Parkinson's disease

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Definition

Parkinson's disease (PD) is a progressive movement disorder marked by tremors, rigidity, slow movements (bradykinesia), and posture instability. It occurs when cells in one of the movement-control centers of the brain begin to die for unknown reasons. PD was first noted by British physician James Parkinson in the early 1800s.

Description

Usually beginning in a person's late fifties or early sixties, Parkinson disease causes a progressive decline in movement control, affecting the ability to control initiation, speed, and smoothness of motion. Symptoms of PD are seen in up to 15% of those ages 65–74, and almost 30% of those ages 75–84.

Most cases of PD are sporadic. This means that there is a spontaneous and permanent change in nucleotide sequences (the building blocks of genes). Sporadic mutations also involve unknown environmental factors in combination with genetic defects. The abnormal gene (mutated gene) will form an altered end-product or protein. This will cause abnormalities in specific areas in the body where the protein is used. Some evidence suggests that the disease is transmitted by autosomal dominant inheritance. This implies that an affected parent has a 50% chance of transmitting the disease to any child. This type of inheritance is not commonly observed. The most recent evidence is linking PD with a gene that codes for a protein called alpha-synuclein. Further research is attempting to fully understand the relationship with this protein and nerve cell degeneration.

PD affects approximately 500,000 people in the United States, both men and women, with as many as fifty thousand new cases each year.

— Laith Farid Gulli, MD

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n.
A progressive nervous disease occurring most often after the age of 50, associated with the destruction of brain cells that produce dopamine and characterized by muscular tremor, slowing of movement, partial facial paralysis, peculiarity of gait and posture, and weakness. Also called paralysis agitans, shaking palsy.

[After James Parkinson (1755-1824), British physician.]

Definition

Parkinson's disease (PD) is a neurodegenerative disorder that causes slowed movements, tremor, rigidity, and a wide variety of other symptoms. "Neurodegenerative" refers to the degeneration, or death, of neurons, the type of cell in the brain that is the basis for all brain activity.

Description

Parkinson's disease occurs when neurons (nerve cells) in a part of the brain called the substantia nigra degenerate, or die off. The loss of these cells disrupts the brain's normal control of movement, causing the person to experience slowed movements, stiffness or rigidity, and tremor.

Demographics

PD is one of the most common neurodegenerative diseases, second only to Alzheimer's disease in the number of people affected. Estimates suggest that approximately 750,000 Americans have PD. It affects older people much more than younger, and indeed, old age is the single greatest risk factor for PD. The average age at diagnosis is 62. Onset before age 40 is extremely rare. Men are slightly more likely to be affected than women.

Causes and symptoms

In the vast majority of cases, the cause of PD is un-known. Besides old age, there are several well-recognized risk factors. These include exposure to pesticides or herbicides, rural living, and drinking well water. Because of this, it is assumed that some type of environmental pollutant, either a pesticide or something associated with its use, is involved in causing PD. Other known risk factors include welding and exposure to manganese, further strengthening the case for an environmental toxin.

There is also evidence that genes play an important role in determining the risk of PD. PD can run in families, affecting members of the family at a much higher rate than expected by chance alone. Among identical twins, the situation is complex: if one twin develops the disease early, the other is more likely to as well; but if one twin has typical late-onset PD, the other is no more likely to develop the disease than would be expected by chance.

Several genes have been identified that cause PD in some people, but the number of people affected by these genes is quite small. Therefore, the interest of these genes is more in what they can reveal about the disease process than in providing the solution to the mystery of what causes PD in most people. Two of the genetic mutations identified involve a protein called alpha-synuclein, whose normal function is unknown. It is believed that the mutations prevent the normal breakdown of alpha-synuclein, leading it to accumulate in the neuron, where it then goes on to damage the cell. Another gene mutation that causes PD affects a protein called parkin, which normally helps break down proteins. It is believed that the loss of parkin causes build-up of proteins (though not of alpha-synuclein), again leading to damage. Researchers believe that environmental toxins may also cause similar problems, and it now seems likely that problems in protein breakdown are a significant step leading to PD, whether of genetic or environmental causation. Finally, a combination of genetic and environmental factors is likely to be important in most cases. For instance, a person with a genetically weaker ability to dispose of proteins, who was also exposed to pesticides, might develop PD, whereas a person with different genes but the same exposure might not.

Whatever the ultimate cause, people with PD share the same pathology, or disease process, in their brains. The symptoms of PD arise when cells in the substantia nigra (SN) degenerate. The SN is located at the base of the brain, near the top of the spinal column. Neurons of the SN receive messages from, and send messages to, several other portions of the brain, all of which are involved in the control of movement. By interacting with these other regions, the SN helps to ensure that movements will be smooth, fluid, and controlled.

SN cells communicate with other cells by releasing the chemical dopamine. Dopamine released by SN cells stimulates cells in other brain regions to act. As SN cells die, they release less dopamine, and the receiving cells are not stimulated as much. This leads to the disordered movement of PD. The SN is also involved in regulating numerous other types of brain behaviors, and late-stage PD is marked by a wide variety of symptoms that probably reflect loss of this regulation.

The earliest symptoms of PD, and the most widely recognized, are tremor, slowed movements (bradykinesia), and stiffness or rigidity. Symptoms often begin on one side of the body, and progress over time to involve both sides. The tremor of PD is a rest tremor—the shaking occurs when the patient is not trying to use the limb, and diminishes when the limb is in use. Bradykinesia and stiffness, along with loss of some balance reflexes, can combine to cause postural instability, and increase the likelihood of falling down.

Other symptoms of PD include:

• orthostatic hypotension, or loss of blood pressure upon standing, which can cause dizziness and fainting
• painful foot cramps
• micrographia, or reduced size of handwriting
• reduced voice volume
• reduced facial expression
• excessive sweating
• constipation
• decreased ability to smell
• male impotence
• drooling
• sleep disturbance
• depression
• anxiety
• panic attacks
• late-stage dementia

Diagnosis

Parkinson's disease is diagnosed by a careful neurological examination, testing movements, coordination, reflexes, and other aspects of function. If the physician suspects PD, the patient will usually be referred to a neurologist for definitive diagnosis. Unilateral (one-sided) tremor, slowed movements, and muscle stiffness are generally enough to confirm the diagnosis; two of the three are usually considered definitive. Several specialized tests may be used, including imaging of the brain with magnetic resonance imaging (MRI) or positron emission tomography (PET). These are not essential to diagnosis in most cases, but may help to confirm the diagnosis in difficult cases and to distinguish PD from similar diseases such as progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy. Clues that the disease is one of these, rather than PD, include early or rapidly progressing dementia, loss of coordination, or early and prominent orthostatic hypotension (lightheadedness upon standing).

Certain medications can cause a PD-like syndrome, and it is important to rule these out. These drugs include certain antipsychotic medications (haloperidol) and antivomiting drugs (metoclopramide).

Treatment team

Treatment of PD is headed by a neurologist, who may be either a general neurologist or a movement disorders specialist. The movement disorders specialist is most likely to be aware of the most current trends in treatment. Since PD therapy continues to undergo rapid advances, it may be an advantage to see a specialist when possible. Other team members may include a speech/language pathologist for addressing voice and swallowing disorders, a geriatric medicine specialist to coordinate other medical and social issues, a neuropsychologist for expertise on cognitive aspects of PD and its treatment, and a neurosurgeon.

Treatment

There are no treatments that have been proven to slow the course of PD, although research published in 2003 suggested that coenzyme Q10 may offer a slight benefit in this regard. The study has not been replicated, and its authors noted it would be premature to recommend treatment with this very expensive supplement. Additional claims have been made that two medications used to treat PD symptoms—selegiline and dopamine agonists—may have some disease-slowing effects. These claims are not widely accepted.

The treatment of the symptoms of PD is complex for several reasons. First, PD is a progressive disease, getting worse over time, so that the medications and doses that work well early in the disease are insufficient later on. Second, the most effective drugs have long-term side effects that are troubling and difficult to control. Third, there are a lot of different treatment options, and finding the right combination can be time consuming. Fourth, the PD patient is likely being treated for other conditions associated with advancing age, and these conditions or their treatment may interfere with treatment of PD. Finally, a major treatment option for late-stage PD is surgery, but the risks of surgery are significant, and determining when and what kind of surgery to perform is a complicated decision.

Once the diagnosis of PD has been made, a central question is when to begin treatment. Treatment is typically not started right away (unless the patient elects to use coenzyme Q10), but instead is delayed until symptoms begin to interfere with his or her ability to work or engage in activities of daily living. This may be a year or even more after diagnosis.

Drug treatment

The next question is what drug to begin with. The most powerful treatment for the symptoms of PD is levodopa, which is taken into the brain and substitutes for the dopamine no longer being made by the substantia nigra. Similar in effect are the dopamine agonists, which mimic the effect of dopamine on the cells that normally receive dopamine from the SN. Three other medications also commonly used in PD, whose effects are not nearly as strong as either levodopa or the dopamine agonists, are anti-cholinergics, selegiline, and amantadine. These are often prescribed early on, when symptoms are not severe, saving the more powerful medications for later on.

Anticholinergics include benztropine and trihexyphenidyl. The loss of SN activity means that another brain system that controls movement, the cholinergic system, is relatively overactive. Anticholinergics dampen the activity of this system, restoring some balance to the control of movement. Anticholinergics are usually well tolerated in younger patients, but their side effects can be a significant barrier to their use in the elderly. Side effects include sedation, confusion, hallucinations, delirium, dry mouth, constipation, and urinary retention.

Selegiline inhibits the action of monoamine oxidase B, an enzyme in the brain that breaks down dopamine. Thus, selegiline prolongs the activity of dopamine in the brain. It can cause insomnia and hallucinations, as well as orthostatic hypotension. It may also interact with certain types of antidepressants, and for this reason, selegiline may be discontinued when beginning treatment for depression. In the early 1990s, selegiline was examined for its potential for neuroprotection, or disease slowing. The results of that trial were inconclusive; selegiline had such a significant and long-lasting symptomatic benefit that it was difficult to examine its disease-slowing effects independently.

Amantadine improves PD symptoms through an un-known mechanism. It is beneficial for each of the major movement symptoms of PD, although its effects are not strong. It also can lessen dyskinesias, which are unwanted movements that develop late in PD due to treatment. Amantadine can cause orthostatic hypotension and confusion.

Most drugs have side effects, and drugs for PD are no exception. The most effective drugs for PD, levodopa and the dopamine agonists, cause a set of side effects called "dopaminergic" side effects, indicating they derive from mimicking the action of dopamine. Dopaminergic side effects include nausea and vomiting, orthostatic hypotension, excessive sleepiness, hallucinations, and dyskinesias (in more advanced patients). Nausea, vomiting, and orthostatic hypotension tend to lessen with use, and do not pose long-term problems for most patients. Excessive sleepiness is a problem for many patients. Dyskinesias are an unavoidable effect of dopaminergic treatments, although dopamine agonists tend to cause less of it than levodopa. Dyskinesias tend to appear after three or more years of successful treatment, and become worse over time. Episodes of dyskinesias can be lessened by reducing the dose of the dopaminergic drug, but may lose symptomatic benefit. Adjusting drugs to minimize dyskinesias while maintaining good symptom control is a central challenge of managing PD.

Levodopa is the most effective treatment for PD symptoms, and is the drug used most often at the beginning of disease in elderly patients, because it is less likely to cause hallucinations than dopamine agonists. It is given in a pill that also contains another medication, called carbidopa, which inhibits an enzyme that would act on dopamine in the bloodstream, thus allowing more of it to reach the brain. In order for levodopa to be taken up by the gut and to pass from the bloodstream to the brain, a carrier that also moves amino acids from food must transport the drug. For this reason, doctors typically suggest that patients avoid taking levodopa with or right after a proteinrich meal. Levodopa may also be given with another medication, called a COMT inhibitor, which further prevents its breakdown in the bloodstream. A new pill combines levodopa, carbidopa, and a COMT inhibitor.

Dopamine agonists are almost as effective as levodopa for combating PD symptoms, and have the advantage that their use does not lead to dyskinesias as frequently as levodopa does. For this reason, many movement disorder specialists begin their patients on a dopamine agonist rather than levodopa. This is especially true for younger patients, who can anticipate more years of dopaminergic therapy, and a higher likelihood of developing dyskinesias as a result. There are four major dopamine agonists available in the United States: pergolide, pramipexole, bromocriptine, and ropinirole. Each is taken as a pill, and can be taken alone or in combination with levodopa or other medications. Some patients respond better to one than another, and inadequate relief from one does not mean the same should be expected from another. The U.S. Food and Drug Administration was expected to approve a fifth dopamine agonist, called apo-morphine, by mid-2004. Unlike the others, it is injected, and provides very rapid, short-term symptomatic relief when a dose of levodopa wears off.

Excessive sleepiness is a potentially dangerous side effect for all the dopaminergic drugs (levodopa and the dopamine agonists). This can take the form of predictable, peak-dose sleepiness, or general increase in sleepiness during the day, or a sudden, unpredictable "attack" of sleepiness and falling asleep. The latter can be dangerous if it occurs while driving or performing another activity requiring full awareness. Patients are cautioned to be aware of changes in sleepiness especially after changing a medication, and to avoid driving whenever possible if excessive sleepiness does become a side effect issue.

Complications of advanced disease

After several years of successful treatment, most patients begin to develop one or more motor complications. These often begin with "wearing off," a reduction in the duration of effect of a given dose of levodopa, which initially can be countered by dosing more frequently. Another complication is "on-off," in which the symptomatic benefit of a given dose suddenly switches off and the patient becomes rigid, with tremor and slowed movements emerging. When this occurs at home, the patient will typically just take another dose of medication, and wait for it to begin to work. It is more of a problem when it occurs while the patient is out and about, and frequent on-off episodes may make the patient reluctant to leave the home. Apomorphine injection may be useful in this situation, since it works very rapidly (approximately seven minutes), and can therefore be used as a "rescue" for sudden off periods. Dyskinesias are a third motor complication. Dyskinesias are uncontrolled writhing movements that typically occur at the peak of effect of a levodopa dose. In some cases for some patients, dyskinesias are mild enough that they are not problematic. In other cases, they interfere with function, and attempting to reduce them becomes an important treatment issue. While drug adjustments can have some effect, as the disease progresses it becomes more and more difficult to maintain adequate symptom control while avoiding dyskinesias. At this stage, the patient may consider surgery for treatment of PD symptoms.

Other complications arise in advanced PD, especially in "non-motor" symptoms, those that do not affect movement. Low voice volume may be amenable to speech therapy treatment, with one of the most effective programs being Lee Silverman voice treatment, which focuses on conscious attempts to increase volume. Orthostatic hypotension may be treatable with increased salt intake, compression stockings, and medication. Drooling may become an issue in later-stage disease; there are both drug treatments and non-drug therapies available to reduce this problem. Constipation is a significant problem for many advanced PD patients, and can be treated with standard measures such as increasing the fiber in the diet and bulking laxatives.

Panic attacks and anxiety are common in PD. These can be addressed both through helping the patient understand that this is a feature of the disease, and through antianxiety medication. Depression affects many PD patients, and can worsen other aspects of the disease. It usually responds well to antidepressant medications. Dementia (loss of memory and impairment of other thinking functions) occurs more frequently in PD patients than in the population at large. Treatment is similar to that in non-PD patients, although some medications cannot be used because they have undesirable side effects for PD patients. Psychosis-hallucinations, paranoia, nightmares, and delusions may be a response to dopaminergic medications. If these side effects cannot be controlled through modification of treatments, an antipsychotic drug may be useful.

Surgery

Brain surgery is a treatment option in late-stage PD. The best candidate is the individual who continues to respond to levodopa, but whose treatment is complicated by unacceptable dyskinesias even after medication adjustment. Dementia or other significant health-related conditions may make the patient unsuitable for the rigors of surgery. The patient is usually evaluated by the neurologist, a neuropsychologist, and a neurosurgeon before deciding whether surgery is the right option.

There are two types of surgery for PD. An "ablative" lesion destroys a small portion of the brain, and in so doing, restores the balance of neural activity within the movement control circuits of the brain; ablation means to destroy or remove. The second option is deep brain stimulation (DBS), which accomplishes the same thing by implanting an electrode in the target brain region; electrical pulses shut the region down. Ablative lesions are simpler and less prone to long-term complications, but they are not adjustable after the lesion has been made. DBS is more complex, expensive, and time consuming, and carries a significant risk for infection or equipment malfunction, but it can be adjusted to more precisely target the brain region, thereby enhancing the surgical effect.

Three brain regions are targeted in PD surgery. Ablation of the thalamus (thalamotomy) is primarily effective in controlling tremor, and is not widely performed any-more since other, more effective targets are available. The globus pallidus internus (GPi) can either be ablated (pallidotomy) or stimulated (GPi DBS), which is effective for all the major motor symptoms of PD (tremor, bradykinesia, rigidity), and can improve them by 25–60%. It is also effective for reducing dyskinesias by up to 90%. The subthalamic nucleus can be stimulated in STN DBS, and is highly effective for all the major motor symptoms and dyskinesias, to a somewhat greater extent than GPi DBS. An additional advantage of STN DBS is that it is safer to do on both sides of the brain (left and right, termed bilateral) than GPi DBS. Therefore, if the patient is affected by disabling symptoms on both sides, as is often the case in advanced PD, bilateral STN DBS may be a better choice.

Clinical trials

Parkinson's disease is the subject of intense research, and there are usually several large and important clinical trials going on at any time. Trials may focus on slowing the disease, determining the best drug treatment, or refining surgical methods and targets.

Two experimental forms of surgery have been the subject of recent clinical trials. The first is the implantation of cells into the substantia nigra to replace the lost dopamine-producing cells. The implanted cells come from fetal tissue. Fetal-tissue transplants have led to success, but also to uncontrolled dyskinesias in some patients. For this reason, such trials on are on hold until a better understanding of this problem is discovered and methods are developed to avoid it.

The second form of surgery delivers a growth factor to the substantia nigra via an implanted pump and tube. The growth factor, called GDNF, has been shown to slow cell death in experimental systems. A small group of patients undergoing this surgery has improved, although these results are quite preliminary.

Prognosis

PD is a progressive disease, and the loss of brain tissue in the SN is inevitable. PD patients tend to live almost as long as age-matched individuals without PD, although with an increasing level of disability. Loss of motor control can lead to an increased risk for falls, and swallowing difficulty can cause choking or aspiration (inhaling) of food. Aspiration pneumonia is a common cause of death in late-stage PD patients.

Resources

BOOKS

Cram, David L. Understanding Parkinson's Disease: A Self-Help Guide. Milford, CT: LPC, 1999.

Hauser, Robert, and Theresa Zesiewicz. Parkinson's Disease: Questions and Answers, 2nd edition. Coral Springs, FL: Merit Publishing International, 1997.

Jahanshahi, Marjan, and C. David Marsden. Parkinson's Disease: A Self-Help Guide. San Diego: Demos Medical Publishing, 2000.

WEBSITES

WE MOVE.http://www.wemove.org (April 27, 2004).

Parkinson's Disease Foundation.http://www.pdf.org (April 27, 2004).

Richard Robinson

A progressive disorder of the nervous system that mainly affects elderly people, with peak onset in the 60s and 70s. Males and females are equally affected. The basic mechanism of the disease is not known. The disease usually occurs sporadically. However, 10–15% of the time it runs in families.

Parkinson's disease is characterized by abnormalities of motor function, several of which predominate, but all do not necessarily occur in all individuals. Slowness of movement and an inability to start a movement are hallmarks of the disease. The motor disturbance also results in diminished facial expression and a decreased rate of blinking. The second important manifestation is stiffness and rigidity so that the person encounters increased resistance when attempting to move a limb and a joint. The third manifestation, in some individuals, is a tremor that may be quite asymmetrical, occurring in just one hand, or may involve both hands and the trunk.

As the disease progresses, problems with balance become quite limiting, and falls may occur frequently. Alternatively, with disease progression, episodes of “freezing” may occur, during which voluntary movement becomes impossible. Finally, some individuals have an associated dementia, which appears to be an integral part of the Parkinson's disease process, although in others it may be a manifestation of Alzheimer's disease. See also Alzheimer's disease.

The basic pathologic change is degeneration of a group of nerve cells deep within the center of the brain in an area called the substantia nigra. These cells use dopamine as their neurotransmitter to signal other nerve cells. As these cells degenerate and stop functioning, dopamine fails to reach the areas of the brain that affect motor functions. The possible role of toxins in the disease process has aroused considerable interest. See also Dopamine.

Therapy for Parkinson's disease is aimed at replacing dopamine. Since the blood-brain barrier prevents dopamine from entering the brain from the bloodstream, a precursor of dopamine (L-dopa) that will enter the brain is given. L-Dopa is usually administered as part of a compound that inhibits the enzymes that break down L-dopa in the liver, thus making a greater part of it available to the brain. See also Motor systems; Nervous system (vertebrate); Sensation.

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n.pr

A progressive neurologic disorder for which there is no known cure that is thought to be the result of neuron degeneration in the section of the brain controlling spontaneous movement and balance. The disease causes postural changes, tremors, muscle rigidity, and weakness. Oral manifestations include difficulty in swallowing and excess salivation.

Definition

Parkinson's disease (PD) is a motor system disorder caused by the chronic, progressive degeneration of neurons (nerve cells) in regions of the brain that control movement. PD causes a decline in the initiation, speed, and smoothness of movement. Over time it may come to affect many bodily functions.

Description

Parkinson's Disease (PD) was first described in 1817 by James Parkinson. It affects more than one million people in the United States, including some 500,000 people who have yet to be diagnosed. About 50,000 new cases are diagnosed each year. The average age of PD onset is 60. Symptoms of PD are seen in as many as 15% of those between the ages 65 and 74 and almost 30% of those between the ages of 75 and 84. Only 5 to 10% of PD cases occur before the age of 50. Young-onset PD occurs in those under age 40. A parent or sibling with PD increases one's risk of developing the disease.

PD results from the degeneration and death of neurons in the substantia nigra, movement control centers on each side of the brain. These cells secrete dopamine, a neurotransmitter that attaches to receptors on cell surfaces in another part of the brain—the corpus striatum—that controls muscle action. When dopamine levels fall, the neurons of the corpus striatum begin to misfire. It is estimated that dopamine-producing cells begin dying about 13 years before PD symptoms become evident. The symptoms of PD begin when about 60% of the dopamine-producing cells have died.

Causes & Symptoms

Causes

Although the cause of Parkinson's Disease (PD) is unknown, it appears to result from a combination of environmental and hereditary factors as well as oxidative damage and aging. Factors for PD may include:

• herbicide and pesticide exposure
• an as-yet-unidentified toxin or virus
• cellular damage from oxidation by free-radicals (atoms or molecules with an unpaired electron)
• loss of dopamine-secreting cells with age, particularly with accelerated aging
• fewer dopamine-secreting cells at birth

Symptoms

Early symptoms of PD often are quite subtle, developing on one or both sides of the body. The primary symptoms of PD are:

• tremors (shaking) while at rest. (The classic PD tremor is the rubbing of the thumb and forefinger at a frequency of about three rubs per second. Tremors may spread to the hands, arms, legs, feet, jaw, and face. The tremors increase with stress. However, many people with PD do not experience tremors)

• slow movement (bradykinesia) or freezing during movement (akinesia)
• stiffness or rigidity of the limbs and trunk
• poor balance leading to frequent falls

Other early symptoms of PD:

• short, shuffling steps
• stooped posture
• masking (reduction) of facial expression and infrequent blinking
• slow or rapid, soft, monotonic (without inflection) speech
• other speech changes
• insomnia, restlessness, and nightmares
• depression
• emotional changes, including fear, irritability, and insecurity
• incontinence
• constipation
• small, illegible handwriting
• frequent, dramatic swings in mobility and moods

Later-stage PD symptoms may include:

• frozen muscles that prevent the initiation of movement
• oily or very dry skin
• sweating
• digestive tract shutdown causing difficulties in swallowing, digesting, and elimination
• auditory and/or visual hallucinations
• progressive deterioration of intellectual function
• (dementia), affecting 30 to 40% of those with late-stage PD
• loss of contact with reality (psychosis)

Medications for PD can also cause some of these symptoms.

Diagnosis

There is no definitive test for PD. Diagnosis is based on a careful medical history and complete neurological examination.

In addition to PD, anything that damages the substantia nigra can cause Parkinson's-like symptoms, called parkinsonism. Possible causes of parkinsonism:

• infection
• nausea
• trauma
• stroke
• exposure to manganese or other toxins
• medications for psychiatric disorders, such as haloperidol (Haldol) or chlorpromazine (thorazine)
• a chemical called MPTP, found as an impurity in some illegal drugs
• epilepsy
• alzheimer's disease
• other neurodegenerative diseases that sometimes are referred to as Parkinson's plus or parkinsonism plus syndromes

Brain scans, blood tests, lumbar puncture, or x rays may be used to rule out causes of parkinsonism other than PD.

Treatment

There is no cure for Parkinson's disease, nor is there a treatment that slows its progression.

Many factors can help relieve PD symptoms, at least temporarily:

• maintaining general health
• regular, moderate, muscle-building exercise
• erequent rest
• smaller, more frequent, meals to accomodate gastrointestinal slowdowns
• physical, occupational, and/or speech therapies
• encouragement and emotional support

Fatigue, anxiety, and depression can aggravate PD symptoms significantly.

Therapies that may relieve muscle tightness in PD:

• acupuncture
• massage
• yoga
• feldenkrais
• t'ai chi
• qigong
• meditation.

A physical therapist can design an appropriate exercise program and suggest strategies and techniques for improving balance and stimulating movement during slowdowns or freezing.

Supplementation therapies for PD:

• amino acids
• essential fatty acids including omega-3 and omega-6 fatty acids, fish oil, and flax oil
• antioxidants including carotenoids (dark green and orange fruits and vegetables) and other bioflavenoids (antioxidants derived from foods)
• vitamins A, B, C, and E
• selenium and zinc
• calcium and magnesium
• coenzyme Q10 (CoQ₁₀)

For more than 4,000 years, practitioners of Ayurveda—traditional Indian medicine—have prescribed mucuna seeds (Mucuna pruriens) to treat Parkinson's disease. Mucuna contains a natural form of levodopa.

Allopathic Treatment

Drugs

The pharmacological treatment of Parkinson's disease is very complex. Although many drugs may relieve at least some symptoms of PD, their effectiveness varies with the patient and the progression of the disease. Side effects may preclude the use of the most effective dose or require another drug to counteract them.

LEVODOPA. Levodopa (L-dopa, L-3,4-dihydroxyphenylalanine) has been the standard treatment for PD since the 1960s and remains one of the best drugs for treating symptoms, particularly tremors and movement problems. Levodopa (Laradopa) is a naturally occurring derivative of dopamine that is converted into dopamine in the brain. However, unlike dopamine, levodopa can reach the brain from the bloodstream. Levodopa treatment may begin at the onset of PD symptoms or when the symptoms begin to interfere with daily life. At least 75% of patients are helped to some degree by levodopa and the drug enables many people with PD to live relatively normal lives for a number of years. Levodopa normally is prescribed only in combination with other drugs.

Side effects of levodopa:

• nausea and vomiting
• low blood pressure, particularly when standing up, resulting in dizziness and fainting
• dyskinesias (abnormal movements including twisting and tics) in at least 50% of patients
• agitation
• hallucinations

These effects usually lessen after several weeks on levodopa.

After five or more years on levodopa, many patients develop:

• motor fluctuations, including "peak-dose" dyskinesias when the drug is at its highest level in the brain
• on-off phenomena—significant changes in response as the drug levels fluctuate
• unpredictable responses to the drug

The levodopa dosage is usually increased when these changes occur. However, dyskinesias may increase with increasing dosages.

Levodopa is an amino acid that is absorbed from the digestive system by the same transporters that carry amino acids from dietary proteins. Therefore some healthcare practitioners may limit or redistribute protein intake to improve levodopa adsorption into the bloodstream.

ENZYME INHIBITORS. Since levodopa and dopamine are amino acids, they can be broken down by the same enzyme systems that break down other amino acids. Therefore the two most-commonly prescribed forms of levodopa include an amino-acid-decarboxylase (AADC) inhibitor: carbidopa (in Sinemet) or benzaseride (in Madopar). These drugs enable more levodopa to enter the brain and may reduce some side effects. Controlled-release formulations (Sinemet CR) can prolong the interval between doses. Carbidopa also prevents vitamin B₆ (pyridoxin) from interfering with levodopa.

Catechol-O-methyltransferase (COMT) also breaks down levodopa. The COMT inhibitor entacapone (Comtan) prolongs the effects of levodopa and may moderate its fluctuations. Stalevo contains levodopa, carbidopa, and entacapone. Although the COMT inhibitor tolcapone (Tasmar) reduces the average required dosage of levodopa by 25%, it is no longer commonly used because of severe side effects and possible liver damage and failure.

Selegiline (deprenyl) inhibits monoamine oxidase B (MAO-B), which metabolizes dopamine in the brain. Selegiline can delay levodopa treatment for an average of nine months and also is used in combination with levodopa (Eldepryl) in early-stage PD. Common side effects include dyskinesias, dry mouth, and mood swings.

DOPAMINE AGONISTS. Dopamine agonists (DAs) are drugs that activate dopamine receptors, mimicking the effects of dopamine. In younger adults with early-stage PD, DAs appear to be more effective than levodopa. More often, DAs are used in conjunction with Sinemet to prolong the action of levodopa and reduce levodopa-induced dyskinesias. Although they are expensive, DAs may postpone or prevent the need for expensive neurosurgery at later stages of PD.

DAs include:

• Bromocriptine (Parlodel
• Pergolide (Permax)
• Pramipexole (Mirapex)
• Ropinirole (Requip)

Side effects of DAs are similar to those of levodopa, including drowsiness and confusion. DAs may cause dyskinesias in at least 50% of patients. Pergolide has been associated with a type of heart disease.

ANTICHOLINERGIC DRUGS. The neurotransmitters dopamine and acetylcholine balance each other's effects in the brain. Anticholinergics help maintain this balance when dopamine levels fall. Although they may control tremors in early-stage PD, their side effects—including dry mouth, urine retention, severe constipation, blurred vision, confusion, memory loss, and hallucinations—are usually too severe for older patients or those with dementia. Anticholinergics rarely work for very long. Trihexyphenidyl (Artane) and benztropine (Cogentin) are the most common anticholinergics for PD.

OTHER DRUGS. Other common PD medications:

• Diphenhydramine (Benadryl), an antihistamine, and antidepressants such as amitryptiline (Elavil), have similar effects as anticholinergics and may be appropriate for older patients.
• Amantadine (Symmetrel) is an antiviral drug used in later-stage PD, particularly to treat tremors and levodopa-induced dyskinesias. Its effects include increased dopamine release and blocking of glutamate, an amino acid that destroys neurons. Side effects include swollen ankles and purple mottling of the skin.
• Clozapine (Clozaril) is particularly effective for psychiatric symptoms of late-stage PD, including psychosis and hallucinations.

Although drug therapies can relieve most symptoms of early-stage PD, as the disease advances, drug responses begin to fluctuate and their overall effectiveness decreases.

Surgery

Surgery may be used to help manage severe or debilitating PD symptoms when drug treatments fail.

Pallidotomy uses an electrical current to destroy a small amount of brain tissue in the globus pallidus, which is over-stimulated by the corpus striatum in PD. Pallidotomy may relieve tremors and slow, rigid movements, and decrease dyskenisias caused by drug therapy, by interfering with the neural pathway between the globus pallidus and the thalamus (a major transmission center in the brain). The benefits often do not last and the surgery may cause slurred speech, disabling weakness, and vision problems, particularly with a double pallidotomy (surgery on both sides of the brain).

Thalamotomy reduces hand and arm tremors by destroying small amounts of tissue in the thalamus. Because a double thalamotomy leaves patients extremely weak and with slurred speech, it usually is performed on only one side of the brain, relieving tremors on the opposite side of the body.

With deep brain stimulation (DBS), a device similar to a heart pacemaker sends signals to fine electrodes implanted in the subthalamic nuclei or the globus pallidus (Activa Therapy). The electrical pulses appear to interrupt signals from the thalamus that are involved in tremors. DBS restores a balance between excitatory (tending to excite) and inhibitory (interfering or retarding) signals in brain signal transmission centers, thereby decreasing or abolishing dyskinesias without slowing normal movement. Patients use a magnetic device to adjust stimulation in one or both halves of the brain, as the response dictates. DBS usually results in a significant improvement in some motor symptoms, including tremors and peak-dose dyskinesias, and improves motor function and mobility. It also enables patients to take higher doses of levodopa.

The implantation of fetal cells to replace the dopamine-producing cells of the substantia nigra appears to benefit only patients under age 60. It can have serious side effects and about 15% of patients later develop severe dykinesia due to dopamine-overproduction.

The use of stem cells derived from embryos discarded by infertility clinics is a potentially useful treatment for PD. However, it remains morally and ethically controversial.

Prognosis

There is no way to predict the course of PD. Many people live active, productive lives for 12 to 15 years. However, in others the disease progresses rapidly. Regardless of treatment, PD symptoms worsen with time and become less responsive to drug therapy. Most people with PD experience some additional problem every year. A small number of patients eventually become completely incapacitated. Although PD is not fatal, its effects can lead to fatal accidents or illnesses.

Prevention

There are no clear risk factors or preventions for PD. Central body obesity may increase the risk. Some studies have found that coffee drinking or hormone replacement therapy (HRT) in postmenopausal women may decrease the risk of PD. However, heavy coffee drinking in combination with HRT appears to increase the risk of Parkinson's disease.

Resources

Books

Federoff, Howard J., et al., editors. Parkinson's Disease: The Life Cycle of the Dopamine Neuron. New York: New York Academy of Sciences, 2003.

Foltynie Thomas, et al. Parkinson's Disease: Your Questions Answered. New York: Churchill Livingstone, 2003.

Kondracke, Morton. Saving Milly: Love, Politics, and Parkinson's Disease. New York: Public Affairs, 2001.

Mittel, Charles S., editor. Parkinson's Disease: Overview and Current Abstracts. New York: Nova Science, 2003.

Mosley, Anthony D., and Deborah S. Romaine. The Encyclopedia of Parkinson's Disease. New York: Facts on File, 2004.

Pahwa, Rajesh, et al., editors. Handbook of Parkinson's Disease. 3rd ed. New York: Marcel Dekker, 2004.

Weiner, William J., et al. Parkinson's Disease: A Complete Guide for Patients and Families. Baltimore: Johns Hopkins University Press, 2001.

Periodicals

Ascherio, A., et al. "Caffeine, Postmenopausal Estrogen, and Risk of Parkinson's Disease." Neurology 60, no. 5 (March 11, 2003): 790–95.

Powers, K. M., et al. "Parkinson's Disease Risks Associated with Dietary Iron, Manganese, and Other Nutrient Intakes." Neurology 60 (June 2003): 1761–66.

Van Camp, Guy, et al. "Treatment of Parkinson's Disease with Pergolide and Relation to Restrictive Valvular Heart Disease." Lancet 363, no. 9416 (April 10, 2004): 1179–83.

Organizations

American Parkinson Disease Association, Inc. 1250 Hylan Blvd., Suite 4B, Staten Island, NY 10305. 800-223-2732. apda@apdaparkinson.org. .

Michael J. Fox Foundation for Parkinson's Research. Grand Central Station, P. O. Box 4777, New York, NY 10163. 800–708–7644. .

National Parkinson Foundation, Inc. 1501 NW Ninth Ave./Bob Hope Road, Miami, FL 33136–1494. 800–327–4545. .

Parkinson Alliance. P.O. Box 308, Kingston, NJ 08528-0308. 800–579–8440. admin@parkinsonalliance.org. .

Parkinson's Action Network. 1000 Vermont Ave. NW, Washington, DC 20005. 800–850–4725. 202–842–4101. info@ parkinsonsaction.org. .

Parkinson's Disease Foundation. 710 West 168th Street, New York, NY 10032-9982. 800–457–6676. 212–923–4778. info@pdf.org. .

Other

NINDS Parkinson's Disease Information Page. National Institute of Neurological Disorders and Stroke. August 17, 2001 [cited May 12, 2004]. .

Talampanel in Parkinson Disease: Why the Excitement? National Parkinson Foundation, Inc. [Cited May 12, 2004]. .

[Article by: Paula Ford-Martin; Margaret Alic, PhD]

A chronic disease of the nervous system that usually strikes in late adult life, resulting in a gradual decrease in muscle control. Symptoms of the disease include shaking, weakness, and partial paralysis of the face. Certain drugs can help alleviate some of its symptoms.

The name given to a syndrome, or characteristic set of symptoms, shown by patients with lesions to certain subcortical areas of the brain. From the patient's point of view the main complaints are of involuntary tremor in the limbs together with a difficulty in initiating and controlling voluntary movements, and some general changes in posture, mood, and level of activity. There is no pain, little loss of sensation or awareness, and the mental state often remains well preserved. From the scientific point of view Parkinsonism is of interest because of the insight it gives into the processes involved in translating thoughts and intentions into the appropriate actions for their overt expression. It produces a number of behavioural changes stemming from a disruption of the brain mechanisms that mediate these processes.

Originally called the 'shaking palsy', the syndrome was first described by the surgeon James Parkinson in 1817. Nowadays it is termed 'idiopathic paralysis agitans' in recognition of its status as a naturally occurring degenerative disease of the nervous system of late middle or old age, and of its main features of impaired voluntary movement and a noticeable, continuous, induced shaking of the limbs at rest. The disease has an insidious onset, and there is a tendency for the patient's condition to deteriorate slowly, but it may remain stable for long periods. This is Parkinson's disease proper, for which no cause is yet definitely known — it is almost certainly not hereditary, but no definite link has been established with any slow virus, dietary deficiency, chemical toxin, or other suggested environmental cause.

The characteristic features, however, may occur as 'symptomatic Parkinsonism' in adults of any age as a result of a wide range of damage to the brain, including metal poisoning, anoxia (oxygen deficiency), strokes, certain drug overdoses, and infections. One special instance of the last category was the epidemic viral disease of the 1920s called 'encephalitis lethargica', which is often held to be the cause of a certain kind of Parkinsonism in that generation. In the 1980s a dramatic series of cases occurred in California in young heroin addicts who injected themselves with a designer drug containing the toxic side product MPTP, which destroys the same cells in the brain as are affected in idiopathic Parkinsonism.

The main defining features of Parkinsonism involve the motor system, and comprise tremor of the limbs at rest, a relatively slow repetitive oscillation which disappears during sleep or deliberate movement; increased rigidity of the limbs to passive movement; and akinesia, an impairment of the voluntary control of movement. Other symptoms which may be associated with these include difficulties in maintaining or adjusting posture; difficulties in walking steadily or with normal-size steps; an immobile facial expression; loss of strength in and modulation of the voice; eye movement abnormalities; and an inability to get up out of a bed or low chair without help. The disease in fact affects all the forms of action, communication, and expression by which we interact with the environment and with each other.

In all Parkinsonian disorders the parts of the brain affected are groups of cells lying in the centre and at the base of the forebrain — the basal ganglia. These nuclei have extensive and complex connections, and form part of several circuits through different levels of the brain. Neural activity in these circuits involves the neurotransmitter dopamine, whose progressive depletion underlies the disease, at first disrupting, and ultimately blocking, transmission through the pathways. A number of drug therapies are now available to patients to help them regain biochemical balance in the system and restore normal movement.

Pathways through the basal ganglia include some to and from the autonomic nervous system (which controls bodily functions), the cortex, and the limbic system. So it is not surprising that other symptoms often associated with the disease include: autonomic changes such as excessive sweating or trouble with digestion; cognitive changes, with impaired memory and thinking ability; and personality changes, most notably depression and lethargy or increased irritability. Although the last may be a reflection of the patients' reaction to their impaired movement or embarrassing tremor, some observers think that they stem directly from the effects of the disease on the working of those circuits in the brain concerned with an individual's cognitive and emotional state. On this view Parkinsonism has a widespread effect on behaviour, and may be seen as a neuropsychological and neuropsychiatric disease.

1. Motor symptoms: the role of the basal ganglia in movement
2. Cognitive and personality changes: the role of the basal ganglia in general behaviour

1. Motor symptoms: the role of the basal ganglia in movement

While tremor is obvious and embarrassing, the impairment of voluntary movement is the disabling symptom of Parkinsonism. In its extreme form, untreated, it results in an immobile 'frozen' state where the patient remains fixed in a catatonic, typically crouching, posture. Even mild cases sometimes experience 'freezing' when walking or shifting posture.

More often, however, the mild form results in a subtle disturbance of movement, involving both a retardation in initiating movements (akinesia) and slowness and clumsiness in carrying them out (bradykinesia). There is an obvious lack of control, with patients complaining that their hands and fingers 'won't do what I tell them to'. Movements are slow and appear uncoordinated, as if the patient has lost the art of automatically performing familiar skills and has to think about and monitor his actions all the time as he carries them out. But the limbs are not numb, nor paralysed, although the grip may be weak and writing become small and spidery. When doing things slowly movements may be reasonably accurate, and visual control is still precise enough to allow fine adjustments of the fingers — patients who continue (on a good day) to mend watches or carve wood have been known. Moreover the muscles themselves and their immediate control from the motor cortex (see Fig. 1) are still intact, because they respond normally to direct stimulation.

Thus the components of movement appear to be intact in Parkinsonism, but patients have difficulty in coordinating them so as to produce effective actions. There is a dissociation of some kind between thought and action, suggesting that the basal ganglia play a crucial role in the neurological systems that underlie perceptual motor coordination. Parkinsonism disrupts the process at the very centre where the orders for movement are formulated; the patient's difficulty stems from faulty instructions being sent to the motor system, rather than from the motor system responding inaccurately.

Recently, anatomical studies have shown that the basal ganglia provide a connecting link between those areas of the brain mediating thought and those directly initiating movement. They receive inputs from the association cortex of the forebrain (frontal and parietal areas especially) and send their main outputs to the motor cortex and the red nucleus which innervate spinal motor neurons. In this respect they are similar to the cerebellum, another structure known to be concerned with the control of movement. The two subcortical areas are in fact connected in parallel between association and motor cortex (see Fig. 1).


Fig. 1. The pathways concerned in the planning, execution, and control of voluntary movement.
On this model it may be postulated that the idea or initial plan for a movement takes place in the cortex, that this is passed on to the basal ganglia and cerebellum where some kind of 'programming' of orders for the contraction of muscles takes place, and that these are then passed on to the motor cortex for transmission to the muscles. The subcortical structures may thus be a kind of 'general staff' of the motor system, organizing the force, duration, timing, and coordination of various kinds of movement.

This physiological model reinforces the notion of the basal ganglia and cerebellum as interface mechanisms between cognitive and motor systems of the brain, providing the means by which general intentions and ideas for action are translated into specific programmes of movement for their fulfilment. If either is damaged, therefore, connections through one pathway will be impaired, but those through the other will still be intact. So patients will not be paralysed, but will lose some aspect of control according to the function disrupted by the lesion. Exactly how the two structures divide control is not known, but there are several possibilities. Some workers have suggested that each is concerned with a different kind of movement (the cerebellum generating visually controlled and the basal ganglia proprioceptively controlled movements), others that each controls a different parameter of movement (for example, the basal ganglia determining the strength to be put into a muscle contraction while the cerebellum regulates its spatial position or timing). These, and other, possibilities are open to experimental test — showing that the disturbed nervous system may be a good proving ground for theories of how the normal system works.

Experimental investigations of Parkinsonian movement, by the author and others, have found that Parkinsonian patients asked to hit a visual target with hand or arm movements from a stationary starting point have difficulty executing quick, large-amplitude aiming movements which are pre-programmed and executed as discrete units (ballistic movements). They can, however, perform small or slow movements under continuous visual correction reasonably well. Patients with cerebellar action tremor show just the reverse. Parkinsonian subjects tend not to increase the amount of force they put into large-amplitude ballistic movements appropriately, so that their movements undershoot the target point (hypokinesia) and are more erratic. Similar dissociable effects between 'ballistic' and visually guided movements have been found in monkeys who, in an experiment, track a target while output from either the basal ganglia or cerebellum is temporarily experimentally inactivated by cooling. These features may underlie the slowness and clumsiness in executing movements which characterize bradykinesia in Parkinson's disease.

If bradykinesia reflects a difficulty in programming individual muscle actions appropriately to achieve an intended movement, akinesia reflects a difficulty in the accurate selection and initiation of responses, that is, in the formation and implementation of 'motor plans'. This is the point at which a general decision or intention is specified as a particular set of actions to achieve it — in computer terms an 'algorithm' for movement. Often it involves switching in a repertoire of well-learnt sequences of movement (as in playing scales or chords on a piano) but it may involve assembling new patterns and sequences for the immediate task in hand. It also involves timing (when to start and stop movements) and whether to control movements through vision, touch, or proprioception — or without feedback — in short, what strategy to adopt to achieve the goal originally set.

There is some evidence that Parkinsonian patients lose their facility in such higher-level aspects of a motor plan. They are slow in initiating movements of any kind, even when not aiming at a target but just responding to a signal as quickly as possible. They take longer to switch from one movement or movement sequence to another, even when using different limbs where there is no overlap of musculature involved. They have difficulty doing two things at once, and in running off rapid sequences where they cannot monitor each movement separately. They sometimes 'freeze' while walking or getting up out of a chair, as if unable to coordinate and synchronize an action involving several groups of muscles. They have difficulty tracking a continuously moving target on a screen if the target disappears for even short periods, as if they need continual visual information to initiate successive actions. (Tremor patients carry on through such gaps in visual data quite well.) And they tend not to make use of any available advance information about impending movements to reduce their reaction time or events, as normals do, as if the initiation of movements has to be done from an external trigger signal, Parkinsonian subjects being unable to begin them spontaneously.

Such rather curious Parkinsonian characteristics suggest that the basal ganglia are especially involved in assembly, selection, and triggering sequences of action, which explains why Parkinsonian subjects may tire quickly with repeated movement, be unable to do two things at once, or find difficulty in switching from one action to another. The functions disrupted are at the transition point between cognition and action, and are central to the control of behaviour. It is not surprising, therefore, that Parkinson's disease affects other aspects of behaviour as well, both mental and social.

2. Cognitive and personality changes: the role of the basal ganglia in general behaviour

In his original definition of the disease, Parkinson specifically excluded mental changes, declaring 'the senses and intellect being uninjured'. Since then, many observers have disagreed with him, and associated Parkinsonism with dementia or other psychological disturbances. In this they possibly mistake the outward appearance of the untreated advanced stage, with its profound motor immobility and unresponsiveness, for an inner mental deterioration. Nowadays it is generally agreed that Parkinsonian patients may show impairments on a range of cognitive activities, and personality changes too. But their nature is not certain, nor what are the crucial underlying changes in the brain.

Some studies emphasize certain subtle perceptual–motor difficulties in Parkinsonism. The only sensory deficit reported is a slight blurring of vision, possibly due to a retinal dopamine deficiency; otherwise there seems to be little disturbance of the ability to register and identify sensory information. But patients are reported as showing perceptual difficulties in the ability to use sensory information to guide their actions, especially where this involves orientation in space. Thus they have been reported as showing deficits in locating parts of the body correctly from diagrams; in following a given route round a room from a map; in setting a tilted rod to the vertical with the body itself tilted; and in correctly copying or making up gestures with the arms. In all these cases, the difficulty appears to lie in keeping track of one's own movements so as to maintain one's orientation in space, and results from a loss of the reafferent information that one gets from one's own movements. But perceptual judgements of external objects and space are still intact.

Thus the Parkinsonian difficulty is not a cognitive deficit per se, but rather a deficit in the use of knowledge for action. It raises the intriguing possibility that motor and behavioural systems use a different sensory input from that, through the cortex, which underlies our conscious perception, so that one's actions may be initiated by signals and controlled by systems not directly amenable to awareness, which is a dissociation commonly found in motor-skills learning and performance.

On standardized tests of intellectual function, Parkinsonian patients often do badly, but this is probably at least partly due to motor difficulties on timed tasks which require manipulation of materials. On many tasks of perception, memory, and reasoning, Parkinsonian patients show little deficit. Or they may have lower scores than normal without showing any qualitative differences typical of dementia, indicating rather a slowness in thinking (bradyphrenia). Where there is often a specific impairment is in what is termed mental 'set' (that is, the ability to choose one behavioural or mental strategy when several alternatives are available, and then either to maintain it or to switch to another strategy, as appropriate). This deficit in mental control parallels some of the motor difficulties described above, implying that the mental and motor effects of Parkinsonism are similar.

Some years ago, attention was drawn to the existence of ascending dopamine pathways through the basal ganglia from cell bodies in the reticular core of the brain to forebrain areas, especially the prefrontal cortex and the limbic system of the temporal lobes (Fig. 2). Disturbance of these diffuse projections might well interfere with the activity of the innervated structures, producing cognitive impairments or emotional changes respectively. There are several theories of this kind.

Parkinsonism and dementia as diseases of a common core. According to this theory, a loss of neurons in the reticular core of the brain will at first produce symptoms appropriate to whichever structure first loses its input. As neuronal losses increase, symptoms typical of other diseases of old age (dementia, depression, and Parkinsonism) will appear as all three systems are affected. This theory is supported by a number of anatomical and biochemical studies showing similar neuronal changes in Parkinsonism and dementia, and clinically there is often overlap of symptoms too. But not all advanced Parkinsonian patients show signs of dementia, so the overlap may be coincidental.Loss of arousal. On this theory, ascending projections through the basal ganglia are necessary to activate or initiate cortical activity. Loss of this facility means that patients show lethargic thinking and behaviour because they lack arousal, resulting in inefficient mental activity, although the mechanisms of thought, memory, and thinking are themselves still intact. Undoubtedly lethargy and a lack of spontaneous activity are often observed in Parkinsonism, particularly in the advanced stages, and increasing motivation can improve performance (although it does not always do so).

In the past, advanced cases deteriorated into a 'frozen' state of rigid immobility and unresponsiveness to external stimuli. The discovery in the 1960s of drugs which rectified the biochemical deficiency of Parkinsonism led to dramatic increases in the level of spontaneous activity, even in long-standing catatonic cases. The effect has been appropriately described as 'awakening' by Oliver Sacks (1973) in a vivid and moving account.

Frontal syndrome. This theory proposes that Parkinsonian patients show behavioural effects similar to those of frontal cortical damage, that is, personality and behavioural symptoms rather than loss of intellectual capacity and awareness. The mental set effects described above would fit this description, as would other observations of such frontal signs as perseveration — being unable to change an adopted strategy or sequence of behaviour if conditions change during a task, as, for example, in perceptual adaptation or on tasks where the requirements or rules change on different trials. The theory emphasizes the close mutual interconnections of parts of the basal ganglia with prefrontal cortical areas, and it is likely that cortical and subcortical areas of the brain work together as an integrated unit, such that disruption at any point in the circuit impairs the function of the whole.

An extension of this theory attributes the personality changes often found in the disease (notably depression and irritability), as well as the autonomic changes, to basal ganglia connections with the limbic system. The limbic system is a complex circuit of pathways connecting structures on the inside borders of the cortex with central structures in the brain stem and cerebrum, and is often described as the cerebral mechanism of emotional behaviour. Parts of the frontal lobes form an important link in this circuit, so frontal symptoms might well be accompanied by disturbances of mood and personality. Some authorities, therefore, describe Parkinsonian behavioural changes as frontal–limbic dementia, or subcortical dementia, to distinguish them from senile dementia (Alzheimer's disease) with its global deterioration in memory, thought, and language.

Of particular interest is the finding that while a deficiency of dopamine is associated with Parkinsonism, overactivity in the dopamine system produces schizophrenia-like behavioural effects (see dopamine neurons in the brain). This opens up the possibility that it is the biochemical status of the nervous system that underlies psychological and psychiatric changes in Parkinsonian patients and schizophrenics. It also holds out hope for the continued development of effective treatment, but, as with studies of the biochemical basis of schizophrenia, the exact relation of the mechanisms of the nervous system to the characteristics of the mind remains elusive. Progress in this problem may well depend as much on advances in our understanding of the latter as of the former.


Fig. 2. Dopamine pathways through the limbic system.


(Published 1987)

— K. A. Flowers

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