What is MPTP?

Can toxins cause parkinsonism?

There are some known toxins that can cause parkinsonism, most notoriously a chemical called MPTP, found as an impurity in some illegal drugs

Is heroin assocated with parkinson disease?

There seems to be no direct link between heroin use and Parkinson's disease (please correct me if I'm wrong). There is a link however between the synthetic heroin analog MPPP and Parkinson's disease. In the synthesis of this (illegal) drug, traces of the neurotoxin MPTP are sometimes formed, which destroys the same cells in the brain (the substantia nigra) that are affected in Parkinon's disease. For more information, please see http://en.wikipedia.org/wiki/MPTP

Who discovered deep brain stimulation?

It was discovered by Professor Benabid at his clinic in Grenoble, France. Benabid noticed that signs of Parkinson's were present in young drug addicts who had injected themselves with a form of MPTP

What is something unhealthy for nervous system and why?

Tetrodotoxin is a neurotoxin. It acts to neuronal depolarization and prevent subsequent action potentials via binding to the voltage gated sodium channels on the cell membrane. In a healthy neuron, these voltage gated sodium channels are critical for generation of an action potential in response to graded depolarization (I.e. EPSP). As the neuron is depolarized, these channels open and allow for the influx of sodium ions into the cell, which in turn further depolarized the neuron in a positive feedback loop. Tetrodotoxin (TTX) is the toxin found in blowfish (fugu). Another harmful substance for the nervous system is manganese which causes manganism, resembling some aspects of Parkinson's disease. Off the top of my head: 6-HO-dopamine, MPTP, ibotenic acid. Wikipedia these neurotoxins for their respective mechanisms of action Source: degrees in neuroscience and neuropharmacology

What does MPP stand for?

MPP or M.P.P. may refer to: * Marginal physical product * Marijuana Policy Project, organization in the United States * Massively parallel processing, in parallel computing ** Goodyear MPP, an early implementation of massively parallel processing * Master Production Planning * Master of Public Policy, an academic degree * Maximum Power Point (see Maximum power point tracker) * Member of Provincial Parliament, an elected member of the Legislative Assembly of Ontario, Canada * Merriweather Post Pavilion in Columbia, Maryland * Metroid Prime Pinball, a pinball video game for the Nintendo DS * Micro perforated plate, a type of sound absorber * Micro Precision Products, a British camera manufacturer * Mobile Positioning Protocol * Modus ponens, a principle in propositional logic * Molded Paper Pulp, a packaging and padding material made from wet paper fiber, formed and dried into rigid boxes and shapes. * Molypermalloy Powder, a low-loss alternative to ferrite toroidal Inductor cores, typically consisting of 79% nickel, 17% iron and 4% molybdenum alloy powder * mpp, Microsoft Project Plan file format * MPP+, 1-methyl-4-phenylpyridine, a toxic metabolite of MPTP causing symptoms of Parkinson's disease

What diseases acts like Parkinsons Disease?

* Postencephalitic parkinsonism. Just after the first World War, a viral disease, encephalitis lethargica, attacked almost 5 million people throughout the world, and then suddenly disappeared in the 1920s. Known as sleeping sickness in the United States , this disease killed one third of its victims and led to post-encephalitic parkinsonism in many others. This resulted in a particularly severe form of movement disorder that appeared sometimes years after the initial illness. (In 1973, neurologist Oliver Sacks published Awakenings, an account of his work in the late 1960s with surviving post-encephalitic patients in a New York hospital. Using the then-experimental drug levodopa, Dr. Sacks was able to temporarily "awaken" these patients from their statue-like state). In rare cases, other viral infections, including western equine encephalomyelitis, eastern equine encephalomyelitis, and Japanese B encephalitis, have caused parkinsonian symptoms.* Drug-induced parkinsonism. A reversible form of parkinsonism sometimes results from use of certain drugs, such as chlorpromazine and haloperidol, which are prescribed for patients with psychiatric disorders. Some drugs used for stomach disorders (metoclopramide), high blood pressure (reserpine), and epilepsy (valproate) may also produce parkinsonian symptoms. Stopping the medication or lowering the dosage of these medications usually causes the symptoms to go away.* Toxin-induced parkinsonism. Some toxins - such as manganese dust, carbon disulfide, and carbon monoxide - can cause parkinsonism. The chemical MPTP also causes a permanent form of parkinsonism that closely resembles PD. Investigators discovered this reaction in the 1980s when heroin addicts in California who had taken an illicit street drug contaminated with MPTP began to develop severe parkinsonism. This discovery, which showed that a toxic substance could damage the brain and produce parkinsonian symptoms, caused a dramatic breakthrough in Parkinson's research: for the first time, scientists were able to simulate PD in animals and conduct studies to increase understanding of the disease.* Arteriosclerotic parkinsonism. Sometimes known as pseudoparkinsonism, vascular parkinsonism, or atherosclerotic parkinsonism, arteriosclerotic parkinsonism involves damage to the brain due to multiple small strokes. Tremor is rare in this type of parkinsonism, while dementia - the loss of mental skills and abilities - is common. Antiparkinsonian drugs are of little help to patients with this form of parkinsonism.* Parkinsonism-dementia complex of Guam. This disease occurs among the Chamorro populations of Guam and the Mariana Islands and may be accompanied by a motor neuron disease resembling amyotrophic lateral sclerosis (Lou Gehrig's disease). The course of the disease is rapid, with death typically occurring within 5 years.* Post-traumatic parkinsonism. Also known as post-traumatic encephalopathy or "punch-drunk syndrome," parkinsonian symptoms can sometimes develop after a severe head injury or frequent head trauma that results from boxing or other activities. This type of trauma also can cause a form of dementia called dementia pugilistica.* Essential tremor. Essential tremor, sometimes called benign essential tremor or familial tremor, is a common condition that tends to run in families and progresses slowly over time. The tremor is usually equal in both hands and increases when the hands are moving. The tremor may involve the head but usually spares the legs. Patients with essential tremor have no other parkinsonian features. Essential tremor is not the same as PD, and usually does not lead to it, although in some cases the two conditions may overlap in one person. Essential tremor does not respond to levodopa or most other PD drugs, but it can be treated with other medications.* Normal pressure hydrocephalus. Normal pressure hydrocephalus (NPH) is an abnormal increase of cerebrospinal fluid (CSF) in the brain's ventricles, or cavities. It occurs if the normal flow of CSF throughout the brain and spinal cord is blocked in some way. This causes the ventricles to enlarge, putting pressure on the brain. Symptoms include problems with walking, impaired bladder control leading to urinary frequency or incontinence, and progressive mental impairment and dementia. The person also may have a general slowing of movements or may complain that his or her feet feel "stuck." These symptoms may sometimes be mistaken for PD. Brain scans, intracranial pressure monitoring, and other tests can help to distinguish NPH from PD and other disorders. NPH can sometimes be treated by surgically implanting a CSF shunt that drains excess cerebrospinal fluid into the abdomen, where it is absorbed.* Progressive supranuclear palsy. Progressive supranuclear palsy (PSP), sometimes called Steele-Richardson-Olszewski syndrome, is a rare, progressive brain disorder that causes problems with control of gait and balance. People often tend to fall early in the course of PSP. One of the most obvious signs of the disease is an inability to move the eyes properly. Some patients describe this effect as a blurring. PSP patients often show alterations of mood and behavior, including depression and apathy as well as mild dementia. The symptoms of PSP are caused by a gradual deterioration of brain cells in the brainstem. It is often misdiagnosed because some of its symptoms are very much like those of PD, Alzheimer's disease, and other brain disorders. PSP symptoms usually do not respond to medication.* Corticobasal degeneration. Corticobasal degeneration results from atrophy of multiple areas of the brain, including the cerebral cortex and the basal ganglia. Initial symptoms may first appear on one side of the body, but eventually affect both sides. Symptoms are similar to those found in PD, including rigidity, impaired balance and coordination, and dystonia. Other symptoms may include cognitive and visual-spatial impairments, apraxia (loss of the ability to make familiar, purposeful movements), hesitant and halting speech, myoclonus (muscular jerks), and dysphagia (difficulty swallowing). Unlike PD, corticobasal degeneration usually does not respond to medication.* Multiple system atrophy. Multiple system atrophy (MSA) refers to a set of slowly progressive disorders that affect the central and autonomic nervous systems. MSA may have symptoms that resemble PD. It also may take a form that primarily produces poor coordination and slurred speech, or it may have a mixture of these symptoms. Other symptoms may include breathing and swallowing difficulties, male impotence, constipation, and urinary difficulties. The disorder previously called Shy-Drager syndrome refers to MSA with prominent orthostatic hypotension - a fall in blood pressure every time the person stands up. MSA with parkinsonian symptoms is sometimes referred to as striatonigral degeneration, while MSA with poor coordination and slurred speech is sometimes called olivopontocerebellar atrophy.* Dementia with Lewy bodies. Dementia with Lewy bodies is a neurodegenerative disorder associated with abnormal protein deposits (Lewy bodies) found in certain areas of the brain. Symptoms can range from traditional parkinsonian symptoms, such as bradykinesia, rigidity, tremor, and shuffling gait, to symptoms similar to those of Alzheimer's disease. These symptoms may fluctuate, or wax and wane dramatically. Visual hallucinations may be one of the first symptoms, and patients may suffer from other psychiatric disturbances such as delusions and depression. Cognitive problems also occur early in the course of the disease. Levodopa and other antiparkinsonian medications can help with the motor symptoms of dementia with Lewy bodies, but they may make hallucinations and delusions worse.* Parkinsonism accompanying other conditions. Parkinsonian symptoms may also appear in patients with other, clearly distinct neurological disorders such as Wilson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, and Creutzfeldt-Jakob disease. Each of these disorders has specific features that help to distinguish them from PD. MSA, corticobasal degeneration, and progressive supranuclear palsy are sometimes referred to as "Parkinson's-plus" diseases because they have the symptoms of PD plus additional features.

What is the designer drug?

Designer drug is a term used to describe psychoactive drugs which are created (or marketed, if they had already existed) to get around existing drug laws, usually by modifying the molecular structures of existing drugs to varying degrees, or less commonly by finding drugs with entirely different chemical structures that produce similar subjective effects to illegal recreational drugs.In the United States, the Controlled Substances Act was amended by the Controlled Substance Analogue Enforcement of 1986, which attempted to ban designer drugs pre-emptively by making it illegal to manufacture, sell, or possess chemicals that were substantially similar in chemistry and pharmacology to Schedule I or Schedule II drugs. Other countries have dealt with the issue differently. In some, they simply ban new drugs as they become a concern, as do Germany, Canada, and the United Kingdom.Most of the best known research chemicals are structural analogues of tryptamines or phenethylamines, but there are also many other completely unrelated chemicals which can be considered as part of the group. It is very difficult to determine psychoactivity or other pharmaceutical properties of these compounds based strictly upon structural examination. Many of the substances have common effects whilst structurally different and vice versa. As a result of no real official naming for some of these compounds, as well as regional naming, this can all lead to (and is anecdotally known to have led to) potentially hazardous mix ups for users. Some common designer drugs include:Opioids* α-methylfentanyl, became well known as "China White" on the heroin market * parafluorofentanyl * 3-methylfentanyl, extremely potent opioid, allegedly used as a chemical weapon by the Russian military in the Moscow theater hostage crisis * MPPP, especially famous due to an impurity in some batches called MPTP which caused permanent Parkinsonism with a single useTryptamine-based* 4-Acetoxy-DiPT, N,N-diisopropyl-4-acetoxytryptamine * 5-MeO-AMT, 5-methoxy-alpha-methyltryptamine * 5-MeO-DIPT, 5-methoxy-di-isopropyltryptamine (also known as "Foxy" or "Foxy Methoxy") * 5-MeO-DMT, 5-methoxy-dimethyltryptamine * AMT, α-methyltryptamine * AET, α-ethyltryptamine * DiPT, N,N-diisopropyl-tryptamine * DPT, N,N-dipropyltryptaminePhenethylamine-based* 2C-B, 4-bromo-2,5-dimethoxyphenethylamine * 2C-C, 2,5-dimethyoxy-4-chlorophenethylamine * 2C-I, 2,5-dimethoxy-4-iodophenethylamine * 2C-E, 2,5-dimethoxy-4-ethyl-phenethylamine * 2C-T-2, 2,5-dimethoxy-4-ethylthiophenethylamine * 2C-T-7, 2,5-dimethoxy-4-(n)-propylthiophenethylamine * 2C-T-21, 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine * MDMA, 3,4-methylenedioxymethamphetamine * MDEA, 3,4-methylenedioxy-N-ethylamphetamine * DOB, 2,5-dimethoxy-4-bromoamphetamine * DOM, 2,5-dimethoxy-4-methylamphetamine * TMA-2, 2,4,5-Trimethoxyamphetamine * PMA, a highly dangerous analogue of MDMA responsible for many accidental deathsPCP analogues* TCP, 1-[1-(2-thienyl)-cyclohexyl]-piperidine or thienylcyclohexylpiperidine * PCE, (1-Phenylcyclohexyl)ethylamine * PCPy, 1-(1-phenylcyclohexyl)pyrrolidine * 4-MeO-PCPPiperazine-based* BZP, benzylpiperazine * TFMPP, 3-Trifluoromethylphenylpiperazine, has the unique distinction of being the only drug to be emergency scheduled into Schedule I and then allowed to become legal because the DEA was unable to justify permanent scheduling * mCPP, 1-(3-chlorophenyl)piperazine * pFPP, 1-(4-fluorophenyl)piperazineSteroids* Norbolethone * THG, "The Clear" * Madol (sometimes confusingly referred to as "DMT")Stimulants* Geranamine * 4-Methylaminorex * MDPV * Desoxypipradrol * Diphenylprolinol * MephedroneSedatives* GBL, gamma-butyrolactone, both a precursor to and substitute for GHB * 1,4-Butanediol, another GHB analogue * Methylmethaqualone, an analogue of the sedative methaqualone * MebroqualoneErectile dysfunction* Acetildenafil * Aminotadalafil * Homosildenafil * Hydroxyacetildenafil * Hydroxyhomosildenafil * Piperidino-acetildenafil * Piperidino-vardenafilCannabinoids* THC-O-acetate * JWH-018 - found as an active ingredient in herbal smoking blends such as "Spice". * JWH-073 * JWH-200 * CP 47,497 * CP 55,940

Secondary parkinsonism?

DefinitionSecondary parkinsonism is similar to Parkinson's disease, but it is caused by certain medicines, a different nervous system disorder, or another illness.Alternative NamesParkinsonism - secondaryCauses, incidence, and risk factorsParkinson's disease is one of the most common nervous system (neurologic) disorders of the elderly. "Parkinsonism" refers to any condition that causes Parkinson's-type abnormal movements. These movements are caused by changes in or destruction of the nerve cells (neurons) that produce the chemical dopamine in a certain area of the brain.Secondary parkinsonism may be caused by disorders such as:EncephalitisMeningitisStrokeOther disorders can also damage the dopamine neurons and produce this condition, including:Corticobasal degenerationDiffuse Lewy body diseaseMultiple system atrophyProgressive supranuclear palsyAnother common cause of secondary parkinsonism is medication, such as:Antipsychotics (haloperidol)MetoclopramidePhenothiazine medicationsIf they damage the area of the brain that contains the dopamine neurons, the following may cause secondary parkinsonism:Brain damage caused by anesthesia drugs (such as during surgery)Carbon monoxide poisoningExposure to toxinsOverdoses of narcoticsThere have been cases of secondary parkinsonism among intravenous drug users who injected a substance called MPTP, which can be produced when making a form of heroin. These cases are rare and have mostly affected long-term drug users.Secondary parkinsonism caused by antipsychotics or other medications is usually reversible if identified soon enough. However, it may not be reversible if it is caused by:Drug-related brain damageInfectionsToxinsSymptomsSymptoms of parkinsonism may include:Decrease in facial expressionsDifficulty starting and controlling movementSoft voiceSome types of paralysisStiffness of the trunk, arms, or legsTremorAlthough cognitive problems are not as common in Parkinson's disease, they may be more likely in secondary parkinsonism. This is because the diseases that cause secondary parkinsonism often lead to dementia.For a more detailed description of symptoms, see Parkinson's disease.Signs and testsThe health care provider may be able to diagnose secondary parkinsonism based on your history, symptoms, and a physical examination. However, the symptoms may be difficult to assess, particularly in the elderly.Examination may show:Difficulty starting or stopping voluntary movementsIncreased muscle toneProblems with postureSlow, shuffling walk (gait)Tremors of the Parkinson's typeReflexes are usually normal.Tests are not usually specific for secondary parkinsonism. However, they may be used to confirm or rule out other disorders that can cause similar symptoms.TreatmentTreatment is aimed at controlling symptoms. If the symptoms are mild, no treatment may be needed.If the condition is caused by a medication, the benefits of the medication should be weighed against the severity of symptoms. Medications should be stopped or changed if the risks outweigh the benefits.Treating underlying conditions such as stroke or infections can reduce symptoms.Medications may be used if symptoms interfere with the ability to perform daily activities. The medication, dose, timing, or combination of medications may need to be adjusted as symptoms change.Many of the medications used to treat this condition can cause severe side effects. Monitoring and follow-up by the health care provider are important. Secondary parkinsonism tends to be less responsive to medical therapy than Parkinson's disease. However, medications are worth trying if the cause of the condition is not treatable.Medications used to treat symptoms of Parkinson's disease are:Levodopa (L-dopa), Sinemet, levodopa and carbidopa (Altamet)Pramipexole (Mirapex), ropinirole (Requip), bromocriptine (Parlodel)Selegiline (Eldepryl, Deprenyl), rasagiline (Azilect)Amantadine or anticholinergic medications (to reduce early or mild tremors)Entacapone (to prevent the breakdown of levodopa)For a more detailed description of treatment, see Parkinson's disease.Support GroupsSee: Parkinson's disease - support groupExpectations (prognosis)What will happen varies and depends on the cause of the disorder. If the disorder is caused by medications, it may be treatable. All other causes are not reversible and tend to get worse over time.ComplicationsDifficulty performing daily activitiesDifficulty swallowing (eating)Disability (varying degrees)Injuries from fallsSide effects of medicationsSide effects from loss of strength (debilitation):AspirationDeep vein thrombosisMalnutritionCalling your health care providerCall your health care provider if:Symptoms of secondary parkinsonism develop, come back, or get worseNew symptoms appear, including: Changes in alertness, behavior, or moodDelusional behaviorDizzinessHallucinationsInvoluntary movementsLoss of mental functionsNausea or vomitingPossible side effects of medicationsSevere confusion or disorientationDiscuss the situation with your health care provider if you are unable to care for the person at home (after treatment begins).PreventionTreating conditions that cause secondary parkinsonism may decrease the risk.Only use medications under a health care provider's supervision. People with conditions (such as schizophrenia) that require long-term use of antipsychotics should be carefully monitored to prevent the development of secondary parkinsonism. Newer antipsychotic medications are less likely to cause secondary parkinsonism.ReferencesLang A. Parkinsonism. In: Goldman L, Ausiello D. Cecil Textbook of Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier;2007:chap 433.Lang AE. When and how should treatment be started in Parkinson disease? Neurology. 2009;72(7 Suppl):S39-43.Lewitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med. 2008;359(23):2468-76.

Is exposure to pesticides a cause of parkinson's disease?

Can peticide exposure cause Parkinson’s? Parkinson’s disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. The major pathologic feature of PD is the profound loss of pigmented neurons, mainly in the pars compacta of the substantia nigra (SN). Associated with this neuronal loss is the presence of large eosinophilic inclusions, called Lewy bodies, within the remaining pigmented neurons, made up of a series of proteins, including neurofilaments, α-synuclein fibrils, ubiquitin, parkin, and proteasomal elements. The first clinical signs of PD, however, become apparent only after the loss of about 70–80% of dopaminergic neurons (Schapira 1999), and although the diagnosis of PD is entirely clinical, histopathology on autopsy is the only way to definitively confirm a diagnosis. The mean age of onset of PD is typically between 60 and 65 years, and in Europe the prevalence of PD has been estimated to be 1.8% in persons ≥ 65 years of age (de Rijk et al. 2000), with an incidence of approximately 16–19 per 100,000 per year (Twelves et al. 2003). Although age is unequivocally associated with increasing PD risk, the underlying process of PD is distinct from the natural aging process (Goldman and Tanner 1998). PD prevalence is also similar among ethnic groups living in the same location (Morens et al. 1996), but may differ among ethnic groups living in different locations (Schoenberg et al. 1988) Genetic factors can influence the risk of PD, and higher rates of PD have been found in relatives of those with PD (Foltynie et al. 2002). However, twin studies have consistently shown low rates of concordance (5–8%) in monozygotic and dizygotic twins (Foltynie et al. 2002), suggesting that other factors play a part in the etiology of PD. A number of causative factors have been found to induce parkinsonism similar to that of idiopathic PD, including vascular insults to the brain, repeated head trauma, neuroleptic drugs, and manganese toxicity (Adler 1999). In particular, the toxicant 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) resulted in the development of acute parkinsonism, similar to the idiopathic disease in nearly all clinical, pathologic, and biochemical features, in a small group of drug addicts (Langston et al. 1983). It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. This rekindled an interest in the possible role of exogenous toxicants in the development of PD and parkinsonism generally, in particular, compounds that are toxicologically or structurally similar to MPTP, including pesticides such as rotenone and paraquat (Goldman and Tanner 1998). Numerous epidemiologic and toxicologic studies have examined pesticides as a risk factor for PD and parkinsonism and the possible mechanisms by which pesticides may act. Review undertaken on behalf of the U.K. Advisory Committee on Pesticides. In addition, we identified three autopsy studies that examined the levels of various pesticides and their metabolites in the brains of PD cases (Corrigan et al. 1998, 2000; Fleming et al. 1994). Exposure In most studies, a positive association was observed between exposure to herbicides and PD risk. In one study, exposure to herbicides was a significant independent risk factor after adjustment for insecticide and other exposures (Semchuk et al. 1992). Exposure to insecticides is also generally positively associated with PD (Figure 2). Fungicide exposure was not found to be a significant risk factor for PD, nor was exposure to rodenticides (Behari et al. 2001) or acaricides (Hertzman et al. 1994; In two studies, paraquat exposure was shown to be significantly associated with PD (Hertzman et al. 1990; Liou et al. 1997), especially with > 20 years of exposure (Liou et al. 1997). However, other studies have not found a significant association, although PD risk was still elevated (Firestone et al. 2005; Hertzman et al. 1994; Kamel et al. 2001). Other specific groups of pesticides have also shown positive associations with PD, including organochlorines (Figure 2). Three autopsy case–control studies found increased levels of dieldrin and lindane in the brains of deceased PD patients compared with other diseased brains (Corrigan et al. 1998, 2000; Fleming et al. 1994). Positive associations were also seen with exposure to organophosphates and carbamates pesticides (Firestone et al. 2005; Wechsler et al. 1991; The relationship between exposure duration and PD risk was investigated in six case– control studies. Four found a significant association between increasing pesticide exposure duration and PD risk (Chan et al. 1998; Gorell et al. 1998; Liou et al. 1997; Seidler et al. 1996) The remaining two studies showed nonsignificant positive associations with exposure duration (Jiménez-Jiménez et al. 1992; Zayed et al. 1990). These studies suggested that PD risk is increased when the duration of exposure to pesticides exceeds a particular threshold, because associations were often only significant for the longest exposure duration categories (e.g., > 10 or > 20 years) A positive association was also observed with high doses of pesticides compared with low doses (Nelson et al. 2000), although the risk with regular use was seen to be lower compared with occasionaluse (Kuopio et al. 1999). In addition, several studies observed a positive correlation with duration of exposure to, and high doses of, herbicides and insecticides (Nelson et al. 2000; Seidler et al. 1996). Significant increases in PD risk were also associated with a history of occupational use of pesticides between the ages of 26 and 35 years, herbicides between the ages of 26 and 35, 36 and 45, and 46 and 55 years, and insecticides between the ages of 46 and 55 years (Semchuk et al. 1992). In a few of these studies, multivariate analyses were performed to examine the relationship between the various risk factors. Koller et al. (1990) found that wellwater consumption was dependent on rural living, suggesting the risk factors were interrelated. In one study, well-water use was found to be positively and independently associated with PD (Zorzon et al. 2002) Several studies have also found farming to be an independent risk factor, in addition to pesticide exposure (Gorell et al. 1998; Zorzon et al. 2002) Other sources of cases included lists of patients receiving anti-PD drugs, residential care centers, community or support groups, or door-to-door surveys. Sources of controls included the general population, the spouses of cases, electoral rolls, subjects suggested by their cases, and friends and relatives of the cases. Use of hospitals could result in selection bias for both cases and controls if attendance was influenced by factors such as severity of PD (with particularly severe or mild conditions being admitted elsewhere or not attending), geographic location, and social class. The use of neighborhood controls or friends and relatives of cases can result in the exposure prevalence being similar in both cases and controls, resulting in overmatching, driving the risk estimate toward the null. defined a case on the basis of the presence of two or more of the cardinal signs of PD (tremor, rigidity, bradykinesia, and postural instability); some also used additional criteria, including responsiveness to L-dopa therapy and/or a progressive disorder. Other diagnostic criteria used included the Unified Parkinson’s Disease Rating Scale, the Hoehn and Yahr PD Staging Scale, and the UK PD Society Brain Bank Clinical Diagnosis Criteria (Fahn and Elton 1987; Hoehn and Yahr 1998; Hughes et al. 1992a Misdiagnosis is especially common during the early stages of the disease, even among movement disorder specialists (Litvan et al. 1996) The Movement Disorder Society Scientific Issues Committee suggested that this limitation could strongly affect the power of epidemiologic studies and clinical trials (Litvan et al. 2003) to detect a risk, by classifying individuals as cases when they should not be. A few studies found that pesticide exposure was not a significant risk factor after adjustment for confounding variables (Chan et al. 1998; Stern et al. 1991; Taylor et al. 1999; Werneck and Alvarenga 1999). In contrast, pesticide exposure was shown to be a significant risk factor after adjustment in several studies (Butterfield et al. 1993; Gorell et al. 1998; Hertzman et al. 1990; Hubble et al. 1993; Liou et al. 1997; Menegon et al. 1998; Seidler et al. 1996; Semchuk et al. 1992; Zorzon et al. 2002). These studies were not consistent in the variables used to adjust risk, and some did not include risk factors found to be associated with PD and related to pesticide exposure, such as rural living, well-water consumption, and farming as an occupation, which could result in residual confounding. Studies that have investigated these factors in relation to PD have found ORs to be generally of the same order and direction as those for pesticide exposure. Many studies have postulated that these factors and exposure to pesticides are closely linked and interrelated. However, there still remains uncertainty as to the exact nature of the relationship between farming, rural living, and pesticide exposure and their relationship to PD risk. Exposure assessment. Assessment of exposure to pesticides relied upon subjects recalling their lifetime exposures over some previous 20–30 years, leading potentially to differential recall bias. For individuals occupationally exposed to pesticides, the accuracy of their historical self-reported pesticide exposure was high for broad categories of pesticides and commonly used pesticides, but not for specific pesticides (Engel et al. 2001; Hoppin et al. 2002). However, the accuracy of recall for nonoccupational or residential exposure is questionable (Teitelbaum 2002) The questions used to assess pesticide exposure varied considerably between studies and in some reports were not given. A number of studies simply asked “Have you ever been exposed to pesticides?” the assessment of exposure in most studies does not take into account the timing of exposure compared with onset of symptoms, the dose of pesticide, the mechanism of exposure, or the chemical classes of the pesticides. Furthermore, the exposure category pesticides represents many hundreds of chemicals, and these may not be comparable between studies. It could be that exposure to only a few pesticide compounds results in an increased risk of developing PD At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure Given the complexity of the many factors and substances to which the populations described in the epidemiologic studies have been exposed, in this section we review experimental studies on relevant pesticides to gain an insight on whether single or groups of pesticides, or related substances, may contribute to the apparent increase in PD seen in these populations. Several factors to be considered when assessing the mechanistic evidence for a role for pesticides in PD development and to identify further candidate substances for consideration in experimental or epidemiologic studies: a) effects on the striatal dopaminergic system (these may include a decrease in dopamine levels and/or an increase in dopamine turnover as a shortterm compensatory mechanism, which would be identified by an increase in metabolites or the enzyme tyrosine hydroxylase); b) effects on the SN (most dopaminergic neurons are present in the basal ganglia, including the SN, and changes in the SN—although not necessarily specific—would be expected to occur with an agent involved in the development of PD); and c) mechanistic effects (for example, on oxidative stress, mitochondrial dysfunction/ complex I inhibition, and α-synuclein levels and aggregation. Rotenone Rotenone is a naturally occurring insecticide and is a well characterized, high-affinity specific inhibitor of complex I (NADH-dehydrogenase). It is extremely hydrophobic and crosses biologic membranes easily. Therefore, unlike MPTP, rotenone does not require a dopamine transporter (DAT) for access to the cytoplasm and therefore is likely to produce systemic inhibition of complex I (Betarbet et al. 2000). Continuous infusion of rats with rotenone reduces specific complex I binding by 75%, at a low free-rotenone concentration in the brain of about 20–30 nmol/L, accompanied by nigrostriatal dopaminergic lesions, suggesting that striatal nerve endings are affected earlier and more severely by rotenone than are nigral cell bodies (Betarbet et al. 2000). Rats with these lesions had cytoplasmic inclusions containing α-synuclein in the nigral neurons, which resembled the pale body precursors to Lewy bodies found in humans with PD. Rotenone-treated animals also developed motor and postural deficits characteristic of PD, the severity of which correlated with the extent of the pathologic lesions, even after cessation of the rotenone treatment. However, Betarbet et al. (2000) also reported that rotenone seems to have little toxicity when administered orally (Sherer TB, Greenamyre JT, unpublished data) Other experiments suggest that dopaminergic synapses in the SN pars compacta and in the nigrastriatal pathway are sensitive to the action of rotenone (Alam and Schmidt 2002). This is in contrast to the findings of Betarbet et al. (2000), who found that changes in the SN were later events. In behavioral tests, the treated animals showed a dose–dependent increase in catalepsy and decrease in locomotion. The authors surprisingly suggested that this (sub)chronic intraperitoneal dosing was comparable with chronic environmental exposure and was thus comparable with a real-life situation. In mice and rat neuron–glial cell cultures, a nontoxic or minimally toxic concentration of rotenone and the inflammatory agent lipopolysaccharide synergistically induced dopaminergic degeneration (Gao et al. 2003). Niehaus and Lange (2003) have suggested that inflammatory factors such as lipopolysaccharide might be an environmental factor in the development of PD. The presence of brain microglia has been implicated in rotenone neurotoxicity, and these cells release reactive oxygen species as well as inflammatory factors (Gao et al. 2002; Liu and Hong 2003). Paraquat. Paraquat is a nonselective contact herbicide with high pulmonary toxicity (Corasaniti et al. 1998). One of the major considerations in relation to the potential neurotoxicity of paraquat is the extent to which it can cross the blood–brain barrier (BBB). Paraquat is a charged molecule, which may not cross the BBB, and it is not metabolized to a species more likely to gain access to the brain (Sanchez-Ramos et al. 1987). Naylor et al. (1995) found that after subcutaneous administration to neonatal, adult, and aging rats, most of the paraquat associated with structures lying outside the BBB (pineal gland and linings of the cerebral ventricles) or without a BBB [anterior portions of olfactory bulb, hypothalamus, and area postrema (Naylor et al. 1995; Widdowson et al. 1996)]. Overall, paraquat did not appear to pose a major neurotoxicologic risk in brain areas with a functional BBB. However, in the only study identified in which paraquat was given orally, neonatal mice dosed on gestation days 10 and 11 showed hypoactivity and reductions in striatal dopamine and dopamine metabolite levels (Fredriksson et al. 1993); this contrasts with the increase in activity and dopaminergic systems associated with PD-like mechanisms. Other groups have reported that paraquat administered by intraperitoneal injection can cross an intact BBB (Corasaniti et al. 1998; Shimizu et al. 2001). Further experiments suggested the involvement of the neutral amino acid transporter in the carriage of paraquat into the brain, followed by transportation into striatal, possibly neuronal, cells, in a Na+-dependent manner (Shimizu et al. 2003). Inhibition of paraquat uptake into rat striatal tissues, including dopaminergic terminals, has also been shown to operate by a specific dopaminetransport inhibitor (Shimizu et al. 2001). Although not directly relevant to human exposure pathways, paraquat has been shown to be neurotoxic after direct injection into areas of the brain (Bagetta et al. 1992; Calò et al. 1990; Corasaniti et al. 1992, 1998; De Gori et al. 1988; Iannone et al. 1988, 1991). Depending on the brain region into which the paraquat was injected, it produced different behavioral patterns, increased locomotor activity, and caused convulsions; these effects were accompanied by neuronal cell death. In general, these studies suggest that paraquat neurotoxicity is not specific to the dopaminergic nigrostriatal system because effects were observed when paraquat was injected into regions of the brain where other neurotransmitter systems are located. Several studies have observed neurotoxicity after systemic administration of paraquat. An increase in dopaminergic neuronal death in the SN pars impacta was observed in treated rats, with no depletion in striatal dopamine but enhanced dopamine synthesis indicated by increased tyrosine hydroxylase activity (McCormack et al. 2002). The authors suggested that the apparent discrepancy between neurodegeneration and a lack of dopamine loss was probably a reflection of compensatory mechanisms by which neurons that survive damage were capable of restoring neurotransmitter tissue levels. When rats were treated intravenously with paraquat, the brains had lower complex I activity and higher levels of lipid peroxides (indicating free radical activity) and a lower level of dopamine in the striatum (Tawara et al. 1996). Mice treated with paraquat showed an up-regulation and aggregation of α-synuclein (Manning-Bog et al. 2002). However, the studies of Woolley et al. (1989) in mice and of Naylor et al. (1995) in rats The major pathologic feature of PD is the profound loss of pigmented neurons, mainly in the pars compacta of the substantia nigra (SN). Associated with this neuronal loss is the presence of large eosinophilic inclusions, called Lewy bodies, within the remaining pigmented neurons, made up of a series of proteins, including neurofilaments, α-synuclein fibrils, ubiquitin, parkin, and proteasomal elements. Combination of paraquat and maneb Maneb [manganese ethylenebisdithiocarbamate (manganese-EBDTC)] is a dithiocarbamate herbicide, and the areas of use of maneb and paraquat have a marked geographic overlap in the United States (Thiruchelvam et al. 2000a). Mice exposed to paraquat or maneb, either alone or in combination, showed a sustained decrease in motor activity only in the combined exposure groups, with increased striatal dopamine and dopamine metabolite levels immediately postinjection, decreasing after 7 days, and reduced levels of tyrosine hydroxylase and DAT in the dorsal striatum (Thiruchelvam et al. 2000a, 2000b). Combined exposure thus potentiated effects that appear to target the nigrostriatal dopaminergic systems. The authors suggested that mixtures of pesticides could play a role in the etiology of PD. In a series of studies on developmental exposure to the combined pesticides, mice had reduced motor activity and striatal dopamine levels (Thiruchelvam et al. 2002). Although the greatest loss of nigrostriatal dopaminergic cells was seen after combined treatment, there was significant loss with all treatments after rechallenge when adult, suggesting that a state of silent toxicity had been unmasked upon adult rechallenge. There was also evidence that prenatal exposure to maneb may lead to alterations of the nigrostriatal dopaminergic system and enhanced susceptibility to adult exposure to paraquat (Sherer et al. 2002). In a further study on mice of different ages using higher doses (Thiruchelvam et al. 2003), reduction in locomotor activity and motor coordination and reduction in dopamine metabolites and turnover were greatest in the oldest mice (18 months of age). The decrease in the number of nigrostriatal dopaminergic neurons was progressive, particularly in the oldest mice given paraquat and maneb in combination. The result demonstrates an enhanced sensitivity of the aging dopamine pathway particularly to paraquat and maneb. Dithiocarbamates. There is some evidence for the neurotoxicity of dithiocarbamates, including studies on the manganese-containing pesticide maneb, alone or in combination with paraquat. Although manganese has been shown to cause PD-like effects in workers at high occupational exposure, it affects the globus pallidus rather than the SN and is also resistant to the beneficial effects of L-dopa. However, neurotoxic effects have been observed in toxicologic studies with the nonmanganese- containing parent compound, EBDTC, from which maneb is derived (McGrew et al. 2000). Cyclodienes. Bloomquist and colleagues have carried out studies examining possible effects of the organochlorine cyclodiene pesticides, in particular, dieldrin and heptachlor, on possible biomarkers of PD. Heptachlor increased the maximal rate of striatal dopamine uptake, which was attributed to induction of the DAT and a compensatory response to elevated synaptic levels of dopamine (Bloomquist et al. 1999; Kirby et al. 2001; Miller et al. 1999). Kirby et al. (2001) suggested that heptachlor and perhaps other organochlorine pesticides exert selective effects on striatal dopaminergic neurons and may play a role in the etiology of PD. There is some evidence that dieldrin may interfere with electron transport and increase the generation of superoxide radicals (Stedeford et al. 2001). In proliferating PC12 cells exposed to dieldrin, there was evidence for increased oxidative stress. In mesencephalic cell cultures (Sanchez-Ramos et al. 1998) and PC12 cells (Kitazawa et al. 2001), there was a rapid release of dopamine and its metabolite, followed by apoptotic cell death. Although the convulsant and proconvulsant actions of endosulfan have been attributed to an antagonistic action on GABA, a dopaminergic involvement has been suggested for its induction of hypermotor activity and circling movement (Ansari et al. 1987; Paul and Balasubramaniam 1997). Administration of endosulfan during gestation and lactation in rats up to 2–3 weeks of age produced a significant decrease in the affinity and maximum numbers of striatal dopaminergic receptors without affecting other receptor profiles, suggesting that dopaminergic receptors are unusually sensitive to the action of endosulfan (Seth et al. 1986). Pyrethroids. During investigations into the possible involvement of the pyrethroid permethrin and the organophosphate chlorpyrifos on the etiology of PD and Gulf War illness, mice treated with permethrin showed increased dopamine uptake at low doses (e.g., 134% at 1.5 mg/kg), whereas at higher doses dopamine uptake was depressed [e.g., 50% at 25 mg/kg (Karen et al. 2001)]. Reduced mitochondrial function was observed in in vivo synaptosome preparations, and although striatal dopamine levels were not decreased, there was an increased dopamine turnover and decreased motor activity. Although frank parkinsonism was not observed, dopaminergic neurotransmission was affected by exposure to permethrin. Mice treated with deltamethrin showed a 70% increase in maximal dopamine uptake in ex vivo synaptosomes suggestive of an up-regulation in DAT expression (Kirby et al. 1999). Unlike MPTP, deltamethrin did not decrease dopamine, although there was some evidence of increased turnover. When the pyrethroid insecticide fenvalerate was given orally to rats, there was a pronounced, but not dose-related, inhibition of dopamine and its metabolites and decreased dopamine binding in several brain regions, including the corpus striatum (Husain et al. 1991). In another study, fenvalerate or cypermethrin given during gestation and lactation to pregnant and nursing dams (Malaviya et al. 1993) showed a significant increase in dopamine and muscarinic receptors of striatal membranes in the pups. Malaviya et al. (1993) suggested that the findings demonstrated disturbance of both the dopaminergic and cholinergic pathways. Other pesticides. Although there is evidence for neurotoxic effects of some other pesticides, all the mechanistic systems seen in PD are not consistently effected Interaction of pesticides with α-synuclein. The formation of Lewy bodies may be integral to the cause of the disease rather than being an accompanying effect. Studies in vitro have suggested that a number of pesticides (alone or in combination with certain metals) may induce a conformational change in α-synuclein and accelerate the formation of α-synuclein fibrils (Uversky et al. 2001, 2002). Pesticides known to induce this effect are hydrophobic and include rotenone, DDT, 2,4-dichlorophenoxyacetic acid, dieldrin, diethyldithiocarbamate, paraquat, maneb, trifluralin, parathion, and imidazoldinethione; those having no significant effect include iprodione, glyphosate, methomyl, thiuram, mevinphos, carbaryl, alachlor, thiobencarb, and also MPP+ Conclusions The epidemiologic studies suggest a relatively consistent association between exposure to pesticides and an increased risk of developing PD, despite differences in study design, case ascertainment and definition, control selection, and pesticide exposure assessment. Particular classes of pesticides found to be associated with PD include herbicides, particularly paraquat, and insecticides; evidence from case reports and case–control studies for an association with exposure to fungicides alone is equivocal. Duration of exposure has also been found to be a risk factor, with those exposed to pesticides for > 10 or 20 years being associated with a increased risk of developing PD. However, in addition to pesticides, several other risk factors are associated with an increased risk of developing PD, including rural living, well-water consumption, and farming. We found no studies that have been able to determine whether these risk factors are independent risk factors or correlated with pesticide exposure. The toxicologic evidence suggests that, with certain routes of administration, rotenone and paraquat may have neurotoxic actions that could potentially play a role in the development of PD. These include effects on dopaminergic systems in the SN, and α-synuclein aggregation. There is also some evidence that the mechanisms of neurotoxicity associated with exposure to pyrethroids are those that would be suggestive of a role in the development of PD and that dithiocarbamates may interact with other xenobiotic agents to increase neurotoxicity. Studies on various other pesticides suggest that, while they have neurotoxic actions, they do not act on systems in the brain of relevance to PD. However, many of these studies reviewed were designed to elicit acute toxicity in order to study the mechanisms of action. We identified no study that administered pesticides at levels comparable with those encountered by pesticides users, nor were the routes of administration those that would be experienced by pesticide users (i.e., oral, inhalation, or dermal). As a result, it is difficult to interpret the relevance of such studies to humans, although the difficulty in modeling a disease such as PD is acknowledged. Of potential toxicologic importance are the few studies that reported dopaminergic neurotoxicity after combined low-level exposure to multiple environmental neurotoxicants, including paraquat and maneb, the combined effects of pesticides and metals on α-synuclein, and rotenone and lipopolysaccharide (which may be present due to inflammation or infection). For example, although PD is a disease of aging, the studies of Thiruchelvam et al. (2003) on the developmental exposure to maneb and paraquat indicate that early exposure may lead to PD-like toxic effects upon adult rechallenge. Such studies suggest that exposure to multiple low-level environmental neurotoxicants, perhaps at an early age, may be an etiologic factor in the development of PD. Recent toxicologic studies have suggested that multiple genetic and environmental factors could be involved in the etiology of PD. Studies with transgenic mice suggest that the genetic background and expression of the α-synuclein gene may have a role to play in neurodegeneration of the SN (Thiruchelvam et al. 2004) and may also lead to increased vulnerability to the neurotoxic effects of the pesticides maneb and paraquat. There is evidence that developmental exposure to pesticides may have an increased neurodegenerative effect as well as making the SN more susceptible to subsequent adult exposure to pesticides, and that combined exposure to pesticides such as maneb and paraquat has a greater neurotoxic effect than either pesticide alone (Cory- Slechta et al. 2005). Other recent studies also suggest some interaction between the neurodegenerative effects of pesticides and inflammatory proteins produced by microglia in the SN (Gao et al. 2003, Liu and Hong 2003). These genetic and environmental factors could be considered in future epidemiologic studies of this multifactorial disease. Most of the epidemiologic studies that we reviewed used a case–control design with relatively small numbers of cases. Pesticide exposure history was, by necessity, collected retrospectively, generally using questionnaires. Information and recall bias are inherent limitations of this type of design. The exposure assessments were also limited in their collection of information on the types of pesticides, specific chemicals, and levels of exposure experienced. Of all the studies we reviewed, the two most reliable were large case–control studies that attempted to investigate exposure to different groups of pesticides (Semchuk et al. 1992; Seidler et al. 1996). Despite these considerations, it seems unlikely that the relatively consistent association between PD and reported exposure to pesticides observed in the epidemiology studies could be explained wholly by a combination of chance, bias and confounding, and selective reporting. The toxicologic literature indicates several areas that would benefit from further research, including the effect of exposure at different ages, early exposure and developmental changes, the role of inflammatory disease, and the potential for gene–environment interactions. Epidemiologic studies of an appropriate design and size, that collect detailed information on exposure to specific pesticides and other chemicals, including early life exposures, would be required to investigate these issues. Studies to date have not had sufficient power to disentangle the relative importance of intercorrelated risk factors and to evaluate each risk with any confidence. We are aware of several ongoing studies that are addressing some of these areas of concern. In conclusion, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists, but it is not sufficient to conclude that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined exposure to pesticides and other exogenous toxicants. In addition, the multifactorial etiology of PD hampers unequivocally establishing the role of any individual contributory causal factor. I believe so, but am not sure....

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