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What Causes
   Parkinson's Disease
 - Biologic Mechanisms 
   and Genetic Factors
 - Environmental 
   Assaults and 
  Oxygen-Free Radicals
What Are the 
   Symptoms of 
   Parkinson's Disease   
Who Gets Parkinson's 
   Disease 

   

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Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. It occurs when cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra . Nerve cells in the substantia nigra send out fibers to the corpus stratia , gray and white bands of tissue located in both sides of the brain. There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Dopamine is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss 
of dopamine in the corpus stratia is the primary defect in Parkinson's disease. This loss negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.



What Causes Parkinson's Disease 
Parkinson's disease is sometimes referred to as idiopathic, which means that the primary cause is unknown, in order to distinguish it from parkinsonism, which are the symptoms occurring from a known cause. Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, researchers now must discover how this dopamine is lost. Studies indicate that the culprit is not a single cause, but is a combination of genetic susceptibility and environmental assaults.


Biologic Mechanisms and Genetic Factors
Studies suggest that genetic factors are important in causing Parkinson's. Although one suggested that they are rarely critical in cases that develop after the age of fifty, twin studies indicate they may play a role in many cases of Parkinson's disease. Even with some understanding of the abnormal biological mechanisms in the brain that cause Parkinson's disease, no one knows at this time how long it takes before nerve damage and dopamine loss trigger symptoms. At this time, the best guess is about five years.

Complex I and Oxygen-Free Radicals. Some research is focusing on the 
observation that some Parkinson's patients have a 30% to 40% decrease in an enzyme called complex I. This enzyme is found in mitochondria, thread-like structures in cells that generate energy. Low amounts of complex I lead to energy loss and the inability of the cell to withstand the assault of oxygen free radicals, which are 
unstable molecules produced by the natural chemical processes in the body. Because free radicals are missing an electron, they tend to bind with other molecules in the body. This can set off a chemical chain reaction that damages any type of cell, including nerve cells in the brain, and even interferes with their DNA. People who have insufficient amounts of complex I, either from genetic abnormalities or other factors, may be more susceptible to developing Parkinson's disease from exposure to chemicals and toxins.

NMDA Receptors. Also of interest are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events 
that trigger oxygen-free radicals. Agents inhibiting the NMDA receptors now show promise in treating Parkinson's.

Immune Factors. An overresponsive immune system may also play a role in perpetuating Parkinson's disease by producing certain factors called cytokines 
(eg, interleukin-1, tumor necrosis factor) in response to the initial damage, which can further injure cells in the brain.

Defective Alpha Synuclein and Lewy Bodies. Some experts are studying abnormalities in a protein called alpha synuclein, which has been detected in some early-onset Parkinson's patients of European descent. A genetic defect causes the alpha synuclein proteins to collect and clump together, most likely forming fibrous deposits known as Lewy bodies in the substantia nigra, the place in the brain where dopamine is first released. Lewy-body deposits are found not only in the brains of patients with Parkinson's disease, but are also present in smaller numbers in other neurologic diseases and in people without neurologic symptoms. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. Some experts believe that the formation of Lewy bodies occurs in very early stages of Parkinson's and may be a harbinger of the full-blown disease. In any case, the defective alpha synuclein 
protein itself appears to be rare and is unrelated to the much more common cases 
of Parkinson's disease.

Parkin Gene. Researchers have also discovered a gene that may be responsible 
for a rare form of Parkinson's disease that occurs in children and adolescents. The gene regulates a newly found protein that the researchers call parkin and is similar 
to a protein known as ubiquitin found in Parkinson's disease and other neurologic diseases. Whether this defective protein will be relevant for late-onset Parkinson's 
is unknown.


Environmental Assaults and Oxygen-Free Radicals
Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that can injure cells and even affect genetic material. Such oxidative stress may play a major role 
in the deterioration of nerve cells that lead to Parkinson's. Influenza and other potent viruses have been associated with the development of parkinsonism; in one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism. Recent biochemical advances have identified immune factors that suggest a viral presence in Lewy bodies and swollen nerve pathways. Intense exposure to certain environmental and industrial chemicals may also trigger oxidation leading to nerve damage.


Aging Process
Most, but not all, Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any further stress on these transporters might trigger Parkinson's disease in the 
aging brain.


Causes of Parkinsonism and Diseases that Mimic Parkinson's Disease
In many patients, the symptoms of Parkinson's disease have an identifiable cause, 
in which cases the syndrome is known as parkinsonism.

Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to some studies, patients who experience drug-induced parkinsonism may actually be at an increased risk of developing Parkinson's disease later in life. A number of drugs can cause these symptoms, including nearly all used to treat schizophrenia and other psychoses (eg, haloperidol (Haldol), thioridazine (Mellaril), and chlorpromazine (Thorazine)). Valproate (Depakote), used for epilepsy, also causes reversible parkinsonism. Metoclopramide (Octamide, Maxolon, Reglan), used for stomach disorders, is an important cause of these symptoms in the elderly; the symptoms persist sometimes for months after the drug has been withdrawn. The common antidepressants known as selective serotonin-reuptake inhibitors (SSRIs), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), may cause Parkinson-like symptoms. Studies have also found a link between meperidine (Demerol) and Parkinson's.

Other Neurologic Conditions. Many medical conditions may cause symptoms of Parkinson's disease. Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control. Coexisting Alzheimer's disease may confuse the diagnosis. In one study 23% of people with Alzheimer's also met the criteria for Parkinson's disease. A disease known as dementia with Lewy bodies has similar symptoms, but is marked by early dementia. Some people have a condition called essential tremor, which unlike the tremor of Parkinson's disease, often occurs in the head and voice and is usually worse during motion, as opposed to rest. Progressive supranuclear palsy has similar symptoms, but involves less tremor and earlier rigidity, and it tends to affect both sides of the body symmetrically. Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, and a number of degenerative neurologic diseases. There have also been reports of parkinsonian symptoms developing or worsening as a result of subdural hematomas (a collection or clot of blood on the surface of the brain). Such patients recover after removal of 
the hematomas.

Gluten. One study found that an immune response to a protein found in gluten, a substance in wheat, rye, and barley can cause muscle weakness and neurologic problems similar to parkinsonism.



What Are the Symptoms of Parkinson's Disease 
Tremors
Symptoms often start with an occasional tremor in one finger that spreads over time to involve the whole arm. The tremor is often rhythmic, 4 to 5 cycles per second, and frequently causes an action of the thumb and fingers known as the pill-rolling tremor. Tremor is present when the limb is at rest or held up in a stiff unsupported position and usually disappears briefly during movement. Tremors can also occur in the head, lips, tongue, and feet, although they do not occur during sleep. In one study, 44% of patients reported experiencing internal tremors lasting less than half an hour, but occurring several times a week. Symptoms can occur on one or both sides of 
the body.


Motion and Motor Impairment
Slowness of motion ( bradykinesia) is one of the classic symptoms of Parkinson's disease. Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady and cause a person to fall. After a number of years, muscles may freeze up or stall, usually when a patient is making a turn or passing through narrow spaces, such as a doorway. Intestinal motility, eg, swallowing, digestion, and elimination, may also slow down, causing eating problems and constipation. The muscle rigidity ( akinesia) experienced in Parkinson's disease often begins in the legs and neck. Muscle rigidity in the face 
can produce a mask-like, staring appearance. Hand deformities may develop in 
late stages, causing severe discomfort and limitation. Handwriting, for instance, often becomes diminutive. Normally spontaneous muscle movements, such as blinking, may need to be done consciously.


Speech Impairment
More 70% of Parkinson's patients, by some estimates, develop some speech difficulty caused by rigidity of the facial muscles, loss of motor control, and impaired breath control. Tone can become monotonous, words may be repeated over and over, or the rate of speech may even be very fast. Swallowing may be difficult.


Depression and Mental Problems
Depression is often present as one of the first symptoms and is probably partially caused by a chemical imbalance in the brain. Because depression is common in 
old age or can be caused by other factors, the patient often does not connect it with other early symptoms of Parkinson's. Defects in thinking, memory, language, and problem solving skills often occur later on (and sometimes in early untreated patients). Dementia occurs in almost 30% of Parkinson's patients who are usually older individuals who have had major depression.


Other Symptoms of Parkinson's Disease
The sense of smell is impaired in about 70% of patients. Vision is also affected, including color perception. The patient may experience changes in sensations of temperature, hot flashes, excessive sweating, and cramps and burning in the legs. Restless legs syndrome affects some patients; this irresistible urge to move the calves often occurs at night, disturbing sleep. Parkinson symptoms that may occur after encephalitis include greasy skin and hair, tics, spasms, rapid and repetitive speech, and oculogyric crises--disturbances in which the eyes become fixed in one direction for minutes or even hours. In people with a history of migraine, the onset of Parkinson's is associated with change in migraine symptoms (most often improvement). Constipation is a major problem for Parkinson patients and occurs both as a result of the disease and a side effect of its treatment. Laxatives, stool softeners, and other medications may be prescribed. The drug cisapride (Propulsid) appears to help some people with constipation and a poor response to levodopa 
[ see Diet, in this report ]. Bladder control and urinary incontinence are also 
problems that can be helped by taking Sudafed.



Who Gets Parkinson's Disease 
Parkinson's disease itself affects people worldwide, including more than a million people in North America. The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) appear in an estimated 8 million people over 65. In one study, parkinsonism occurred in about 15% of people 65 to 74 years of age, about 30% in those 75 to 84, and over half of people older than 85. It should be noted that this particular study included people with very mild symptoms and the percentages are higher than ones using stricter criteria.


Age and Gender
The average age of onset of Parkinson's disease is 55. The elderly are at higher 
risk for both parkinsonism and Parkinson's disease, although there is some evidence that the very elderly (over 75) are at low or no risk. About 10% of Parkinson's cases are in people younger than 40 years old. One study suggested that the disease progresses more rapidly in men than women, but these results may only indicate that men are less responsive to the treatments for Parkinson's. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor.


Relatives
People with siblings or parents who developed Parkinson's at a younger age are 
at higher risk for Parkinson's disease, but relatives of those who were elderly when they had the disease appear to have an average risk.


Ethnicity
African- and Asian-Americans have a lower risk than European-Americans.


Exposure to Toxic Substances
A higher incidence of parkinsonism is found in people who live in rural areas, particularly those who drink private well water or are agricultural workers, indicating that the higher risk is due to exposure to pesticides and herbicides. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum and others) has also been linked with parkinsonism, which is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear.


Smoking
Cigarette smokers appear to have a lower risk for Parkinson's disease, indicating some protection by nicotine. This finding, of course, is no excuse to smoke, but such protection may help researchers develop new therapies.



How Serious Is Parkinson's Disease 
General Outlook
Parkinson's disease is not fatal, but it reduces longevity. It also seriously impairs the quality of life and may sometimes lead to severe incapacity within 10 to 20 years. Treatments are increasingly effective, however, in alleviating symptoms and even slowing progression of the disease. Over time the side effects of many of these medications can be nearly as distressing as the disease itself, and the drugs may eventually lose their effectiveness. Parkinson's disease is sometimes categorized as either tremor predominant or postural instability and gait disturbed (PIGD). In younger patients tremor is usually predominant and progression of the disease is slow, although younger patients have a higher risk of developing dyskinesias (the inability to control their muscles). Elderly people are more apt to have PIGD. Some studies have suggested that early PIGD symptoms predict a faster decline than having tremor predominant. Gait disturbance is a particularly serious sign in the elderly.


Impact on Emotions and Mental Status
The emotional and psychiatric impacts of the symptoms are devastating. In addition, nearly all drug treatments used for Parkinson's disease have side effects that cause neurologic and psychiatric disturbances. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly 
dependent on their support.

Depression. Depression is extremely common, affecting up to 40% of Parkinson's patients, although one study found that only about 7% of patients met the criteria for major depression. Such patients were generally much older and already had mental or psychiatric problems. Depression in the remaining population was generally mild and most likely due to the emotional effect of the disease on the lives of both patients and their families, not actual physical changes in the brain.

Dementia. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. In one study, 28% of all patients and two thirds of those over 85 had dementia.



What Will Confirm the Diagnosis of Parkinson's Disease 
Underdiagnosis and misdiagnosis of Parkinson's disease are common. Researchers are hopeful that objective and simple blood or imaging tests will be available in the near future to identify the disease early in its development. At this time, however, the disease is diagnosed almost primarily by its symptoms.


Diagnosing by Symptoms
Studies indicate that general neurologists make an incorrect initial diagnosis of Parkinson's disease in between 25% and 35% of cases; a 2000 study suggested 
that specialists in Parkinson's disease and movement disorders do better, with a mistaken positive diagnosis of only about 8%. In addition, because early symptoms are so mild, Parkinson's disease can be missed, particularly in young adults. Too often, a younger person with Parkinson's may be diagnosed with mental illness, because even the physician may suspect the disease only in older people. Therefore, a medical and personal history that includes any medications being 
taken and exposure to environmental toxins is very important. Repeated 
assessment of symptoms over time is also important to improving the accuracy of diagnosis.

Parkinson's is strongly suspected in patients who have a powerful early response to the drug levodopa, who have a tremor when their limb is relaxed, and whose symptoms appear on one side of the body. Early gait disturbance often indicates a disease other than Parkinson's disease. Even these criteria are not clear-cut. For example, about 25% of Parkinson's patients will not have a tremor. Some patients with a condition called multiple system atrophy will have a good initial response to levodopa, but it is not sustained. People who have parkinsonism, but not Parkinson's disease, often have additional neurologic symptoms.

In later stages of Parkinson's disease, the symptoms are usually unmistakable, and the problem can often be diagnosed using simple physical tests and a medical and personal history. Slowness and difficulty of movement are usually the first symptoms, so the patient will be asked to walk and probably to get out of a chair, preferably a deep one. The physician will also check for tremors and rapid movements of the hands and fingers, although sometimes the tremor is not present, making a definite diagnosis more difficult. Although imaging techniques are not usually necessary when physical symptoms of Parkinson's disease are obvious, they are occasionally used to rule out other medical problems.


Imaging Tests
Imaging tests, such as magnetic resonance imaging (MRI), are somewhat useful in ruling out other, rare neurologic conditions such as hydrocephalus or brain tumors. Single photon emission computed tomography (SPECT) is an advanced imaging technique showing great promise. It is used in combination with a drug that is tagged with a radioisotope. By revealing how the drug accumulates in the brain, SPECT 
may eventually be an accurate method for detecting early and late stages of Parkinson's and allowing physicians to gauge disease progression and effectiveness of treatment.