure. An additional trial, called SURE-PD, is studying urate, a normal constituent in blood. Several studies have shown that people with high natural levels of urate seem to be protected from PD. Last among the neuroprotective agents in early phase trials is PYM50028 (Cogane), which is derived from the extract of the sasparilla plant.
Preclinical: Discovery and Validation
In earlier preclinical discovery phase, much of the excitement surrounds neuroprotective strategies, some of them using recent discoveries about the genetic causes of PD. Drugs under investigation target the proteins produced by the genes known as alphasynuclein and LRRK2. Another approach in this phase is reducing inflammation in the brain. A third approach is studying the use of growth factors and neuroregenerative approaches as an attempt to not onlystop the progress of Parkinson's disease, but also to reverse it.
Looking Forward
It is always difficult to predict which potential therapies will work and which will not. At each step along this pipeline, research becomes much more expensive. And for every potential therapy that enters the process, perhaps one in a thousand will end up being approved for use.
That said, we can forecast that the drugs most likely to emerge soon from the pipeline are symptomatic treatments that have been studied the longest (in Phase II and Phase III trials). These treatments include those that are finding new ways to use levodopa and dopamine agonists as well as those that aim to address fatigue, constipation and memory loss.
Neuroprotective and restorative treatments are being studied at earlier phases in the pipeline. Within about three years, the hope is that modestly effective neuroprotective therapies perhaps CoQ10, creatine or isradipine will be approved.
While we cant know exactly whats next, we can be optimistic at the level and type of research ongoing for Parkinsons, all of which aims to improve and perhaps more importantly, reverse the course of Parkinsons for all of those living with the disease.
Dr. Standaert is John and Juanelle Strain Professor and Vice Chair of Neurology at the University of Alabama at Birmingham. In the last year, Dr. Standaert has served as a consultant to Solvay Pharmaceuticals, manufacturer of Duodopa, and Teva Neuroscience, manufacturer of Azilect. He recently presented this topic at one of PDFs PD ExpertBriefings.
Clinical Trials
What are Clinical Trials?
A clinical trial is a human research study designed by scientists and medical experts to answer questions about a disease and potential new therapies. They are an essential and necessary component of the scientific research process. Simply put, there is no other way for research to show that a proposed treatment works.
Learn more by reading below:
Do all clinical trials test drug therapies? How are clinical trials conducted?
Benefits and risks of clinical trials How can I learn more about clinical trials and find a trial near me?
Do all clinical trials test drug therapies?

There are two main types of clinical trials: interventional and observational.
Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective. These trials might ask a participant to take an experimental new drug or undergo surgery.
Observational trials address health issues in large groups of people or populations in natural settings. Participants in these trials may be asked to answer questions about their family histories or give blood samples, but they do not receive treatment for their disease. Some observational trials are even open to healthy volunteers.
How are clinical trials conducted?

Clinical trials that test drugs are conducted in a series of carefully monitored phases designed to answer specific questions.
Phase I: In a Phase I trial, researchers test a new drug or treatment in people for the first time. A small group of people, typically fewer than 100, are monitored to evaluate the drug or treatment's safety, determine a safe dosage range, and identify side effects.
Phase II: Phase II trials study the effectiveness of a drug or treatment in a larger group of people.
Phase III: In this phase, the study drug or treatment is given to a large group of several hundred to several thousand people. This large-scale testing gives more detailed information about the drug's benefits, effectiveness, and the range of possible side effects.
Phase IV: Phase IV studies are usually conducted on drugs that have already been approved by the FDA. These trials are run to determine additional uses for an approved drug or further study its safety in large numbers of participants.
Benefits and Risks of Clinical Trials

Participating in a clinical trial can be a rewarding experience. Consider the following benefits when deciding if you should join a clinical trial:
You will have access to leading healthcare professionals, cutting-edge new treatments and high standards of care. Joining a clinical trial can increase your knowledge and understanding of your disease. People who take part in clinical trials are contributing to science that may benefit themselves and others. The medications that you take now are available only because people before you have volunteered in clinical trials.
Although every effort is made to ensure that clinical trials are as safe as possible, clinical trials that test new therapies are experiments and can involve risks.
Here are some of the risks to consider:
There may be undesirable side effects to the treatment. A health professional will explain the possible risks and side effects during the informed consent process. The treatment may not be effective for the participant.
People with PD should also keep in mind that they may not receive the experimental treatment because they may be randomly assigned to the "control" group and receive either a different dose of the "test" treatment, a treatment that is already available that is considered standard therapy for the disease, or a sugar pill (placebo). The control group is used as a basis for comparison. In many studies, the researcher is not aware of who is taking the treatment and who is in the control group. The study might have time and travel requirements that are demanding. These are some issues you should address when talking to a clinical investigator.
How Can I Learn More About Clinical Trials and Find a Trial Near Me?
Visit www.PDtrials.org, for more information on clinical trials. PDtrials can help you to learn about trials near you and what questions to ask if you are thinking of participating.
PDtrials was created in 2004 to increase the PD community's awareness of clinical trials and provide up-to-date information on trials enrolling participants. This project is led by the Parkinson's Disease Foundation in collaboration with the American Parkinson Disease Association, Inc., The Michael J. Fox Foundation for Parkinson's Research, National Parkinson Foundation, Parkinson's Action Network, The Parkinson Alliance and WE MOVE. The campaign is advised by the National Institute of Neurological Disorders and Stroke (National Institutes of Health), the Parkinson Study Group, the Parkinson Pipeline P roject and The Parkinsons Institute and Clinical Center.
If you are interested in research, you may want to consider applying to become a PDF Research Advocate, so you can be trained to influence research and speed new and effective treatments for Parkinson's. Visit PDF's Parkinson's Advocates in Research page to learn about upcoming trainings.
Web Resources:
Centerwatch www.centerwatch.com An information service for patients, pharmaceutical companies and research centers that are involved in clinical research. Centerwatch publishes a wide range of newsletters, books and directories.
Review an extensive list of clinical trials being conducted across the world. Subscribe to a free email service which notifies you about new Parkinsons clinical trials in your area.
National Institutes of Health www.clinicaltrials.gov A resource site developed by the National Institutes of Health to provide patients, family members and the general public with current information about clinical research studies.
Find out about current PD clinical trials.
Access information describing the clinical trials process.
Parkinson Pipeline Project www.pdpipeline.org A patient perspective on new Parkinsons therapies currently in the pharmaceutical pipeline. This website depends on the work of volunteers; contact the webmaster if you would like to help.
Parkinson Study Group (PSG) www.parkinson-study-group.org A nonprofit, cooperative group of Parkinsons disease experts from medical centers in the US and Canada dedicated to improving PD treatments through clinical trials.
Identify references in scientific and academic journals relating to PD research and clinical trials. Find out about PSG clinical trials that are in progress.
Statistics on Parkinson's
Who Has Parkinson's?
As many as one million Americans live with Parkinson's disease, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease. Approximately 60,000 Americans are diagnosed with Parkinson's disease each year, and this number does not reflect the thousands of cases that go undetected. An estimated seven to 10 million people worldwide are living with Parkinson's disease. Incidence of Parkinsons increases with age, but an estimated four percent of people with PD are diagnosed before the age of 50.
Men are one and a half times more likely to have Parkinson's than women.
What Does Parkinson's Cost?
The combined direct and indirect cost of Parkinsons, including treatment, social security payments and lost income from inability to work, is estimated to be nearly $25 billion per year in the United States alone. Medication costs for an individual person with PD average $2,500 a year, and therapeutic surgery can cost up to $100,000 dollars per patient.
Chasing the Cure

Many scientists believe that the cure for Parkinsons will come from a deeper understanding of what causes the disease. What is the reason that dopamine neurons begin to degenerate and die?
If the cause of the neurodegeneration can be identified, perhaps a specific treatment can be developed to slow, stop or reverse its process. Future treatment strategies may include the delivery of substances or genetic material directly to the brain. They may involve replacing neurons. However, these techniques are in the earliest stages of development. For people living with Parkinsons disease and their fam ilies, the progress is always too slow. But there are reasons to be optimistic. It is anticipated that many scientific advances will be translated into benefits for people with Parkinsons, and so the hope for a cure is linked with true promise and great optimi sm.
For more on this topic, read the article below by Stanley Fahn, M.D., PDF's Scientific Director, originally printed in the Fall 2009 edition of the PDF newsletterNews & Review.
Chasing the Cure

Whats happening in research on Parkinsons disease (PD)? This question is always uppermost on the minds of people with Parkinsons and their family members. To answer it, I have looked back at the research conducted in the past decade or so. It turns out that between 1997 and 2007, more than 23,000 scientific articles addressing Parkinsons were published.
This large number reflects the excitement stirring in this field. But what did the research yield? While we have much further to go in our understanding of Parkinsons disease and towards our goal of finding a cure, I expect that you will be as impressed as I am by the serious investment of time and resources that is going into this important research.
Genetic and Environmental Causes of PD To me, the most exciting and important area of PD research during this period is genetics. Although few cases of Parkinsons disease can be attributed to genes alone, identifying the types of genetic mutations that lead to PD has given researchers tools for unraveling the molecular mechanisms that underlie the disease.
In 1997, scientists described the first gene known to be mutated, or changed, in PD. The gene named SNCA, or PARK1 (the first in a series of PARK genes that now number more than a dozen) codes for alpha-synuclein, a protein that we have since learned may play a very important role in the development of PD. While mutations in this gene are very rare, the discovery that an alteration of alpha-synuclein is involved in PD spurred researchers to study it. They found that this protein is present in the Lewy body, a foreign inclusion in neurons that is the pathologic hallmark for PD.
Another important genetic discovery related to alpha-synuclein was that the mutation known as PARK4 was actually a triplication of the normal SNCA gene, meaning that people with PARK4 had extra copies of the gene and thus, an excess of normal alphasynuclein. So, too much alpha-synuclein and not just an abnormal form of the protein can cause Parkinsons, albeit in very few people. Partly because of this discovery, much research in the last decade has focused at the molecular level on the mechanisms by which the alpha-synuclein protein contributes to the death of dopamine neurons. It is now understood as one of three elements within the dopamine neuron the other two are dopamine and calcium that interact to cause neurodegeneration.
There are several other genes that have been implicated in PD. Some rare mutations are implicated in the onset of PD at a young age, usually before the age of 30; these genes are PARK2, PARK6 and PARK7. Their abnormal gene products appear to affect the function of the energy factory of the cell the mitochondrion. The most common mutations that contribute to Parkinsons occur in the gene known as PARK8 or LRRK2. Mutations in many different parts of this gene have been discovered, and they can occur in people who do not have a family history of PD. In fact, mutations in this gene have been identified in more than two percent of people with Parkinsons in North America and England, who do not have a family history of the disease. They are found even more frequently among people with Park insons disease who are of Portuguese, Spanish, Ashkenazi Jewish and North African descent. It is not yet understood how the abnormal LRRK2 protein causes PD. This should be an area of intense research in the future. Since Parkinsons usually cannot be attributed entirely to genetics, scientists have also studied environmental contributions. A large study of identical twins in which at least one member of the pair was diagnosed with PD helped to sort out the relative genetic and environmental contributions. The researchers found that when PD was diagnosed before the age of 50, it was much more likely to have a strong genetic component than when it was diagnosed later in life.
Environmental toxins have long been considered a potential trigger for PD and much research has focused on pesticides. From research on laboratory animals and also from studies that collected data on large numbers of people who were exposed to pesticides (known as epidemiological studies), we have learned that the chemicals rotenone and paraquat contribute to PD. But the relationship of pesticide exposure to Parkinsons remains unresolved, and the search for an explanation continues.
Scientists are also investigating whether an underlying genetic predisposition could combine with pesticide exposure to result in PD. In the meantime, some things in the environment have been shown to correlate with a lower risk of Parkinsons. Smoking cigarettes is one (although it can lead to other health problems); others are drinking coffee, having higher levels of uric acid in the bloodstream, and having gout.
How PD Begins: A New Theory We have long known that the motor symptoms of Parkinsons begin when dopamine-producing cells die in a part of the brain called the substantia nigra. This is often the point at which people with Parkinsons first receive a diagnosis. Then, along came a theory suggesting that at this point, people are already at a relatively advanced stage of the disease, and that PD actually starts earlier, with changes in other areas of the brain and elsewhere in the body.
The theory was first proposed a few years ago by the German researcher Heiko Braak, M.D. He and his colleagues examined the autopsied brains of people who had died with Parkinsons and found that alpha-synuclein protein accumulated in areas other than the substantia nigra. These areas, including the pons and the medulla in the brainstem, control body functions such as digestion, heartbeat and the regulation of sleep. His team also found widespread deposits of alpha-synuclein in nerve cells in the gut. These discoveries led Dr. Braak to propose that alpha-synuclein abnormalities begin to accumulate in lower regions of the nervous system, eventually reaching higher areas in the brain. Dr. Braaks hypothesis has stimulated much discussion and debate among
researchers. His observations may explain some of the nonmotor symptoms of PD, such as constipation, changes in sleep and mood and decreased sense of smell.
Beyond noting accumulations of alpha-synuclein, new research has shed light on other molecular mechanisms by which neurons degenerate in PD, including oxidative stress, alteration of the mitochondria and inflammation. The understanding of these processes has led to new ideas for developing therapies for Parkinsons. Diagnosing Parkinsons and Measuring Its Progression Partly because of Dr. Braaks hypothesis, researchers are searching for biomarkers to detect PD before the motor symptoms become manifest. One method that has shown promise is neuroimaging that is, getting a picture of the brain using techniques known as positron emission tomography (PET) and single photon emission computed tomography (SPECT). In clinical trials evaluating people newly diagnosed with PD that also included one of these imaging techniques, ten to 15 percent of these individuals had scans without evidence of a dopaminergic deficit meaning they did not have PD at all and there was some other cause of their tremor and slowness. These individuals did not respond to levodopa therapy. Some PET techniques have been helpful in differentiating PD from atypical parkinsonisms, such as multiple system atrophy and progressive supranuclear palsy. Such tools could be helpful in both diagnosing PD and treating it earlier in its progression.
Findings in the Clinic James Parkinsons original description of PD stated that the senses and intellects were uninjured in the disease. But we have known for many years that this is not the case, possibly because with modern treatment, people with PD live much longer than ever before. In the past decade, physicians have developed a keener awareness of nonmotor symptoms of Parkinsons and their impact on quality of life for people with PD. These symptoms include personality changes such as the development of passivity, difficulty making decisions, loss of motivation, anxiety, depression and bradyphrenia (slowness in thinking). These and other nonmotor symptoms including such problems as fatigue, sleep disturbances, constipation, bladder disturbances and changes in sensory perception can become more serious when motor problems of PD are controlled with medications. Fortunately, many of these nonmotor symptoms can respond to treatment.
Effective medications that can reduce the severity of PD, however, are not always free of side-effects. Sometimes, serious adverse effects of hallucinations, delusions and paranoia can occur. The drug clozapine, not yet approved for PD, has been shown in clinical trials to ease such side-effects without aggravating Parkinsonian motor symptoms. In addition, in some people, PD medications known as dopamine agonists have been found to cause impulsive behaviors most commonly pathologic gambling, compulsive eating and shopping and hypersexuality. Reducing or stopping the medication eliminates these problems.
Researchers have learned that cognitive decline often occurs in people with PD when they reach an advanced age. This process has been traced to the presence of Lewy bodies in the brains cerebral cortex, t he area that is responsible for reasoning and decision-making. One medication, rivastigmine (Exelon), is currently approved for and has been shown to be modestly effective for treating dementia in people with Parkinsons.
Advances in Treating PD
With therapies already in hand to control the symptoms of PD, the focus in recent years has been a search for medications that slow the rate at which PD progresses. Some drugs that looked promising based on testing in animals turned out not to be effective in humans. One class of drugs that may be effective in this regard is the MAO-B inhibitors. One of these is selegiline (Eldepryl, Zelapar); another is rasagiline (Azilect). Other agents, Coenzyme Q10 and creatine, are still in clinical trials. In other reassuring news, scientists found that levodopa which was long suspected of worsening oxidative stress and possibly hastening the progression of PD in fact may slow it down. The challenge of slowing down the progression of PD is also being addressed by scientists who are interested in exploring the neuroprotective value of physical exercise.
A number of controlled clinical trials have tested new therapies that control, but do not slow, symptoms. In general, researchers found a trade-off between the new treatments and levodopa, the gold standard: that is, the drugs that reduced motor fluctuations and dyskinesias (involuntary twisting and writhing movements) were less powerful than levodopa in alleviating Parkinsonian symptoms. One new medication, rotigotine (Neupro), a dopamine agonist administered by a skin patch, came to market, but is currently unavailable in the US due to manufacturing problems.
Also, in the last decade, surgical deep brain stimulation (DBS) has been validated as an effective therapy for reducing dyskinesias and motor fluctuations in people who otherwise respond well to levodopa. However, many questions remain unanswered, including optimal timing of surgery and the long term outcome (more than five years after surgery) of the procedure. Other surgical approaches to therapy, including gene therapy, are now in clinical trials.
A Wealth of Discoveries
Space limitation allows me to discuss only a tiny fraction of what we have discovered about PD during the last decade. I could go on to write, for example, about studies on biomarkers that may someday help predict PD risk. This and other discoveries will be in the news in the near future. Parkinsons research is a growing field, and with each year we will see advances in both laboratory a nd clinical science.
Stanley Fahn, M.D., is the H. Houston Merritt Professor of Neurology and Director of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University. He has served as the Scientific Director of PDF since 1973.

What Is Parkinson

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What Is Parkinson

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What is Parkinsons Disease?

How is Parkinsons Diagnosed?

Why Arent There Tests to Diagnose Parkinsons?

Parkinsonisms and Parkinson's Plus Syndromes

Find out more by reading detailed descriptions of Parkinson's symptoms below:

Primary Motor Symptoms

Secondary Motor Symptoms

loss of sense of smell, constipation

Other Nonmotor Symptoms

Some of these important and distressing symptoms include:

What Causes Parkinson's?

Read more below about each of these:

Genetic Factors Environmental Factors

Genetics and Parkinson's Disease: What Have We Learned?

Causal Genes: Alpha-synuclein

Assessing Your Genetic Risk

Environmental Factors and Parkinson's: What Have We Learned?

Potential Risk Factors

Potential Protective Factors

The Search for Proof

Medications & Treatments

Low blood pressure, nausea, confusion,

First course of treatment; converts to dopamine to manage major

Antacids, antiseizure drugs, antihypertensives, anti-depressants, high protein food

50/200 mg dyskinesia, dry mouth, dizziness symptoms

Low blood pressure, nausea, confusion,

First course of treatment; converts to dopamine to manage major

Antacids, antiseizure drugs, antihypertensives, anti-depressants, high protein food

50/200 mg dyskinesia, dry mouth, dizziness symptoms and

may prolong effectiveness

12.5/50/200 Dyskinesia, mg nausea, diarrhea,

Levodopa/ 25/100/200 Entacapone mg

hyperkinesia, abdominal pain, dizziness,

18.75/75/200 harmless mg discoloration of 31.25/125/200 mg urine, saliva and/ or sweat

Low blood pressure, nausea, confusion,

First course of treatment; converts to dopamine to manage major

Antacids, antiseizure drugs, antihypertensives, anti-depressants, high protein food

25/250 mg dyskinesia, dry mouth, dizziness symptoms; also

tablet for patients with (Parcopa) swallowing difficulties

APOKYN injection (apomorphine hydrochloride)

.02 mL during off periods

Adjunct levodopa therapy to treat off periods

Low blood pressure,

First course of treatment alone or with levodopa;

Alcohol, antipsychotics, blood pressure lowering medications

nausea, edema, confusion, dry mouth, depression, headaches

mimics dopamine to manage major symptoms

AVAILABLE INITIAL DOSING DOSES

Rotigotine Transdermal System (Neupro)

4 mg/24hrs patch a day 6 mg/24hrs 8 mg/24hrs

Sedatives and tranquilizers; metocipramide, thiozanthenes, cimetidine,

Pramipexole dihydrochloride extendedrelease

.375 mg 1x/day Somnolence (sleepiness),

For the treatment of the signs and symptoms of early Parkinsons

Dose may be increased

nausea, constipation, dizziness, fatigue,

gradually, not more

AVAILABLE INITIAL DOSING DOSES

frequently than every 5 to 7

hallucinations, dry mouth, muscle spasms, and peripheral edema

Abdominal pain, sleep

First course of treatment alone or with levodopa;

Alcohol, antidepressants, Cipro, antipsychotics, benzodiazipines