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Parkinson's disease
Specialty	Neurology
Frequency	0.2% (Canada)

Parkinson's disease (also known as PD or Parkinson disease) is a degenerative disorder of the central nervous system, that affects the control of muscles, and so may affect movement, speech and posture. Parkinson's disease belongs to a group of conditions called movement disorders. It is often characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are due to excessive muscle contraction, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. PD is both chronic, meaning it persists over a long period of time, and progressive.

PD is the most common cause of parkinsonism, a group of similar symptoms. PD is also called "primary parkinsonism" or "idiopathic PD" ("idiopathic" meaning of no known cause). While most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders.

History

The symptoms of Parkinson's Disease have been known and treated throughout history. An ancient civilization in India practiced their medical doctrine Ayurveda. They described the symptoms and proposed methods of treatment as far back as 5000 B.C.. The Huang di nei jing su wen (known as the Su wen), is the oldest existing Chinese medical text written around 500 B.C.. It also describes the symptoms of Parkinson's Disease . The Ancient Greeks as well as physicians of the 18th century have also noted other references to the disease. However, it was not formally recognised and its symptoms documented until 1817 in An Essay on the Shaking Palsy by the British physician Dr. James Parkinson. Parkinson's disease was then known as paralysis agitans. The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Swedish scientist Arvid Carlsson who later went on to win a Nobel prize. L-dopa entered clinical practice in 1967, and the first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.

Symptoms

The primary symptoms of Parkinson's Disease are due to excessive muscle contraction. This starts as muscle rigidity, which as it worsens can cause a slowing of physical movement (bradykinesia), and in severe cases can cause a loss of physical movement (akinesia). Tremor occursin about 70% of patients.Typical other symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Individual patients' symptoms may be quite dissimilar; progression is also distinctly individual. Main article : Symptoms of Parkinson's Disease

Diagnosis

There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal.

Descriptive epidemiology

The worldwide prevalence of Parkinson's disease is 4 to 6 million people. There are over 1.5 million in China alone. The disease usually has a long, subtle onset, so diagnosis occurs most often after many years of subclinical disease . Prevalence estimates range from a low of 7 per 100,000 in Ethiopia to a high of 329.3 per 100,000 in Nebraska, U.S.A. (although that figure was arrived at using capture-recapture estimates), and 328.3 cases per 100,000 in the Parsi community in Bombay, India. The greatest prevalence of any country is the U.S.A., with between 100 and 250 cases per 100,000.

The average age at which symptoms begin is 55-60, and although cases at ages as low as 11 have been reported it is highly unusual for people under 30 to develop Parkinson's. It occurs in all parts of the world, but appears to be more common in people of European ancestry than in those of African ancestry. Those of East Asian ancestry have an intermediate risk. It is more common in rural than urban areas in developed countries, but the converse is true in poorer countries, leading Tanner to speculate about environmental causes . There is a suggestion of increased prevalence in the California Hispanic population. About 2% of the population develops the disease some time during life .

Related diseases

There are other disorders that are called Parkinson-plus diseases. These include:

• Multiple System Atrophy (MSA)
  • Shy-Drager syndrome (SDS)
  • Striatonigral degeneration (SND)
  • Olivopontocerebellar atrophy (OPCA)
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)

Patients often begin with typical Parkinson's disease symptoms which persist for some years; these Parkinson-plus diseases can only be diagnosed when other symptoms become apparent with the passage of time. These Parkinson-plus diseases usually progress more quickly than typical ideopathic Parkinson disease. The usual anti-Parkinson's medications are typically either less effective or not effective at all in controlling symptoms; patients may be exquisitely sensitive to neuroleptic medications like haloperidol. Additionally, the cholinesterase inhibiting medications have shown preliminary efficacy in treating the cognitive, psychiatric, and behavioral aspects of the disease, so correct differential diagnosis is important.

There are other medical disorders, some of whose symptoms can coincide with those of Parkinson's disease : * Wilson's disease,* Essential tremor,* Cerebellar thoracic outlet syndrome,* Antiphospholipid syndrome,* Vascular parkinsonism,* Encephalitis lethargica, * Hydrocephalus.

Pathology

Main article: Pathology of Parkinson's Disease

The primary symptoms of Parkinson's disease are due to excessive muscle contraction. Acetylcholine stimulates muscle contraction via the cholinergic receptors. Dopamine reduces muscle contraction via the dopamine receptors. Dopamine deficiency rather than acetylcholine excess is normally responsible for excessive muscle contraction. Dopamine is formed in the dopaminergic neurons by the following pathway: L-tyrosine → L-dopa → dopamine. This requires a number of coenzymes and cofactors in order to function properly. Once dopamine is produced it stimulates the dopamine receptors, which lower muscle contraction via the G proteins. As a result of faulty dopamine formation widespread cell damage can occur.

Pathophysiology

Most people with Parkinson's disease are described as having idiopathic Parkinson's disease (having no specific cause). There are far less common causes of Parkinson's disease including genetic, toxins, head trauma, and drug induced Parkinson's disease.

Genetic

In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations (Contursi). These account for a small minority of cases of Parkinson's disease. Somebody who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.

Genetic forms that have been identified include:

external links in this section are to OMIM

• PARK1 (OMIM #168601), caused by mutations in the SNCA gene, which codes for the protein alpha-synuclein. PARK1 causes autosomal dominant Parkinson disease. So-called PARK4 is probably caused by triplication of SNCA.
• PARK2 (OMIM *602544), caused by mutations in protein parkin. Parkin mutations may be one of the most common known genetic causes of early-onset Parkinson disease. In one study, of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% homozygous mutations. Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.

• PARK3 (OMIM %602404), mapped to 2p, autosomal dominant, only described in a few kindreds.
• PARK5, caused by mutations in the UCHL1 gene (OMIM +191342) which codes for the protein ubiquitin carboxy-terminal hydrolase L1
• PARK6 (OMIM #605909), caused by mutations in PINK1 (OMIM *608309) which codes for the protein PTEN-induced putative kinase 1.
• PARK7 (OMIM #606324), caused by mutations in DJ-1 (OMIM 602533)
• PARK8 (OMIM #607060), caused by mutations in LRRK2 which codes for the protein dardarin. In vitro, mutant LRRK2 causes protein aggregation and cell death, possibly through an interaction with parkin. LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a penetrance of nearly 100% by age 80. G2019S is the most common known genetic cause of Parkinson disease, found in 1-6% of U.S. and European PD patients. It is especially common in Ashkenazi Jewish patients, with a prevalence of 29.7% in familial cases and 13.3% in sporadic.
• PARK12 (OMIM %300557), maps to the X chromosome

Toxins

Main article: Toxic causes of Parkinson's Disease

There are a number of toxins that may cause Parkinson's disease or cause symptoms mimicking Parkinson's disease. These include : Paraquat (herbicide), Rotenone (pesticide), Maneb (fungicide), Manganese, MPTP (drug by product), Toluene (solvent), N-hexane (solvent), Carbon disulfide (usually in solvents or pesticides), Carbon monoxide, Mercury, Cyanide, and Copper.

Head trauma

Past episodes of head trauma are reported more frequently by sufferers than by others in the population. A methodologically strong recent study found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects.

Drug-induced

Antipsychotics, which are used to treat schizophrenia and psychosis, can induce the symptoms of Parkinson's disease by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can eventually cause the symptoms of Parkinson's Disease that it initially relieves. Dopamine receptors can also eventually contribute to Parkinson's disease symptoms by increasing the sensitivity of dopamine receptors.

Treatment

Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.

Levodopa

The most widely used form of treatment is L-dopa in various forms. L-dopa is transfomed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.

Carbidopa and Benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are general given as combination preparations of carbidopa/levodopa (co-careldopa BAN) co-careldopa combined L-dopa and carbidopa in fixed ratios in such branded products of Sinemetand Parcopa and Benserazide/levodopa (co-beneldopa BAN) as Madopar. There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.

Talcopone inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa. However, due to its side effects, such as possible liver failure is limited in its availability. A similar drug, entacapone, has similar efficacy and has not been shown to cause significant alterations of liver function. Stalevo contains Levodopa, Carbidopa and Entacopone.

Mucuna pruriens, is a natural source of therapeutic quantities of L-dopa.

Dopamine agonists

The dopamine-agonists bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), cabergoline (Cabaser), apomorphine (Apokyn), and lisuride (Revanil), are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and /or insomnia. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms.

MAO-B inhibitors

Selegiline (Eldepryl) and rasagiline (Azilect) reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons. By-products of selegiline include amphetamine and methamphetamine, which can cause side effects such as insomnia. Use of L-dopa in conjunction with selegiline has increased mortality rates that have not been effectively explained. Another side effect of the combination can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa ; however subsequent studies have not confirmed this finding. Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.

Surgical interventions

Treating PD with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. Deep brain stimulation is presently the most used surgical means of treatment.

Currently under investigation is gene therapy. This involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). The gene used leads to the production of an enzyme called glutamic acid decarboxylase (GAD), which catalyses the production of a neurotransmitter called GABA. GABA acts as a direct inhibitor on the overactive cells in the STN.

GDNF infusion involves, by surgical means, the infusion of GDNF (glial-derived neurotrophic factor)into the basal ganglia using implanted catheters. Via a series of biochemical reactions, GDNF stimulates the formation of L-dopa. GDNF therapy is still in development.

In the future, implantation of cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells may become available. Even these, however, will not constitute cures because they do not address the considerable loss of activity of the dopaminergic neurons.

Nutrients

Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat Parkinson's disease or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms. Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients. Another complementary approach is Dopavite, a nutritional supplement which contains both of these substances and all the other nutrients required for dopamine formation. However, the efficacy of this nutritional supplement has not been validated in clinical trials.

More limited efficacy has been obtained with the use of THFA, NADH, and pyridoxine—coenzymes and coenzyme precursors involved in dopamine biosynthesis. Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells. However, in the randomized controlled trial, DATATOP of patients with early PD, no beneficial effect for vitamin E compared to placebo was seen

Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.

Physical exercise

Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion.

Prognosis

PD is not by itself a fatal disease, but it does get worse with time. The average life expectancy of a PD patient is generally the same as for people who do not have the disease. However, in the late stages of the disease, PD may cause complications such as choking, pneumonia, and falls that can lead to death.

The progression of symptoms in PD may take 20 years or more. In some people, however, the disease progresses more quickly. There is no way to predict what course the disease will take for an individual person. One commonly used system for describing how the symptoms of PD progress is called the Hoehn and Yahr scale.

Another commonly used scale is the Unified Parkinson's Disease Rating Scale (UPDRS). This much more complicated scale has multiple ratings that measure mental functioning, behavior, and mood; activities of daily living; and motor function. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much treatments are helping them.

With appropriate treatment, most people with PD can live productive lives for many years after diagnosis.

Notable Parkinson's sufferers

One famous sufferer of young-onset Parkinson's is Michael J. Fox, who has written a book about his experience of the disease. The film Awakenings (starring Robin Williams and Robert De Niro and based on genuine cases reported by Oliver Sacks) deals sensitively and largely accurately with a similar disease, postencephalitic parkinsonism.

Other famous sufferers include Pope John Paul II, artist Salvador Dali, evangelist Billy Graham, former US Attorney General Janet Reno, boxer Mohammad Ali, dictators Adolf Hitler, Franco and Mao Zedong, and numerous actors such as Terry Thomas, Kenneth More, Vincent Price and Michael Redgrave.

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Some of this article contains text from the public domain document at http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm

External links

• The Parkinson's Disease Forum - new research, news reports, new books, web sites
• European Parkinson's Disease Association
• Parkinson Society Canada
• Parkinson's Disease Foundation
• Hope For A Cure Foundation for Parkinson's Research
• Dr. Abe Lieberman's Ask the Doctor Parkinson Forum
• National Parkinson Foundation, Inc.
• American Parkinson's Disease Association
• Michael J. Fox Foundation for Parkinson's Research
• Parkinson's Disease Society (UK)
• Parkinson's NSW (In AUS)
• MyParkinsonsInfo.com
• The PD Webring
• WEMOVE: Worldwide education and awareness for movement disorders
• NETRP Web site
• Northwest Parkinson's Foundation
• Parkinson's Resources on the WWWeb
• Parkinson's Disease Pictures
• Parkinson's Drug Comparison Chart (PDF)
• International Society for Posture and Gait Research (ISPGR)
• HollyRod Foundation
• Parkinson's speech wikibook
• Lee Silverman Voice Therapy

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