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| ==Pathophysiology== | | ==Pathophysiology== |
| In the brain the direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of [[dopamine]] results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to [[hypokinesia]].
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| 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. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
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| The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein [[alpha-synuclein]] bound to ubiquitin in the damaged cells. The [[alpha-synuclein]]-ubiquitin complex cannot be directed to the proteosome. This [[protein]] accumulation forms proteinaceous cytoplasmic inclusions called [[Lewy bodies]]. Latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.<ref>"Parkinson's Disease Mechanism Discovered," [http://www.hhmi.org/news/lindquist20060622.html HHMI Research News] June 22, 2006.</ref>
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| Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to [[neuromelanin]] in the affected neurons of the [[substantia nigra]]. So, [[neuromelanin]] may be acting as a protective agent. Alternately, neuromelanin (an electronically active semiconductive polymer) may play some other role in neurons.<ref>{{cite journal | author = McGinness J, Corry P, Proctor P | title = Amorphous semiconductor switching in melanins. | journal = Science | volume = 183 | issue = 127 | pages = 853-5 | year = 1974 | pmid = 4359339 | url=http://www.drproctor.com/os/amorphous.htm | format=Reprint}}</ref> That is, coincidental excessive accumulation of transition metals, etc. on [[neuromelanin]] may figure in the differential dropout of pigmented neurons in Parkinsonism. The most likely mechanism is generation of [[reactive oxygen species]].<ref name="Jenner1998">{{cite journal | author = Jenner P | title = Oxidative mechanisms in nigral cell death in Parkinson's disease. | journal = Mov Disord | volume = 13 Suppl 1 | issue = | pages = 24-34 | year =1998 | pmid = 9613715}}</ref>
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| Iron induces aggregation of synuclein by oxidative mechanisms.<ref>{{cite journal | author = Kaur D, Andersen J | title = Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility? | journal = Aging Cell | volume = 1 | issue = 1 | pages = 17-21 | year = 2002 | pmid = 12882349 | url=http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1474-9728.2002.00001.x | format=PDF}}</ref> Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a [[Genetically modified organism|transgenic mouse model]] of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the [[Platelet-derived growth factor|platelet-derived-growth factor]]-β promoter.<ref>{{cite journal |author=Masliah E, Rockenstein E, Veinbergs I, ''et al'' |title=Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders |journal=Science |volume=287 |issue=5456 |pages=1265-9 |year=2000 |pmid=10678833 |doi=}}</ref>
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| <gallery>
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| Image:DA-loops in PD.jpg|Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.
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| </gallery>
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| The symptoms of Parkinson's disease result from the loss of pigmented [[dopamine]]-secreting (dopaminergic) cells, secreted by the same cells, in the [[substantia nigra|pars compacta]] region of the [[substantia nigra]] (literally "black substance"). These neurons project to the [[striatum]] and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the [[direct pathway]] and excitation of the [[indirect pathway]].
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| ===Genetic===
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| In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations ([[Contursi]], Italy). 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.
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| Genetic forms that have been identified include:
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| :''external links in this section are to [[OMIM]]''
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| {| class="wikitable"
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| | '''Type''' || '''OMIM''' || '''[[Locus (genetics)|Locus]]''' || '''Details'''
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| | ''PARK1'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=168601 OMIM #168601] || 4q21 || caused by mutations in the ''[[SNCA]]'' gene, which codes for the [[protein]] [[alpha-synuclein]]. PARK1 causes [[autosomal dominant]] Parkinson disease. So-called ''PARK4'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605543 OMIM #605543]) is probably caused by triplication of ''SNCA''.<ref>{{cite journal |author=Singleton AB, Farrer M, Johnson J, ''et al'' |title=alpha-Synuclein locus triplication causes Parkinson's disease |journal=Science |volume=302 |issue=5646 |pages=841 |year=2003 |pmid=14593171 |doi=10.1126/science.1090278}}</ref>
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| | ''PARK2'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602544 OMIM *602544] || 6q25.2-q27 || caused by mutations in protein [[Parkin (ligase)|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.<ref>{{cite journal | author=Poorkaj P ''et al.'' | title=''parkin'' mutation analysis in clinic patients with early-onset Parkinson's disease | journal=American Journal of Medical Genetics Part A | year=2004 | volume=129A |
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| issue=1 | pages= 44–50 | url=http://www3.interscience.wiley.com/cgi-bin/abstract/109062750/ABSTRACT?CRETRY=1&SRETRY=0}}</ref> 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).<ref>{{cite journal | author=Ebba Lohmann ''et al.'' | title=How much phenotypic variation can be attributed to parkin genotype? | journal=Annals of Neurology | year=2003 | volume=54 | issue=2 | pages= 176–185|url=http://www3.interscience.wiley.com/cgi-bin/abstract/104536414/ABSTRACT | pmid = 12891670}}</ref>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.
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| | ''PARK3'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602404 OMIM %602404] || 2p13 || autosomal dominant, only described in a few kindreds.
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| | ''PARK5'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191342 OMIM +191342] || 4p14 || caused by mutations in the ''UCHL1'' gene which codes for the protein [[ubiquitin carboxy-terminal hydrolase L1]]
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| | ''PARK6'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM #605909] || 1p36 || caused by mutations in ''PINK1'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM *608309]) which codes for the protein [[PTEN-induced putative kinase 1]].
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| | ''[[PARK7]]'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606324 OMIM #606324] || 1p36 || caused by mutations in [[PARK7|DJ-1]] ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602533 OMIM 602533])
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| | ''PARK8'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607060 OMIM #607060] || 12q12 || 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.<ref>{{cite journal | author=Smith WW ''et al.'' | title=Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration | journal=[[Proceedings of the National Academy of Sciences of the United States of America]] | year=2005 | volume=102 | issue=51 | pages= 18676–18681 | url=http://www.pnas.org/cgi/content/abstract/102/51/18676 | pmid = 16352719}}</ref> LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a [[penetrance]] of nearly 100% by age 80.<ref>{{cite journal |author=Kachergus J, Mata IF, Hulihan M, ''et al'' |title=Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations |journal=Am. J. Hum. Genet. |volume=76 |issue=4 |pages=672-80 |year=2005 |pmid=15726496 |doi=10.1086/429256}}</ref> G2019S is the most common known genetic cause of Parkinson disease, found in 1-6% of U.S. and European PD patients.<ref>{{cite journal |author=Brice A |title=Genetics of Parkinson's disease: LRRK2 on the rise |journal=Brain |volume=128 |issue=Pt 12 |pages=2760-2 |year=2005 |url=http://brain.oxfordjournals.org/cgi/content/extract/128/12/2760 |pmid=16311269 |doi=10.1093/brain/awh676}}
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| </ref> It is especially common in Ashkenazi Jewish patients, with a prevalence of 29.7% in familial cases and 13.3% in sporadic.<ref>{{cite journal | author = Ozelius L, Senthil G, Saunders-Pullman R, ''et al'' | title = LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. | journal = N Engl J Med | volume = 354 | issue = 4 | pages = 424-5 | year = 2006 | pmid = 16436782}}</ref>
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| | ''PARK9'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606693 OMIM #606693] || 1p36 || Caused by mutations in the ''ATP13A2'' gene, and also known as Kufor-Rakeb Syndrome. PARK9 may be allelic to PARK6.
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| | ''PARK10'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606852 OMIM %606852] || 1p || -
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| | ''PARK11'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607688 OMIM %607688] || 2q36-37 || However, this gene locus has conflicting data, and may not have significance.
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| | ''PARK12'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300557 OMIM %300557] || Xq21-q25 || -
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| | ''PARK13'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610297 OMIM #610297] || 2p12 || Caused by mutations in the ''HTRA2'' ([[HtrA serine peptidase 2]]) gene.
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| |}
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| ===Toxins===
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| One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental [[toxin]]s along with exposure to those toxins.<ref>{{cite journal |author=Di Monte DA, Lavasani M, Manning-Bog AB |title=Environmental factors in Parkinson's disease |journal=Neurotoxicology |volume=23 |issue=4-5 |pages=487-502 |year=2002 |pmid=12428721 |doi=}}</ref> This hypothesis is consistent with the fact that Parkinson's disease is not distributed homogeneously throughout the population: rather, its incidence varies geographically. It would appear that incidence varies by time as well, for although the later stages of untreated PD are distinct and readily recognizable, the disease was not remarked upon until the beginnings of the Industrial Revolution, and not long thereafter become a common observation in clinical practice. The toxins most strongly suspected at present are certain [[pesticide]]s and transition-series metals such as manganese or iron, especially those that generate [[reactive oxygen species]],<ref name="Jenner1998">{{cite journal |author=Jenner P |title=Oxidative mechanisms in nigral cell death in Parkinson's disease |journal=Mov. Disord. |volume=13 Suppl 1 |issue= |pages=24-34 |year=1998 |pmid=9613715 |doi=}}</ref><ref>{{cite journal |author=Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G |title=Neuroprotective strategies in Parkinson's disease: protection against progressive nigral damage induced by free radicals |journal=Neurotoxicity research |volume=2 |issue=2-3 |pages=293-310 |year=2000 |pmid=16787846 |doi=}}</ref>
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| and or bind to [[neuromelanin]], as originally suggested by G.C. Cotzias.<ref>{{cite journal | author = Cotzias G | title = Manganese, melanins and the extrapyramidal system. | journal = J Neurosurg | volume = 24 | issue = 1 | pages = Suppl:170-80 | year = 1966 | pmid = 4955707}}</ref><ref>{{cite journal | author = Barbeau A | title = Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). | journal = Neurotoxicology | volume = 5 | issue = 1 | pages = 13-35 | year = 1984 | pmid = 6538948}}</ref>. In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed<ref>{{cite journal | author = Ascherio A, Chen H, Weisskopf M, ''et al'' | title = Pesticide exposure and risk for Parkinson's disease. | journal = Ann Neurol | volume = 60 | issue = 2 | pages = 197-203 | year = 2006 | pmid = 16802290}}</ref>.
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| [[MPTP]] is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age. MPTP was notorious for a string of Parkinson's disease cases in California in 1982 when it contaminated the illicit production of the synthetic opiate [[MPPP]]. Its toxicity likely comes from generation of [[reactive oxygen species]] through tyrosine hydroxylation.<ref>{{cite journal | author = Chiueh C, Wu R, Mohanakumar K, Sternberger L, Krishna G, Obata T, Murphy D | title = ''In vivo'' generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. | journal = Ann N Y Acad Sci | volume = 738 | issue = | pages = 25-36 | year = 1994 |pmid = 7832434}}</ref>
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| Other toxin-based models employ PCBs,<ref>{{cite news
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| |first=Leslie
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| |last=Orr
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| |title=PCBs, fungicide open brain cells to Parkinson's assault
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| |date=February 10, 2005
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| |publisher=[[Medical News Today]]
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| |url=http://www.medicalnewstoday.com/medicalnews.php?newsid=19791
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| }}</ref> [[paraquat]]<ref>{{cite journal |author=Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA |title=The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein |journal=J. Biol. Chem. |volume=277 |issue=3 |pages=1641-4 |year=2002 |pmid=11707429 |doi=10.1074/jbc.C100560200 | url=http://www.jbc.org/cgi/content/full/277/3/1641}}</ref> (a herbicide) in combination with maneb (a fungicide)<ref>{{cite journal |author=Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA |title=The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease |journal=J. Neurosci. |volume=20 |issue=24 |pages=9207-14 |year=2000 |pmid=11124998 |url=http://www.jneurosci.org/cgi/content/full/20/24/9207
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| }}</ref> [[rotenone]]<ref>{{cite journal |author=Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT |title=Chronic systemic pesticide exposure reproduces features of Parkinson's disease |journal=Nat. Neurosci. |volume=3 |issue=12 |pages=1301-6 |year=2000 |pmid=11100151 |doi=10.1038/81834}}</ref> (an insecticide), and specific organochlorine pesticides including dieldrin<ref>{{cite journal |author=Kitazawa M, Anantharam V, Kanthasamy AG |title=Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells |journal=Free Radic. Biol. Med. |volume=31 |issue=11 |pages=1473-85 |year=2001 |pmid=11728820 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T38-44HSN76-P&_coverDate=12%2F01%2F2001&_alid=373422978&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4940&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=5a104ac89bd7948e14863371142a639a
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| }}</ref> and lindane.<ref>{{cite journal |author=Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D |title=Organochlorine insecticides in substantia nigra in Parkinson's disease |journal=J. Toxicol. Environ. Health Part A |volume=59 |issue=4 |pages=229-34 |year=2000 |pmid=10706031
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| |url=http://journalsonline.tandf.co.uk/openurl.asp?genre=article&eissn=1087-2620&volume=59&issue=4&spage=229
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| }}</ref> Numerous studies have found an increase in PD in persons who consume rural well water; researchers theorize that water consumption is a proxy measure of pesticide exposure. In agreement with this hypothesis are studies which have found a dose-dependent an increase in PD in persons exposed to agricultural chemicals.
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| ===Head trauma===
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| Past episodes of head trauma are reported more frequently by sufferers than by others in the population.<ref name=Bower>{{cite journal |author=Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA |title=Head trauma preceding PD: a case-control study |journal=Neurology |volume=60 |issue=10 |pages=1610-5 |year=2003 |pmid=12771250 | url=http://www.neurology.org/cgi/content/abstract/60/10/1610}}</ref><ref>{{cite journal |author=Stern M, Dulaney E, Gruber SB, ''et al'' |title=The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients |journal=Arch. Neurol. |volume=48 |issue=9 |pages=903-7 |year=1991 |pmid=1953412 url=http://archneur.ama-assn.org/cgi/content/abstract/48/9/903}}</ref><ref name="Uryu2003">{{cite journal |author=Uryu K, Giasson BI, Longhi L, ''et al'' |title=Age-dependent synuclein pathology following traumatic brain injury in mice |journal=Exp. Neurol. |volume=184 |issue=1 |pages=214-24 |year=2003 |pmid=14637093 |doi=}}</ref>
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| A methodologically strong recent study<ref name=Bower/> found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects. These limitations were overcome recently by Tanner and colleagues,<ref>{{cite journal |author=Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW |title=Head injury and Parkinson's disease risk in twins |journal=Ann. Neurol. |volume=60 |issue=1 |pages=65-72 |year=2006 |pmid=16718702 |doi=10.1002/ana.20882}}</ref> who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization.
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| ===Drug-induced===
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| [[Antipsychotics]], which are used to treat [[schizophrenia]] and psychosis, can induce the symptoms of Parkinson's disease (or parkinsonism) by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
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| ==Associated Disorders==
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| There are other disorders that are called ''[[Parkinson plus syndrome|Parkinson-plus diseases]]''. These include:
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| * [[Multiple system atrophy]] (MSA)
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| * Progressive supranuclear palsy (PSP)
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| * Corticobasal degeneration (CBD)
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| Some people include dementia with Lewy bodies (DLB) as one of the 'Parkinson-plus' syndromes. Although idiopathic Parkinson's disease patients also have Lewy bodies in their brain tissue, the distribution is denser and more widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) might be most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders. The natural history and role of Lewy bodies is very little understood.
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| Patients often begin with typical Parkinson's disease symptoms which persist for some years; these Parkinson-plus diseases can only be diagnosed when other symptoms become apparent with the passage of time. These Parkinson-plus diseases usually progress more quickly than typical ideopathic Parkinson disease. The usual anti-Parkinson's medications are typically either less effective or not effective at all in controlling symptoms; patients may be exquisitely sensitive to neuroleptic medications like [[haloperidol]]. Additionally, the cholinesterase inhibiting medications have shown preliminary efficacy in treating the cognitive, psychiatric, and behavioral aspects of the disease, so correct differential diagnosis is important.
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| [[Wilson's disease]] (hereditary copper accumulation) may present with parkinsonistic features; young patients presenting with parkinsonism may be screened for this rare condition. [[Essential tremor]] is often mistaken for Parkinson's disease but usually lacks all features besides tremor.
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| [[Torsion dystonia]] is another disease related to Parkinson's disease.
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| ==References== | | ==References== |