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Parkinson's disease (paralysis agitans or PD) is a movement disorder 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. Parkinson's disease was first formally recognised and its symptoms documented in 1817 in An Essay on the Shaking Palsy by the British physician Dr James Parkinson. The associated biochemical changes in the brains of patients were identified in the 1960s.

Symptoms

Parkinson disease affects movement (motor symptoms). 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. There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Reduction in dopamine along the non-striatal pathways is the likely explanation for much of the neuropsychiatric pathology associated with Parkinson's disease.

Motor symptoms

The cardinal symptoms are :

• tremor: 4-7Hz tremor, maximal when the limb is at rest, and decreased with voluntary movement. It is typically unilateral at onset. This is the most apparent and well-known symptom. However, an estimated 30% of patients have little perceptible tremor; these are classified as akinetic-rigid.
• rigidity: stiffness; increased muscle tone. In combination with a resting tremor, this produces a ratchety, "cogwheel" rigidity when the limb is passively moved.
• bradykinesia/akinesia: respectively, slowness or absence of movement. Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude.
• postural instability: failure of postural reflexes, which leads to impaired balance and falls.

(The mnemonic TRAP (Tremor; Rigidity; Akinesia/bradykinesia; Postural instability) can be used to remember these symptoms.)

Other motor symptoms include:

• Gait and Posture Disturbances:
  • Shuffling: gait is characterized by short steps, with feet barely leaving the ground, producing an audible shuffling noise. Small obstacles tend to trip the patient
  • Decreased arm swing: a form of bradykinesia
  • Turning "en bloc": rather than the usual twisting of the neck and trunk and pivoting on the toes, PD patients keep their neck and trunk rigid, requiring multiple small steps to accomplish a turn.
  • Stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk (camptocormia).
  • Festination: a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
  • Gait freezing: "Freezing" is another word for akinesia, the inability to move. Gait freezing is characterized by inability to move the feet, especially in tight, cluttered spaces or when initiating gait.
  • Dystonia: abnormal, sustained, painful twisting muscle contractions, usually affecting the foot and ankle in PD patients. This causes toe flexion and foot inversion, interfering with gait. Foot dystonia can be a presenting symptom of PD, especially in younger patients.
• Speech and Swallowing Disturbances
  • Hypophonia: soft speech. Speech quality tends to be soft, hoarse, and monotonous.
  • Festinating speech: excessively rapid, soft, poorly-intelligible speech.
  • Drooling: most likely caused by a weak, infrequent swallow and stooped posture.
  • (Non-motor causes of speech/language disturbance in both expressive and receptive language: these include decreased verbal fluency and cognitive disturbance especially related to comprehension of emotional content of speech and of facial expression
  • Dysphagia: impaired ability to swallow. Can lead to aspiration, pneumonia, and death.
• Other motor symptoms:
  • fatigue (up to 50% of cases);
  • masked facies (a mask-like face also known as hypomimia), with infrequent blinking;
  • difficulty rolling in bed or rising from a seated position;
  • micrographia (small, cramped handwriting);
  • impaired fine motor dexterity and coordination;
  • impaired gross motor coordination;
  • Poverty of movement: overall loss of accessory movements, such as decreased arm swing when walking, as well as spontaneous movement.

Non-Motor Symptoms

Mood disturbances:

• depression: occurs in 40-80% of cases; 20% of depression cases are major depressive disorder; severity and persistence of depression is positively associated with executive dysfunction and dementia;
• anxiety or panic attacks
  Note: 70% of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety; 90% of Parkinson's disease patients with pre-existing anxiety subsequently develop depression);
• apathy or abulia: abulia translates from Greek as the absence or negative of will; apathy is an absence of feeling or desire

Cognitive disturbances:

• slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.
• executive dysfunction, characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpeting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients; it may progress to:
• dementia: a later development in approximately 20-40% of all patients, typically starting with slowing of thought and progressing to difficulties with abstract thought, memory, and behavioral regulation.
• memory loss; procedural memory is more impaired than declarative memory. Prompting elicits improved recall.
• medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened

Sleep disturbances:

• Excessive daytime somnolence;
• Initial, intermediate, and terminal insomnia;
• Disturbances in REM sleep: disturbingly vivid dreams, and REM Sleep Disorder, characterized by acting out of dream content;

Sensation disturbances:

• impaired visual contrast sensitivity, spatial reasoning, colour discrimination, convergence insufficiency (characterized by double vision) and oculomotor control
• dizziness and fainting; usually attributable orthostatic hypotension, a failure of the autonomous nervous system to adjust blood pressure in response to changes in body position
• impaired proprioception (the awareness of bodily position in three-dimensional space)
• loss of sense of smell (anosmia),
• pain: neuropathic, muscle, joints, and tendons, attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at accommodation

Autonomic disturbances:

• oily skin and seborrheic dermatitis;
• urinary incontinence, typically in later disease progression
• constipation and gastricdysmotility: severe enough to endanger comfort and even health
• altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late parkinson disease. Current data addresses male sexual function almost exclusively.

Incidence

There are estimated to be around 4 to 6 million people that have been diagnosed with Parkinson's disease. There are over 1.5 million in China alone. It is likely that there are millions of people with Parkinson's Disease that remain undiagnosed. 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., 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.

Cases of PD are reported at all ages, even as low as 11. However, it is very uncommon in people younger than 30 and the average age at which symptoms begin is 55-60. The risk of developing it substantially increases with age. 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 and men are affected slightly more than women. About 2% of the population develops the disease some time during life.

• List of famous Parkinson's disease patients

Related diseases

Parkinson-Plus diseases

There are other disorders that are called Parkinson-Plus diseases. *for more details see Parkinsonism These include:

• Multiple system atrophy (MSA)
  • Shy-Drager syndrome (SDS)
  • Striatonigral degeneration (SND)
  • Olivopontocerebellar atrophy (OPCA)
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)
• Cerebellar Thoracic Outlet Syndrome
• Antiphospholipid Syndrome
• Vascular Parkinsonism
• Encephalitis Lethargica
• Hydrocephalus
• Essential Tremor
• Wilson's Disease

Pathology

The interaction of Dopamine and Acetylcholine

The primary symptoms of Parkinson's Disease are due to excessive muscle contraction.

Acetylcholine affects muscle contraction via the five cholinergic receptors : m1, m2, m3, m4, and m5. The receptors m1, m3 and m5 are stimulatory. The receptors m2 and m4 are inhibitory. The combined stimulatory effect of m1, m3 and m5 is more powerful in total than the combined inhibitory effect of m2 and m4. So the overall effect of acetylcholine is to stimulate muscle contraction.

Dopamine affects muscle contraction via the five dopamine receptors : D1, D2, D3, D4, and D5. The receptors D2, D3 and D4 are inhibitory. The receptors D1 and D5 are stimulatory. The combined inhibitory effect of D2, D3 and D4 is more powerful in total than the combined stimulatory effect of D1 and D5. So the overall effect of dopamine is to inhibit muscle contraction.

Parkinson's Disease consequently occurs when the effect of dopamine is less than that of acetylcholine. Dopamine deficiency rather than acetylcholine excess is normally responsible for this occurring.

Symptoms usually only begin to appear after a reduction down to about 25% of the normal activity of the dopaminergic neurons. The level of dopamine tends to continue to fall slowly over time, with an attendant worsening of symptoms. The biochemistry of Parkinson's Disease

Dopamine biosynthesis

The primary fault in Parkinson's Disease is that, whatever the cause, there is insufficient dopamine. Dopamine is formed in the dopaminergic neurons by the following pathway :

L-tyrosine >>> L-dopa >>> Dopamine

The first step is biosynthesised by the enzyme Tyrosine 3-Monooxygenase (which is more commonly called by its former name tyrosine hydroxylase). The following is the complete reaction :

L-tyrosine + THFA + O2 + Fe2+ >>> L-dopa + DHFA + H2O + Fe2+

So for L-dopa formation, L-tyrosine, THFA (tetrahydrofolic acid), and ferrous iron are essential. The activity of this enzyme is often as low as 25% in Parkinson's Disease, and in severe cases can be as low as 10%. This indicates that one or more of the elements required for the formation of L-dopa are in insufficient quantities.

The second step in the biosynthesis of dopamine is biosynthesised by the enzyme Aromatic L-amino acid decarboxylase (which is more commonly called by its former name dopa decarboxylase). The following is the complete reaction :

L-dopa + pyridoxal phosphate >>> dopamine + pyridoxal phosphate + CO2

So for dopamine biosynthesis from L-dopa, pyridoxal phosphate is essential. The activity of the enzyme rises and falls according to how much pyridoxal phosphate there is. The level of this enzyme in Parkinson's Disease can also be around 25% or even far less. The biochemistry of Parkinson's Disease

Coenzymes involved in Dopamine biosynthesis

Besides two enzymes being required for the formation of dopamine from L-tyrosine (L-tyrosine >>> L-dopa >>> Dopamine), three coenzymes are also required. Enzymes are substances that will enable a specific chemical reaction to take place in the body. Coenzymes are substances that assist enzymes. Some enzymes (including those involved in dopamine biosynthesis) will not function without coenzymes.

The three coenzymes involved in the formation of dopamine are : THFA (for L-tyrosine to L-dopa), Pyridoxal phosphate (for L-dopa to dopamine), and NADH (for the formation of THFA and Pyridoxal phosphate). They are made from vitamins via the following means :

Folic acid >>> Dihydrofolic acid >>> Tetrahydrofolic acid

Pyridoxine >>> Pyridoxal >>> Pyridoxal 5-Phosphate (this requires zinc as a cofactor)

Nicotinamide >>> NMN >>> NAD >>> NADH (or NADP) >>> NADPH

The biochemistry of Parkinson's Disease: Coenzymes

G proteins

In order to relieve Parkinson's Disease, dopamine (or dopamine agonists) must stimulate dopamine receptors, which must in turn stimulate the G proteins :

L-tyrosine > L-dopa > dopamine > dopamine receptors (D2, D3, D4) > G proteins

G proteins consist of three parts : alpha - beta - gamma, that are lined to each other. There are three types of beta unit (1, 2, 4), and seven types of gamma unit (2, 3, 4, 5, 7, 10, 11). However, they do not matter much to Parkinson's Disease. What matters to Parkinson's Disease are the alpha subunits, because it is actually these that ultimately relieve (or aggravate) Parkinson's Disease. There are five types :

G proteins that aggravate Parkinson's Disease : Gs 1 alpha G proteins that relieve Parkinson's Disease : Gi 1 alpha, Gi 2 alpha, Gi 3 alpha G proteins that have little effect on Parkinson's Disease : Go alpha

The sole purpose of dopamine (or dopamine agonists) stimulating dopamine receptors is to cause the alpha subunits (the active part of G proteins) to break away from the rest of the G protein. Without this occurring almost everybody would have Parkinson's Disease. Once the alpha part of G proteins is released, via cyclic AMP, it takes the final action in the series of event that leads to the ridding of Parkinson's Disease, which is to inhibit the cells it has effect on.The biochemistry of Parkinson's Disease: G proteins

Neuromelanin

In the cells involved in Parkinson's Disease (the dopaminergic neurons) the function is to produce dopamine. In the melanocytes, which are in the skin, the function is to produce the pigment melanin. Melanin is what causes people to suntan. Although they end up with different substances (dopamine and melanin), both of these cells start off with L-tyrosine, and both of them form L-dopa as well :

dopaminergic neurons : L-tyrosine > L-dopa > dopamine

melanocytes : L-tyrosine > L-dopa > melanin

In the dopaminergic neurons, when somebody can not form dopamine, they can accidentally form melanin instead. In the brain it is called neuromelanin because of the different amino acids it is attached to. However, this is not a normal mechanism, and it occurs via a different mechanism from that found in the skin. The formation of neuromelanin in the brain is often claimed to be what happens in healthy brains. Healthy brains are supposed to be darker in the part of the brain called the substantia nigra. However, it is actually due to the biochemical mechanisms not working properly. As not much L-dopa is formed in Parkinson's Disease, there isn't much capacity for that L-dopa to accidentally form melanin in the brain. So people with Parkinson's Disease can tend to have not much pigment in the part of the brain called the substantia nigra. However, that does not cause a medical problem because melanin is not supposed to be in the brain.The biochemistry of Parkinson's Disease: Neuromelanin

Cell damage

The primary natural means via which cell damage can occur in Parkinson's Disease is due to the reaction from L-tyrosine to L-dopa not taking place. The following is what should happen :

L-tyrosine + THFA + O2 + Fe2+ >>> L-dopa + DHFA + H2O + Fe2+

However, if for example, the THFA in the above reaction is lacking, the following can happen instead :

L-tyrosine + Fe2+ + O2 >>> L-tyrosine + Fe3+ + O-2 (superoxide anion)

As can be seen there is no L-dopa formed in the faulty reaction, and the superoxide anion is formed instead. The superoxide anion is one of the most highly destructive elements in cells. The formation of L-dopa can also fail to take place if L-tyrosine is deficient.

So the simplest means of preventing cell damage from taking place is to ensure that you have those substances required for the formation of L-dopa, which are L-tyrosine, THFA (which is made from the vitamin folic acid using nicotinamide), and ferrous iron.

Vitamin C and Vitamin E have been used to try to help to prevent cell damage in Parkinson's Disease. This is because they are claimed to assist in two enzyme reactions in the brain that get rid of the superoxide anion once it has been formed :

Superoxide Dismutase  : 2O-2 + 2H+ >>> H2O2 + O2

Catalase  : H2O2 >>> H2O + 1/2 O2

However, the problem with the use of Vitamin C and Vitamin E in trying to prevent cell damage is that they do nothing at all to prevent the original source of the problem, which is the formation of superoxide anion.The biochemistry of Parkinson's Disease: Cell damage

The Lewy Bodies

Lewy bodies are found in the cytoplasm of neurons, and are composed of densely aggregated filaments. These filaments contain ubiquitin and alpha-synuclein. Lewy Bodies are often associated with Parkinson's Disease. However, they are not unique to Parkinson's Disease, as they also occur in several other medical disorders.

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

Paraquat is a quaternary ammonium herbicide. Other members of this class include diquat, cyperquat, diethamquat, difenzoquat and morfamquat. Pesticides are known to be associated with an increased rate of Parkinson's Disease. Paraquat structurally resembles MPTP and its metabolite MPP+. MPTP and MPP+ are neurotoxic chemicals, that induce Parkinson's Disease in exposed humans. Paraquat might therefore might, as do MPTP and MPP+ inhibit tyrosine hydroxylation, which is essential for the formation of dopamine. Toxic causes of Parkinson's Disease

Rotenone is an insecticide that is known to cause Parkinson's Disease. Insecticides are also known to affect well water. Rotenone is commonly used in powdered form to treat parasitic mites on chickens and other fowl, and so can be found in poultry. Rotenone is produced by extraction from the roots, seeds, and leaves of certain tropical legumes. Rotenone inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So Rotenone causes Parkinson's Disease by lowering dopamine levels. Toxic causes of Parkinson's Disease

Maneb is a fungicide that contains manganese. The major active element of Maneb is manganese ethylene-bis-dithiocarbamate. Pesticides are known to be associated with an increased rate of Parkinson's Disease, so there is a greatly increased likelihood of developing symptoms by people involved in horticulture and agriculture. As Maneb contains manganese it is possible that it causes Parkinson's Disease symptoms via the same means as manganese, which is by inhibiting tyrosine hydroxylation, which is essential for the formation of dopamine. The effects of Maneb are potentiated when there is simultaneous exposure to the pesticide Paraquat. Toxic causes of Parkinson's Disease

Carbon monoxide toxicity is frequent due to the formation of carbon monoxide by very common means such as gas cookers and exhaust fumes. However, it normally requires the person having gone in to a coma as a result of the carbon monoxide poisoning before symptoms of Parkinson's Disease develop. Carbon monoxide causes hemoglobin (which transports oxygen) to turn in to carboxyhemoglobin (which does not transport oxygen). Oxygen is required for the formation of L-dopa. So carbon monoxide may cause Parkinson's Disease symptoms by interfering with the availability of oxygen to the brain. However, the precise means by which it can cause Parkinsonism has still not been proven. Toxic causes of Parkinson's Disease

Manganese can cause Manganism, an irreversible neurological disorder similar to Parkinson's disease. Occupational exposures occur mainly in - welding, mining as miners are surrounded by manganese dust and airborne manganese particles, alloy production, processing, ferro-manganese operations especially in which manganese ore or manganese compounds are turned into steel, and work with agrochemicals. The towns and communities surrounding the areas of manganese heavy industry could also become affected by exposure to manganese. It is also hypothesized that long-term exposure to the naturally-occurring manganese in shower water also puts people at risk. Manganese inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So manganese causes Parkinson's Disease by lowering dopamine levels. Toxic causes of Parkinson's Disease

Mercury toxicity is a known cause of symptoms that include those of Parkinson's Disease, especially tremor. One of the chief targets of the toxin is the enzyme pyruvate dehydrogenase (PDH). The enzyme is irreversibly inhibited by several mercury compounds, the lipoic acid component of the multienzyme complex binds mercury compounds tightly and thus inhibits PDH. However, the cause of the symptoms of Parkinson's Disease is likely to be due to the fact that mercury potently causes the release of dopamine, thereby lowering dopamine levels.Mercury is found in a wqide variety of sources : dietary fish intake, ethnic over-the-counter medications, occupational exposures to mercury vapour, possession of dental amalgam fillings, gold production, skin ointment, some soaps. Toxic causes of Parkinson's Disease

MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a chemical that may be produced accidentally during illicit manufacture of the recreational drug MPPP, which is a synthetic heroin substitute. The neurotoxicity of MPTP was discovered in 1976 after a chemistry graduate student synthesized MPPP incorrectly and injected the result. It was contaminated with MPTP, and within three days he began exhibiting symptoms of acute Parkinson's disease. It was also developed but unused as a herbicide and was distributed on the streets as a synthetic opioid-like drug. MPTP inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So MPTP causes acute Parkinson's Disease by lowering dopamine levels.Toxic causes of Parkinson's Disease

Toluene is a solvent that has been shown to cause or that has been associated with people with Parkinson's Disease. Toluene is used as an octane booster in fuel, as a solvent in paints, paint thinners, chemical reactions, rubber, printing, adhesives, lacquers, leather tanning, disinfectants, and to produce phenol and TNT (a component of explosives). It is also used as a raw material for toluene diisocyanate, which is used in the manufacture of polyurethane foams. The precise means of toxicity is not known.Toxic causes of Parkinson's Disease

N-Hexane, a constituent of solvents has been shown to cause Parkinsonism. Most of the n-hexane used in industry is mixed with similar chemicals called solvents. The major use for solvents containing n-hexane is to extract vegetable oils from crops such as soybeans. These solvents are also used as cleaning agents in the printing, textile, furniture, and shoemaking industries. Use by chemists. Certain kinds of special glues used in the roofing and shoe and leather industries also contain n-hexane. Several consumer products contain n-hexane, such as gasoline, spot removers, quick-drying glues used in various hobbies, and rubber cement. The precise means is not known.Toxic causes of Parkinson's Disease

Carbon disulfide, usually in solvents or pesticides, can cause Parkinson's Disease that is associated with other neurological symptoms. The effects can persist for years after exposure to the carbon disulfide has ceased. Potential sources : pesticides used as fumigants, disulfiram (a drug used in the treatment of chronic alcoholism), industrial solvents, solvents used in the production of viscose rayon and cellophane film. Means of toxicity is not established. However, carbon disulphide interferes with pyridoxal 5-phosphate. Pyridoxal 5-phosphate is essential for the formation of dopamine from L-dopa. So carbon disulphide may cause Parkinson's Disease symptoms by reducing the formation of L-dopa.Toxic causes of Parkinson's Disease

Copper accumulates in Wilson's Disease, which is associated with Parkinson's Disease. Although copper may cause symptoms by other means, there do not appear to be published studies in which copper has otherwise caused Parkinson's Disease. This may be because copper is not normally formed in to a vapour or dust that can readily be inhaled or consumed. Copper can be found in high quantities in copper mines, copper cooking pots, copper plumbing, very excessive consumption of copper nutritional supplements. Excess copper can cause the formation of a copper-dopamine complex, which leads to the oxidation of dopamine to aminochrome. Toxic causes of Parkinson's Disease

Cyanide, usually from the consumption of potassium cyanide or sodium cyanide can result in Parkinsonism. Cyanide is also produced by certain bacteria, fungi, and algae, and are found in a number of foods and plants, such as unprocessed cassava, cherry pits,apricot pits, bitter almonds. Hydrogen cyanide is contained in vehicle exhaust and in tobacco smoke,as does burning plastic.Cyanides are also found in gold processing. Cyanide interrupts the electron transport chain in the inner membrane of the mitochondrion. Cyanide also occupies the place of oxygen in hemoglobin (which transports oxygen). Oxygen is required for the formation of L-dopa. So carbon monoxide may cause Parkinson's Disease symptoms by interefering with the availability of oxygen to the brain. However, the precise means by which it causes Parkinson's Disease has still not been proven. It would be expected that there would be an increase in Parkinson's Disease to people exposed to cyanide in the Bhopal, India plant explosion, but that has not been observed. Toxic causes of Parkinson's Disease

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.

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 due to making the dopamine receptors increasingly less sensitive.

Treatments

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.

Talcopone inhibits the COMT enzyme, thereby prolonging the effects of L-Dopa, and so has 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.

Sinemet contains L-dopa and also carbidopa. Parcopa contains the same two drugs but is orally disintegrating. Madopar contains L-dopa and benserazide. 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. 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 - each can have side effects that damage tha Dopaminergic neurons. Use of L-DOPA in conjunction with Selegiline has increased mortality rates that have not been effectively explained.

Surgical Interventions

Deep brain stimulation is presently the most used surgical means of treatment.

Gene therapy 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. Also used alongside existing treatments is a Parkinson's Disease supplement that contains both of these substances and all the other nutrients required for dopamine formation. 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 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. Coenzyme Q10 has more recently been used for similar reasons.

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

Most older studies have noted increased mortality in patients with Parkinson disease (PD). However, the 2005 Rotterdam Study, which prospectively followed a large cohort of participants, noted only a modest decrease in survival in patients without dementia. A 2004 community-based cohort study of 245 PD patients demonstrated similar findings in patients with clinically definite PD.

The most commonly reported cause of death in PD patients is pneumonia. Swallowing difficulties may lead to aspiration of food, causing aspiration pneumonia (a specific form of pneumonia caused by gastric acid, food and digestive tract bacteria). Onset of dementia doubles the odds of death. Depression more than doubles the odds ratio.

List of deaths from Parkinson's disease

References

1. MD Pell (1996). "On the receptive prosodic loss in Parkinson's disease". Cortex. 32 (4): 693–704.
2. Günther Deuschl, Christof Goddemeier (1998). "Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects". Journal of neurology, neurosurgery, and psychiatry. 64 (March): 320–324.
3. Michael J Frank (2005). "Dynamic Dopamine Modulation in the Basal Ganglia: A Neurocomputational Account of Cognitive Deficits in Medicated and Non-mediacated Parkinsonism". Journal of Cognitive Neuroscience. 17: 51–73.
4. AB Singleton; et al. (2003). "alpha-Synuclein locus triplication causes Parkinson's disease (Brevia)". Science. 302 (5646): 841. {{cite journal}}: Explicit use of et al. in: |author= (help)
5. P Poorkaj; et al. (2004). "parkin mutation analysis in clinic patients with early-onset Parkinson's disease". American Journal of Medical Genetics Part A. 129A (1): 44–50. {{cite journal}}: Explicit use of et al. in: |author= (help)
6. Ebba Lohmann; et al. (2003). "How much phenotypic variation can be attributed to parkin genotype?". Annals of Neurology. 54 (2): 176–185. {{cite journal}}: Explicit use of et al. in: |author= (help)
7. Wanli W. Smith; et al. (2005). "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18676–18681. {{cite journal}}: Explicit use of et al. in: |author= (help)
8. Jennifer Kachergus; et al. (2005). "Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations". American Journal of Human Genetics. 76 (4): 672–680. {{cite journal}}: Explicit use of et al. in: |author= (help)
9. A Brice (2005). "Genetics of Parkinson's disease: LRRK2 on the rise (Scientific Commentary)". Brain. 128 (12): 2760–2762.
10. LJ Ozelius; et al. (2006). "LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews (Letter)". New England Journal of Medicine. 354 (4): 424–425. {{cite journal}}: Explicit use of et al. in: |author= (help)
11. J. H. Bower; et al. (2003). "Head trauma preceding PD". Neurology. 60: 1610–1615. {{cite journal}}: Explicit use of et al. in: |author= (help)
12. M. Stern; et al. (1991). "The epidemiology of Parkinson's disease". Archives of Neurology. 48 (9): 903–907. {{cite journal}}: Explicit use of et al. in: |author= (help)
13. ^ K Uryu; et al. (2003). "Age-dependent synuclein pathology following traumatic brain injury in mice". Experimental neurology. 184 (1): 214–224. {{cite journal}}: Explicit use of et al. in: |author= (help)
14. (unknown) (1986). "(unknown)". Comptes rendus academie des sciences. 302: 435. {{cite journal}}: Cite uses generic title (help)
15. W. Birkmayer and J. G. D. Birkmayer (1986). "Iron, a new aid in the treatment of Parkinson patients". Journal of Neural Transmission. 67 (3–4): 287–292.
16. Early diagnosis and preventive therapy in Parkinson's Disease (1989): 323
17. Lonneke M. L. de Lau; et al. (2005). "Prognosis of Parkinson Disease". Archives of Neurology. 62 (8): 1265–1269. {{cite journal}}: Explicit use of et al. in: |author= (help)
18. Karen Herlofson; et al. (2004). "Mortality and Parkinson disease". Neurology. 62: 937–942. {{cite journal}}: Explicit use of et al. in: |author= (help)
19. TA Hughes, HF Ross, RHS Mindham, EGS Spokes (2004). "Mortality in Parkinson's disease and its association with dementia and depression". Acta Neurologica Scandinavica. 110 (2): 118.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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)
• Can We Prevent Parkinson’s and Alzheimer’s Disease? Article from Journal of Postgraduate Medicine
• International Society for Posture and Gait Research (ISPGR)
• HollyRod Foundation
• Parkinson's speech wikibook
• Lee Silverman Voice Therapy

• Human diseases
• Eponymous diseases
• Geriatrics
• Neurological disorders