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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 Symptom s are:
(The Mnemonic ''TRAP'' ('''T'''remor; '''R'''igidity; '''A'''kinesia/bradykinesia; '''P'''ostural instability) can be used to remember these symptoms.) Other motor symptoms include:
Non-Motor Symptoms Mood disturbances:
Cognitive disturbances:
Sleep Disturbances :
Sensation disturbances:
Autonomic disturbances:
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 often than women. About 2% of the population develops the disease some time during life. RELATED DISEASES Parkinson-Plus diseases There are other disorders that are called Parkinson-Plus Diseases . These include:
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 about a loss of about 75% of the 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 {Link without Title} (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 {Link without Title} (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 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 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 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 {Link without Title} : 2O-2 + 2H+ >>> H2O2 + O2 Catalase {Link without Title} : 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 The Lewy Bodies Lewy bodies are found in the Cytoplasm of neurons, and are composed of densely aggregated Filament s. These filaments contain Ubiquitin and Alpha-synuclein . 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 and head trauma. 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
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 Parkinson's disease. It was also developed but unused as a herbicide. MPTP inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So MPTP causes 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. Toxic causes of Parkinson's Disease Head trauma A methodologically strong recent study 2003 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. TREATMENT Pharmacological Treatments Levodopa The most widely used form of treatment is L-dopa in various forms, although due to feedback inhibition, L-dopa causes a reduction in the endogenous formation of L-dopa. Levodopa was discovered as a Parkinson's treatment by Arvid Carlsson . L-DOPA is a dopamine precursor that is transfomed into dopamine by dopa-decarboxylase, present in the pre-synaptic terminals of dopaminergic neurons present in the basal ganglia. However, only 1-5% of L-DOPA makes it's way to this target site. The remaining 95% of the remaining L-DOPA is converted to dopamine in the periphery by enzymes and is rapidly absorbed into the bloodstream where it causes side effects including nausea and dizzyiness. Therapy for Parkinson disease typically requires an evolving regimen of multiple medications. Medicating to control the side effects of other medications contributes to polypharmacy. To treat the side effects caused by the L-DOPA in the plasma, a drug needed to be developed to successfully inhibit the dopa decarboxylase outside of the central nervous system. Such drugs need to be large molecules that are hydrophillic. The drug, Carbidopa , does this and reduces the effective dose of L-DOPA by 75%. Together, L-DOPA is marketed with carbidopa in one pill as Sinemet. To complement Sinemet, Talcopone (Tasmar), was developed. Talcopone inhibits the COMT enzyme, thereby prolonging the effects of L-Dopa. This too has side effects. Tolcapone has been linked to possibile of liver failure and has been pulled from the market in Canada. It is still available in the United States. A similar drug, entacapone was released in 2000 and has similar efficacy but has not been shown to cause significant alterations of liver function. Foods rich in proteins can reduce the uptake of levodopa, because some Amino Acid s compete with levodopa for cellular receptor sites. This can usually be dealt with by offsetting medication and meal times: consuming the majority of required proteins towards the evening allows patients to use dopamine medication more effectively during the morning and mid-day when mobility is more critical. Dopamine Agonists Other treatments, such as the Dopamine-agonists, Bromocriptine (Parlodel), Pergolide (Permax), Pramipexole (Mirapex) and Ropinirole (Requip) exist and are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and /or insomnia. There are also some reports of people suddenly falling asleep while on these agonists. Dopamine agonists initially stimulate the dopamine receptors but then make them progressively less sensitive, thereby increasing the symptoms. MAO-B Inhibitor Selegiline (Eldepryl) reduces the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons in the basal ganglia. By-products of selegiline include amphetamine and methamphetamine - each can have side effects that kill Dopaminergic neurons, thus worsen the clinical case. Use of L-DOPA in conjunction with Selegiline has increased mortality rates that have not been effectively explained. SSRI's and SSNRI's Dopamine deficiency is central, but deficits of serotonin, norepinephrine, and acetylcholine are also typical. The depression and anxiety states that predominate when serotonin and norepinephrine are deficient are often treated with selective serotonine reuptake inhibitors (SSRIs) like Paxil, Zoloft, or Celexa; there is emerging evidence that the SSNRI (selective serotonin and norepinephrine reuptake inhibitor) Effexor may be particularly effective in Parkinson's disease because it augments two deficient neurotransmitters. Amphetimine-like drugs (Ritalin, Concerta) are being prescribed with increasing frequency to treat the Attention Deficit Disorder (ADD)-like attention problems that are almost universal in Parkinson's disease. Surgical Interventions Surgical interventions are an active area of current research, and Deep Brain Stimulation is presently the most popular and effective such treatment. 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 widespread loss of activity in several different types of cells in the brain and even for the dopamine-producing cells, do not re-establish all of the original connections with neighboring brain cells. Nutrients Early diagnosis and preventive therapy in Parkinson's Disease (1989): 323 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 are beneficial to the patient and essential for maintaining and improving mobility, flexibility, balance and a range of motion, and for a better resistance against many of the secondary symptoms and side effects. There is increasing evidence that exercise is both neuroprotective against the development of Parkinson's disease, and also ameliorative of both severity of symptoms, and also possibly of progression. "Alternative" exercise modalities such as yoga, tai chi, and dance may also hold promise as rehabilitation therapies, due to their integration of movement, thought, feeling, and sensory experience. Exercise has also been shown to effectively improve mild-moderate/ depression. 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