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'''Parkinson's disease''' ('''PD''', also known as '''idiopathic parkinsonism''') is a [[Neurodegeneration|degenerative]] disorder of the [[central nervous system]] mainly affecting the [[motor system]]. Many of the motor symptoms of PD result from the loss of pigmented [[dopamine]]-generating cells in the [[substantia nigra]], a region of the [[midbrain]]. The causes of this [[cell death]] are poorly understood. A progressive reduction in the speed and amplitude of voluntary movement is the only physical sign present in all patients and is responsible for the common early complaints of loss of dexterity, writing difficulties, clumsiness and difficulty walking. Muscular stiffness of the limbs and trunk are also common. Trembling or tremor of one limb at rest, although not necessarily present in all cases, is the commonest symptom leading to accurate diagnosis. Dysfunction of the autonomic nervous system is also common leading to constipation, swallowing and bladder problems and disturbed temperature regulation with excessive sweating. Depression may be an early sign of the disease and frequently develops as a reaction to increasing disability and social isolation. In elderly patients there is an increased risk of cognitive impairment and dementia. Parkinson's disease is more common in older people, with most cases occurring after the age of 60; when it is seen under the age of 45 years, it is called young onset PD.

The main motor symptoms are collectively called '''parkinsonism''', or a "parkinsonian syndrome". Probably fewer than 5% of cases have a clear [[genetics|genetic]] origin, while secondary [[parkinsonism]] is due to known causes like drugs toxins and [[cerebrovascular disease]]. Many risks and protective factors have been investigated but the strongest evidence is for a reduced risk in tobacco smokers (although this may be due to individuals predisposed to PD being less prone to smoking addiction). The [[pathology]] of the disease is believed to be due to the accumulation of abnormal [[protein]]s in [[neuron|nerve cells]]s leading to eventual cell death. The aggregated protein forms microscopic [[Cytoplasmic inclusion|inclusions]] known as Lewy bodies that can be found in the substantia nigra. Bradykinesia and rigidity result from loss of dopamine containing cells in the [[substantia nigra]]. The diagnosis of Parkinson’s disease is based on accurate history taking and a neurological examination. Neuroimaging including CT and MR imaging is useful to exclude other disorders masquerading as Parkinsons disease and dopamine transporter imaging (SPECT scans) can be helpful when the clinical diagnosis is uncertain.

<!-- Treatment -->
[[L-dopa]], the natural [[Precursor (chemistry)|precursor]] of dopamine is the most effective treatment but other drugs including dopamine [[agonist]]s, and [[selective monoamine oxidase inhibitior]]s are useful [[adjuvant]] treatments.  As the disease progresses and [[dopaminergic]] neurons and a variety of other types of neurons continue to be lost, dopaminergic drugs remain effective for most motor symptoms related to dopamine deficiency but the response can vary from hour to hour (motor fluctuations) and most patients also experience the [[side effect|complication]] of involuntary writhing movements ([[dyskinesia]]s). Surgery such as [[deep brain stimulation]], and continuous infusions of dopaminergic drugs such as [[apomorphine]] and [[enteral levodopa]] infusion gels have been used to reduce motor symptoms in cases where oral medications have been ineffective in providing smooth control of dopamine-responsive motor symptoms or where severe tremor or dyskinesias cause disability. Medications to treat non-movement-related symptoms of PD, such as sleep disturbances, bowel and bladder symptoms, drooling of saliva and emotional problems are available. Diet and some forms of rehabilitation have also shown some effectiveness at improving symptoms. Research directions include investigations into new [[animal model]]s of the disease and of the potential usefulness of [[gene therapy]], [[stem cell]] implants and [[neuroprotective]] agents. 

<!-- Epidemiology, history and society -->
The disease is named after the English apothecary surgeon James Parkinson, who published the first detailed description in ''An Essay on the Shaking Palsy'' in 1817.<ref name="An Essay on the Shaking Palsy">{{cite web|url=http://www.gutenberg.org/files/23777/23777-h/23777-h.htm|title=An Essay on the Shaking Palsy|publisher=}}</ref><ref>{{cite journal|name-list-style=vanc|last1=Shulman |first1=Joshua M. |last2=De Jager | first2=Philip L. | last3=Feany | first3=Mel B.|title=Parkinson's disease: genetics and pathogenesis.|journal=Annual Review of Pathology |date=February 2011 |origyear=25 October 2010 | volume=6 |pages=193–222 |pmid=21034221 |doi=10.1146/annurev-pathol-011110-130242}}</ref> Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson's disease day (on the birthday of James Parkinson, 11 April) and the use of a red tulip as the symbol of the disease. People with parkinsonism who have increased the public's awareness of the condition include actor Michael J. Fox, Olympic cyclist Davis Phinney, England football player Ray Kennedy and professional boxer Muhammad Ali.

==Classification==
Parkinsonism is defined as the presence of [[bradykinesia]] (slowness of initiation of movement and motor decrement on repetitive movement) in combination with one of three other physical signs namely muscular ( lead pipe or cogwheel) rigidity, a rest tremor and postural instability.
#

Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause.<ref name="pmid15172778"/><ref name="Jankovic_book-Epidemiology">{{cite book |name-list-style=vanc | last = Schrag | first = Anette |chapter=Epidemiology of movement disorders |editor1-last=Tolosa | editor1-first=E | editor2-last= Jankovic | editor2-first=Joseph J. | title=Parkinson's disease and movement disorders |publisher=Lippincott Williams & Wilkins |location=Hagerstown, Maryland |year=2007 |pages= 50–66 |isbn=978-0-7817-7881-7}}</ref> These identifiable causes may include side of effects of drugs, toxins, infections, metabolic derangement and strategic brain lesions such as strokes. Several neurodegenerative disorders may also present with Parkinsonism and are sometimes referred to as atypical Parkinsonism or Parkinson’s plus syndromes. They include [[multiple system atrophy]], [[progressive supranuclear palsy]], [[corticobasal degeneration]] and [[dementia with Lewy bodies]]. There are also cases of Parkinsonism where the cause has been identified, including gene mutations. 

Scientists sometimes refer to Parkinson’s disease as a [[synucleinopathies|synucleinopathy]] due to an abnormal accumulation of [[alpha-synuclein]] protein in the brain to distinguish it from other neurodegenarations such as [[Alzheimer's disease]] where the brain accumulates [[tau protein]] in the form of [[neurofibrillary tangle]]s, and [[beta amyloid]] in the form of plaques.<ref name="pmid16489609">{{cite journal |name-list-style=vanc | last1=Galpern | first1=Wendy R. | last2=Lang | first2=Anthony E. | title=Interface between tauopathies and synucleinopathies: a tale of two proteins |journal=[[Annals of Neurology]] |volume=59 |issue=3 |pages=449–458 |date=March 2006 | origyear=17 February 2006 |pmid=16489609 |doi=10.1002/ana.20819 | s2cid=19395939 }}</ref> Considerable clinical and pathological overlap exists between [[tauopathy|tauopathies]] and synucleinopathies. The most typical symptom of Alzheimer's disease is [[dementia]].<ref name="pmid16489609"/>

[[Dementia with Lewy bodies]] (DLB) is another synucleinopathy that has close pathological similarities with PD, and especially with the subset of PD cases with dementia. However, the relationship between PD and DLB is complex and still has to be clarified.<ref name="pmid19173762"/> They may represent parts of a continuum with variable distinguishing clinical and pathological features or they may prove to be separate diseases.<ref name="pmid19173762">{{cite journal |name-list-style=vanc | last1=Aarsland | first1=Dag | last2=Londos | first2=E. | last3=Ballard | first3=Clive |title=Parkinson's disease dementia and dementia with Lewy bodies: different aspects of one entity |journal=[[International Psychogeriatrics|Int. Psychogeriatr.]] |volume=21 |issue=2 |pages=216–219 |date=April 2009 | origyear=28 January 2009 |pmid=19173762 |doi=10.1017/S1041610208008612 | s2cid=5433020 }}</ref>

==Signs and symptoms==
[[File:Paralysis agitans-Male Parkinson's victim-1892.jpg|thumb|A man with Parkinson's disease displaying a flexed walking posture pictured in 1892.<ref>Photo by Arthur Londe from ''Nouvelle Iconographie de la Salpètrière'', vol. 5., p.226</ref> |alt=Black and white picture of male with PD stooping forward as he walks. He is viewed from the left side and there is a chair behind him.]]
[[File:Writing by a Parkinson's disease patient.png|thumb|Handwriting of a person affected by PD<ref>{{cite book |title=Lectures on the diseases of the nervous system |last1=Charcot |first1=Jean-Martin |last2=Sigerson |first2=George |date=1879 |location=Philadelphia |publisher= Henry C. Lea |edition=Second |page=113 |quote=The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. (...) the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal — the finer up-strokes, on the contrary, are all tremulous in appearance (...).}}</ref>|alt=French signature reads "Catherine Metzger 13 Octobre 1869"]]
{{Main|Signs and symptoms of Parkinson's disease}}
The most recognizable symptoms in Parkinson's disease affect the initiation and fluency of movement, giving rise to motor symptoms.<ref name=Jankovic2008/> Non-motor symptoms, which include [[autonomic nervous system|autonomic dysfunction]], [[neuropsychiatry|neuropsychiatric]] problems (mood, cognition, behavior or thought alterations), and sensory (especially altered sense of smell) and sleep difficulties, are also common. Some of these non-motor symptoms are often present at the time of diagnosis.<ref name=Jankovic2008/>

===Motor===
{{Further2|[[Parkinsonian gait]]}}

[[Tremor]] is the most apparent and well-known symptom.<ref name=Jankovic2008/> It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses.<ref name=Jankovic2008/> It is usually a rest tremor:  maximal when the limb is at rest and disappearing with voluntary movement and sleep.<ref name=Jankovic2008/> It affects to a greater extent the most [[Anatomical terms of location#Proximal and distal|distal]] part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later.<ref name=Jankovic2008/> Frequency of PD tremor is between 4 and 6 [[hertz]] (cycles per second). A feature of tremor is ''pill-rolling'', the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement.<ref name=Jankovic2008/><ref name="Cooper"/> The term derives from the similarity between the movement in people with PD and the early pharmaceutical technique of manually making pills.<ref name="Cooper">{{cite book |name-list-style=vanc | last1=Cooper | first1=G. | last2=Eichhorn | first2=G. | last3=Rodnitzky | first3=R. L. |chapter=Parkinson's disease | editor-last=Conn | editor-first=P. Michael | title=Neuroscience in medicine|publisher=Humana Press|location=Totowa, NJ|year=2008 |pages= 508–512|isbn=978-1-60327-454-8}}</ref>

[[Bradykinesia]] (slowness of movement) is found in every case of PD, and is due to disturbances in motor planning of movement initiation, and associated with difficulties along the whole course of the movement process, from planning to initiation and execution of a movement.<ref name=Jankovic2008/> Performance of sequential and simultaneous movement is impaired.<ref name=Jankovic2008/> Bradykinesia is the most handicapping symptom of Parkinson’s disease leading to difficulties with everyday tasks such as dressing, feeding and bathing. It leads to particular difficulty in carrying out two independent motor activities at the same time and can be made worse by emotional stress  or intercurrent illnesses. Paradoxically patients with Parkinsons disease can often ride a bicycle or climb stairs more easily than walk on a level. While most physicians may readily notice bradykinesia, formal assessment requires a patient to do repetitive movements with their fingers and feet.

[[Hypokinesia|Rigidity]] is stiffness and resistance to limb movement caused by increased [[muscle tone]], an excessive and continuous contraction of muscles.<ref name=Jankovic2008/> In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).<ref name=Jankovic2008/><ref name="pmid15172778"/><ref name="Banich">{{cite book |name-list-style=vanc | last1=Banich | first1=Marie T. | last2=Compton | first2=Rebecca J. |chapter=Motor control | title=Cognitive neuroscience|publisher=Wadsworth, Cengage learning|location=Belmont, CA|year=2011 |pages= 108–144|isbn=978-0-8400-3298-0}}</ref><ref>{{cite book|title=Oxford Handbook of Clinical Medicine|page=486 |date=4 January 2007 |publisher=[[Oxford University Press]] |name-list-style=vanc | last1= Longmore|first1=Murray|last2= Wilkinson|first2=Ian B.|last3= Turmezei|first3=Tom|last4=Cheung|first4=Chee Kay |isbn=978-0-19-856837-7}}</ref> The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.<ref name="Jankovic_book-Rigidity">{{Cite book |name-list-style=vanc | last1=Fung | first1=Victor S. C. | last2=Thompson | first2=Philip D. | chapter=Rigidity and spasticity | editor1-last=Tolosa | editor1-first=Eduardo | editor2-last=Jankovic | title=Parkinson's disease and movement disorders | publisher=Lippincott Williams & Wilkins | location=Hagerstown, MD | year=2007 | pages= 504–13 | isbn=978-0-7817-7881-7}}</ref> Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.<ref name=Jankovic2008/> In early stages of PD, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.<ref>{{cite book |name-list-style=vanc | last1=O'Sullivan |first1=Susan B |last2=Schmitz |first2=Thomas J |title=Physical Rehabilitation |edition=5th |chapter=Parkinson's Disease |year=2007|publisher=F.A. Davis|location=Philadelphia |pages=856–7 }}</ref>  With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

[[Postural instability]] is typical in later stages of the disease, leading to [[Balance disorder|impaired balance]] and frequent falls,<ref name="OFP"/> and secondarily to bone fractures,<ref name=Jankovic2008/> loss of confidence and reduced mobility. Instability is often absent in the initial stages, especially in younger people, especially prior to the development of bilateral symptoms.<ref name="pmid15172778"/> Up to 40% may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.<ref name=Jankovic2008/>

Other recognized motor signs and symptoms include gait and posture disturbances such as [[Parkinsonian gait|festination]] (rapid shuffling steps and a [[camptocormia|forward-flexed posture]] when walking with absent flexed arm swing. Freezing of gait (brief arrests when the feet seem to get stuck to the floor, especially on turning or changing direction)),<ref name=Jankovic2008/> a slurred monotonous quiet voice,<ref name=pmid20233583>{{cite journal |name-list-style=vanc | last1=Russell | first1=John A. | last2=Ciucci | first2=Michelle R. | last3=Connor | first3=Nadine P. | last4=Schallert | first4=Timothy |title=Targeted exercise therapy for voice and swallow in persons with Parkinson's disease |journal=[[Brain Research (journal)|Brain Research]] |volume=1341 |pages=3–11 |date=23 June 2010 |pmid=20233583 |pmc=2908992 |doi=10.1016/j.brainres.2010.03.029}}</ref> [[hypomimia|mask-like face expression]] and handwriting that gets smaller and smaller are other common signs.<ref name=Jankovic2008/>

===Neuropsychiatric===
Parkinson's disease can cause [[Neuropsychiatry|neuropsychiatric]] disturbances which can range from mild to severe. This includes disorders of cognition, mood, behaviour, and thought.<ref name=Jankovic2008/>

Cognitive disturbances can occur in the initial stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.<ref name=Jankovic2008/><ref name="pmid18175397">{{cite journal |name-list-style=vanc | last1=Caballol | first1=Nuria | last2=Martí | first2=Maria J. | last3=Tolosa | first3=Eduardo |title=Cognitive dysfunction and dementia in Parkinson disease |journal=[[Movement Disorders (journal)|Movement Disorders]] |volume=22 |issue=Suppl 17 |pages=S358–S366 |date=September 2007 |pmid=18175397 |doi=10.1002/mds.21677 | s2cid=3229727 }}</ref>. The most common cognitive deficit in affected individuals is [[executive dysfunction]], which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. Fluctuations in [[attention]] and [[bradyphrenia|slowed cognitive speed]] are among other cognitive difficulties. Memory is affected, specifically in [[Recall (memory)|recalling]] learned information. Nevertheless, improvement appears when recall is aided by cues. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.<ref name="pmid18175397"/>

A person with PD has two to six times the risk of dementia compared to the general population.<ref name=Jankovic2008/><ref name="pmid18175397"/> The prevalence of dementia increases with age and to a lesser degree the duration of the disease.<ref name="pmid18175397"/> Dementia is associated with a reduced [[quality of life]] in people with PD and their [[caregiver]]s, increased mortality, and a higher probability of needing [[nursing home]] care.<ref name="pmid18175397"/>

Behavior and mood alterations are more common in PD without cognitive impairment than in the general population, and are usually present in PD with dementia. The most frequent mood difficulties are [[Depression (mood)|depression]], [[apathy]], [[anhedonia]] and [[anxiety]].<ref name=Jankovic2008/> Establishing the diagnosis of depression is complicated by the fact that the body language of depression may masquerade as PD including a sad expressionlees anxious face, a hang dog appearance, slow movement and monotonous speech.<ref>{{cite book|title=Bradley's Neurology in Clinical Practice: Expert Consult – Online and Print, 6e (Bradley, Neurology in Clinical Practice e-dition 2v Set)|year=2012|publisher=Elsevier/Saunders|location=Philadelphia, PA|isbn=978-1-4377-0434-1|name-list-style=vanc | first1=Evan D. | last1=Murray | first2=Edgar A. | last2=Buttner | first3=Bruce H. | last3=Price|volume=1|edition=6th|pages=102–103 | display-editors=4| editor1-last=Bradley | editor1-first=Walter George | editor2-last=Daroff | editor2-first=Robert B. | editor3-last=Fenichel | editor3-first=Gerald M. | editor4-last=Jankovic | editor4-first=Joseph |chapter=Depression and Psychosis in Neurological Practice}}</ref> Up to 30% of patients with PD may experience symptoms of anxiety, ranging from a generalized anxiety disorder to social fobia, panic disorders and obsessive compulsive disorders. They contribute to impaired quality of life and increased severity of motor symptoms such as on/off fluctuations or freezing episodes. [[Impulse control disorder]]s including pathological gambling, compulsive sexual behaviour, binge eating, compulsive shopping and reckless generosity can be caused by medication, particularly orally active dopamine agonists. The dopamine dysregulation syndrome - with wanting of medication leading to overusage - is a rare complication of l-dopa use (Giovannoni, et al. 2000). Punding in which complicated repetitive aimless stereotyped behaviours occur for many hours is another [[Iatrogenesis|iatrogenic]] disturbance.<ref name=Jankovic2008/><ref name="pmid20123548">{{cite journal |authors=Ceravolo R, Frosini D, Rossi C, Bonuccelli U |title=Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management |journal=Parkinsonism Relat. Disord. |volume=15 |issue=Suppl 4 |pages=S111–5 |date=December 2009 |pmid=20123548 |doi=10.1016/S1353-8020(09)70847-8}}</ref> [[Hallucination#Visual|Formed complex visual hallucination]]s or [[delusion]]s occur in approximately 50% of people over a lifetime with PD and may be a harbinger for dementia. These range from "minor hallucinations" - sense of passage (something quickly passing beside the person) or presence (the perception of something/someone standing just to the side or behind the person) - to full blown vivid, formed visual hallucinations and paranoid [[ideation]]. Unlike [[schizophrenia]], auditory hallucinations are uncommon, and are rarely described as voices. It is now believed that this disturbance is an integral part of the disease but anti-Parkinsonian drugs may be a risk factor. A psychosis with delusions and associated delirium is another recognized complication of drug treatment, but may also be caused by urinary tract infections as frequently occurs in the fragile elderly.<ref>{{cite journal |authors=Shergill SS, Walker Z, Le Katona C |title=A preliminary investigation of laterality in Parkinson's disease and susceptibility to psychosis |journal=J. Neurol. Neurosurg. Psychiatr. |volume=65 |issue=4 |pages=610–1 |date=October 1998 |pmid=9771806 |pmc=2170290 |doi=10.1136/jnnp.65.4.610}}</ref><ref name="pmid20538500">{{cite journal |author=Friedman JH |title=Parkinson's disease psychosis 2010: A review article |journal=Parkinsonism Relat. Disord. |volume= 16|issue= 9|pages= 553–60|date=June 2010 |pmid=20538500 |doi=10.1016/j.parkreldis.2010.05.004 |url=}}</ref> However, it is clear that this is not the only factor, and underlying brain pathology or changes in other neurotransmitters or their receptors (e.g., [[acetylcholine]], [[serotonin]]) are also thought to play a role.

===Other===
In addition to cognitive and motor symptoms, PD can impair other body functions.

Sleep problems are a feature of the disease and can be worsened by medications.<ref name=Jankovic2008/> Symptoms can manifest as daytime [[somnolence|drowsiness]] (including sudden sleep attacks resembling narcolepsy), disturbances in [[Rapid eye movement sleep|REM]] sleep, or [[insomnia]].<ref name=Jankovic2008/> REM behavior disorder (RBD), in which patients act out dreams, sometimes injuring themselves or their bed partner, may begin many years before the development of motor or cognitive features of PD or DLB. 

Alterations in the [[autonomic nervous system]] can lead to [[orthostatic hypotension]] (low blood pressure upon standing), [[Human skin#Oily skin|oily skin]] and [[Hyperhidrosis|excessive sweating]], [[urinary incontinence]] and [[Sexual dysfunction|altered sexual function]].<ref name=Jankovic2008/> [[Constipation]] and [[gastrointestinal dysmotility|gastric dysmotility]] can be severe enough to cause discomfort and even endanger health.<ref name="pmid19691125"/> Changes in perception may include an impaired sense of [[olfaction|smell]], disturbed vision, sensation of pain and [[paresthesia]] (skin tingling and numbness).<ref name=Jankovic2008/> All of these symptoms can occur years before diagnosis of the disease.<ref name=Jankovic2008/>

==Causes==
{{Main|Causes of Parkinson's disease}}
Parkinson's disease in most people is [[idiopathic]] (having no specific known cause). However, a small proportion of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationships have been proven.

===Environmental factors===
Exposure to pesticides and  a history of head injury have been linked with PD but the risk is modest. People who have never smoked cigarettes have an increased risk of developing PD while never drinking caffeinated beverages moderately increases risk. A high serum uric acid has also been found to reduce the risk of PD.

===Genetics===
[[File:Structure of parkin.png|thumb|left| Parkin crystal structure]]
PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease.<ref name="pmid15172778"/>  About 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.<ref name=lesage>{{cite journal |authors=Lesage S, Brice A |title=Parkinson's disease: from monogenic forms to genetic susceptibility factors |journal=Hum. Mol. Genet. |volume=18 |issue=R1 |pages=R48–59 |date=April 2009 |pmid=19297401 |doi=10.1093/hmg/ddp012}}</ref>

Mutations in specific genes have been conclusively shown to cause PD. These genes code for [[alpha-synuclein]] (SNCA), [[Parkin (ligase)|parkin]] (PRKN), leucine-rich repeat kinase 2 ([[LRRK2]] or dardarin), PTEN-induced putative kinase 1 ([[PINK1]]), [[PARK7|DJ-1]] and [[ATP13A2]].<ref name="pmid18398010">{{cite journal |author=Davie CA |title=A review of Parkinson's disease |journal=Br. Med. Bull. |volume=86 |issue= 1|pages=109–27 |year=2008 |pmid=18398010 |doi=10.1093/bmb/ldn013 }}</ref><ref name=lesage/> In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD.<ref name="pmid18398010"/> The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and [[glucocerebrosidase]] (GBA) have been found to be risk factors for sporadic PD. This means that harboring the mutation may not necessarily lead to the disease but puts the individual at an increased risk, often in combination with other risk factors. Mutations in GBA are known to cause [[Gaucher's disease]].<ref name=lesage/> [[Genome-wide association study|Genome-wide association studies]], which search for mutated [[allele]]s with low penetrance in sporadic cases, have now yielded many positive results.<ref name=IPDGC>{{Cite journal | author=IPDGC | title=Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies | journal=Lancet | volume=377 | pages= 641–49 | year=2011 | pmid= 21292315 | doi=10.1016/S0140-6736(10)62345-8 | issue=9766 | last2=Nalls | first2=MA | last3=Plagnol | first3=V | last4=Hernandez | first4=DG | last5=Sharma | first5=M | last6=Sheerin | first6=UM | last7=Saad | first7=M | last8=Simón-Sánchez | first8=J | last9=Schulte | first9=C  | last10=Lesage | first10=S | last11=Sveinbjörnsdóttir | first11=S | last12=Stefánsson | first12=K | last13=Martinez | first13=M | last14=Hardy | first14=J | last15=Heutink | first15=P | last16=Brice | first16=A | last17=Gasser | first17=T | last18=Singleton | first18=A. B. | last19=Wood | first19=N. W. | pmc=3696507| display-authors=8 }}</ref>

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of [[Lewy body|Lewy bodies]].<ref name=lesage/> [[Missense mutation]]s of the gene (in which a single [[nucleotide]] is changed), and [[Gene duplication|duplications]] and triplications of the [[Locus (genetics)|locus]] containing it have been found in different groups with familial PD.<ref name=lesage/> Missense mutations are rare.<ref name=lesage/> On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.<ref name=lesage/> Multiplications have been found in [[asymptomatic carrier]]s, which indicate that [[penetrance]] is incomplete or age-dependent.<ref name=lesage/>

The LRRK2 gene (PARK8) encodes a protein called [[dardarin]]. The name dardarin was taken from a [[Basque language|Basque]] word for tremor, because this gene was first identified in families from England and the north of Spain.<ref name="pmid18398010"/> Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases.<ref name="pmid18398010"/><ref name=lesage/> There are many mutations described in LRRK2, however unequivocal proof of causation only exists for a few.<ref name=lesage/> LRRK2 mutation, especially the commonest (G2019S), may have penetrance as low as 26% in some populations, for example Ashkenazi Jews.

Several Parkinson-related genes are involved in the function of [[lysosome]]s, organelles that digest cellular waste products.  It has been suggested that some forms of Parkinson may be caused by lysosome dysfunctions that reduce the ability of cells to break down alpha-synuclein.<ref>{{Cite journal|title = Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease|url = http://dx.doi.org/10.1080/15548627.2015.1067364|journal = Autophagy|date = 2015-09-02|issn = 1554-8627|pmc = 4590678|pmid = 26207393|pages = 1443–1457|volume = 11|issue = 9|doi = 10.1080/15548627.2015.1067364|first1 = Ziv|last1 = Gan-Or|first2 = Patrick A.|last2 = Dion|first3 = Guy A.|last3 = Rouleau}}</ref>

==Pathology==
[[File:Lewy Body alphaSynuclein.jpg|thumb|right|A [[Lewy body]] (stained brown) in a brain cell of the [[substantia nigra]] in Parkinson's disease. The brown colour is positive [[immunohistochemistry]] staining for [[alpha-synuclein]].|alt=Several brain cells stained in blue. The largest one, a neurone, with an approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears.]]

===Anatomical===
The [[basal ganglia]], a group of brain structures [[wikt:innervated|innervated]] by the dopaminergic system, are the most seriously affected brain areas in PD.<ref name="pmid18781672">{{cite journal |authors=Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, Blesa FJ, Guridi J, Marin C, Rodriguez M |title=Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease |journal=Mov. Disord. |volume=23 |issue=Suppl 3 |pages=S548–59 |year=2008 |pmid=18781672 |doi=10.1002/mds.22062|s2cid=13186083 }}</ref> The most important [[Pathology|pathological]] lesion is cell death in the [[substantia nigra]] and, more specifically, the ventral (front) part of the [[pars compacta]], affecting up to 70% of the cells by the time death occurs.<ref name="pmid18398010"/>

[[Macroscopic]] alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of [[neuromelanin]] pigmentation in the substantia nigra and [[locus coeruleus]].<ref name="Jankovic_book-Neuropathology">{{cite book |author=Dickson DV|chapter=Neuropathology of movement disorders |editor=Tolosa E, Jankovic JJ| title=Parkinson's disease and movement disorders|publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages= 271–83|isbn=978-0-7817-7881-7}}</ref> Several other brain regions show [[neuron]]al loss and [[Lewy body|Lewy bodies]] in many of the remaining nerve cells. Neuronal loss is accompanied by death of [[astrocytes]] (star-shaped [[neuroglia|glial]] cells) and activation of the [[microglia]] (another type of glial cell).<ref name="Jankovic_book-Neuropathology"/>

===Pathophysiology===
[[File:Journal.pone.0008247.g001.png|thumb|A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's disease, as proposed by Braak and colleagues<br>
B. Localization of the area of significant brain [[Voxel-based morphometry|volume reduction]] in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that [[brain stem]] damage may be the first identifiable stage of PD [[neuropathology]]<ref name="pmid20011063">{{cite journal |authors=Jubault T, Brambati SM, Degroot C |editor1-last=Gendelman |editor1-first=Howard E. |title=Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI |journal=PLOS ONE |volume=4 |issue=12 |page=e8247 |year=2009 |pmid=20011063 |pmc=2784293 |doi=10.1371/journal.pone.0008247 |bibcode=2009PLoSO...4.8247J |doi-access=free }}</ref>|alt=Composite of three images, one in top row (referred to in caption as A), two in second row (referred to as B). Top shows a mid-line [[sagittal plane]] of the brainstem and [[cerebellum]]. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". A fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one saggital and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem.]]

The primary symptoms of PD result from greatly reduced activity of [[dopamine]]-secreting cells caused by cell death in the [[pars compacta]] region of the [[substantia nigra]].<ref name="pmid18781672"/>

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the [[Motor cortex|motor]], [[Frontal eye fields|oculo-motor]], [[Cerebral cortex#Association areas|associative]], [[Limbic system|limbic]] and [[orbitofrontal]] circuits, with names indicating the main projection area of each circuit.<ref name="pmid18781672"/> All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.<ref name="pmid18781672"/> Scientifically, the motor circuit has been examined the most intensively.<ref name="pmid18781672"/>

A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.<ref name="pmid18781672"/> In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, [[Inhibitory postsynaptic potential|inhibition]] is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce [[hypokinesia]], an overall reduction in motor output.<ref name="pmid18781672"/>  Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing [[dyskinesia]]s.<ref name="pmid18781672"/>

===Brain cell death===
There is speculation of several mechanisms by which the brain cells could be lost.<ref name="pmid20495568"/> One mechanism consists of an abnormal accumulation of the protein [[alpha-synuclein]] bound to [[ubiquitin]] in the damaged cells. This insoluble [[protein]] accumulates inside neurones forming inclusions called [[Lewy bodies]].<ref name="pmid18398010"/><ref name="pmid20563819">{{cite journal |author=Schulz-Schaeffer WJ |title=The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia |journal=Acta Neuropathol. |volume=120 |issue=2 |pages=131–43 |date=August 2010 |pmid=20563819 |pmc=2892607 |doi=10.1007/s00401-010-0711-0 |url=}}</ref> According to the [[Braak staging]], a classification of the disease based on pathological findings, Lewy bodies first appear in the [[olfactory bulb]], [[medulla oblongata]] and [[pontine tegmentum]]; individuals at this stage may be asymptomatic or may have [[prodrome|prodromal]] non-motor symptoms (such as loss of sense of smell, sleep and some automatic dysfunction). As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the [[midbrain]] and basal [[forebrain]], and, finally, the [[neocortex]].<ref name="pmid18398010"/> These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective (with the abnormal protein sequestered or walled off).<ref name="pmid20495568"/><ref name="pmid20563819"/> Other forms of alpha-synuclein (e.g., oligomers) that are not aggregated in Lewy bodies and Lewy neurites may actually be the toxic forms of the protein. In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. [[Neurofibrillary tangles]] and [[senile plaque]]s, characteristic of [[Alzheimer's disease]], are not common unless the person is demented.<ref name="Jankovic_book-Neuropathology"/>

Other cell-death mechanisms include [[proteosome|proteosomal]] and [[Lysosome|lysosomal]] system dysfunction and reduced [[mitochondria]]l activity.<ref name="pmid20495568"/> Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to [[oxidative stress]], [[protein aggregation]] and neuronal death, but the mechanisms are not fully understood.<ref name="pmid20082992">{{cite journal |author=Hirsch EC |title=Iron transport in Parkinson's disease |journal=Parkinsonism Relat. Disord. |volume=15 |issue=Suppl 3 |pages=S209–11 |date=December 2009 |pmid=20082992 |doi=10.1016/S1353-8020(09)70816-8 |url=}}</ref>

== Diagnosis ==
[[File:PET-image.jpg|upright|thumb|left|[[Fludeoxyglucose]] (<sup>18</sup>F) (FDG) [[Positron emission tomography|PET scan]] of a healthy brain. Hotter areas reflect higher glucose uptake. A decreased activity in the [[basal ganglia]] can aid in diagnosing Parkinson's disease.|alt=Sagittal PET scan at the level of the striatum. Hottest areas are the cortical grey matter and the striatum. ]]
A physician will [[Medical diagnosis|diagnose]] PD from the [[medical history]] and a [[neurological examination]].<ref name=Jankovic2008/> There is no [[Diagnostic test|lab test]] that will clearly identify the disease, but [[Magnetic resonance imaging|MRI]] scans are sometimes used to rule out disorders that could give rise to similar symptoms. People may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis but this is not a reliable test in early disease. The finding of [[Lewy bodies]] in the midbrain on [[autopsy]] is usually considered proof that the person had PD. The progress of the illness over time may reveal it is not PD, and some authorities recommend that the diagnosis be periodically reviewed.<ref name=Jankovic2008/><ref name="Nice-Diagnosis">{{cite book |chapter=Diagnosing Parkinson's Disease |editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| publisher=Royal College of Physicians|location=London| year=2006| isbn= 1-86016-283-5|pages= 29–47}}</ref>

Other causes that can secondarily produce a parkinsonian syndrome are multiple [[cerebral infarction]] and drug-induced parkinsonism.<ref name="Nice-Diagnosis"/> [[Parkinson plus syndrome]]s such as [[progressive supranuclear palsy]] and [[multiple system atrophy]] must be [[Differential diagnosis|ruled out]].<ref name=Jankovic2008/> Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson plus syndromes.<ref name=Jankovic2008/> Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself.<ref name="pmid12464118">{{cite journal |authors=Poewe W, Wenning G |title=The differential diagnosis of Parkinson's disease |journal=Eur. J. Neurol. |volume=9 |issue=Suppl 3 |pages=23–30 |date=November 2002 |pmid=12464118 |doi=10.1046/j.1468-1331.9.s3.3.x}}</ref> Genetic forms with an [[autosomal dominant]] or [[Autosomal recessive|recessive]] pattern of inheritance are sometimes referred to as ''familial Parkinson's  disease'' or ''familial  parkinsonism''.<ref name="pmid15172778"/>

Medical organizations have created [[diagnostic criteria]] to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Queen Square Brain Bank for Neurological Disorders and the U.S. [[National Institute of Neurological Disorders and Stroke]].<ref name=Jankovic2008/>  The Queen Square Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following supportive features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of [[dyskinesia]]s induced by the intake of excessive levodopa.<ref name=Jankovic2008/> [[Accuracy and precision|Accuracy]] of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.<ref name=Jankovic2008/> Very recently, a task force of the International Parkinson and Movement Disorder Society (MDS) has proposed diagnostic criteria for Parkinson’s disease<ref name="Postuma>Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G. "MDS clinical diagnostic criteria for Parkinson's disease." ''Mov Disord.'' 2015 Oct;30(12):1591-601. doi: 10.1002/mds.26424. PMID:26474316</ref> as well as research criteria for the diagnosis of prodromal disease,<ref name="Berg">Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G. "MDS research criteria for prodromal Parkinson's disease" ''Mov Disord.'' 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431. PMID: 26474317</ref> but these will require validation against the more established criteria. 
 

[[Computed tomography]] (CT) and conventional [[magnetic resonance imaging]] (MRI) brain scans of people with PD usually appear normal.<ref name="pmid20351351">{{cite journal |author=Brooks DJ |title=Imaging approaches to Parkinson disease |journal=J. Nucl. Med. |volume=51 |issue=4 |pages=596–609 |date=April 2010 |pmid=20351351 |doi=10.2967/jnumed.108.059998 |s2cid=17720009 }}</ref> These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia [[tumor]]s, [[vascular]] pathology and [[hydrocephalus]].<ref name="pmid20351351"/> A specific technique of MRI, [[diffusion MRI]], has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation.<ref name="pmid20351351"/> Dopaminergic function in the basal ganglia can be measured with different [[Positron emission tomography|PET]] and [[Single photon emission computed tomography|SPECT]] [[radiotracer]]s. Examples are [[ioflupane (123I)|ioflupane (<sup>123</sup>I)]] (trade name ''DaTSCAN'') and [[RTI-55|iometopane]] (''Dopascan'') for SPECT or fluoro-L-dopa (18F)<ref name="pmid20351351"/> and [[DTBZ]]<ref name ="pmid24840973">{{cite journal|last1=Wood|first1=H|title=Parkinson disease: 18F-DTBZ PET tracks dopaminergic degeneration in patients with Parkinson disease.|journal=Nature Reviews. Neurology|date=June 2014|volume=10|issue=6|pages=305|pmid=24840973|doi=10.1038/nrneurol.2014.81|s2cid=30591628}}</ref> for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing<ref name="pmid20351351"/>and distinguish it from drug-induced parkinsonism. Reduced dopaminergic activity is, however, also seen in the Parkinson-plus disorders so they are not reliable in distinguishing PD from other neurodegenerative causes of parkinsonism and therefore of limited use in this clinical situation.

==Prevention==
Exercise in [[middle age]] may slightly reduce the risk of PD later in life.<ref name=Neuro2011/> [[Caffeine]] also appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee.<ref name="pmid20182023">{{cite journal |authors=Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A|title=Caffeine exposure and the risk of Parkinson's disease: a systematic review and meta-analysis of observational studies |journal=J. Alzheimers Dis.|volume=20 |issue=Suppl 1 |pages=S221–38 |year=2010 |pmid=20182023 |doi=10.3233/JAD-2010-091525|url=http://iospress.metapress.com/content/r817357v22l37j8w/fulltext.html}}</ref> Although tobacco smoke causes adverse [[Health effects of tobacco|health effects]], decreases life expectancy and quality of life, it may reduce the risk of PD by a third when compared to non-smokers.<ref name="pmid16713924"/> The basis for this effect is not known, but possibilities include an effect of [[nicotine]] as a dopamine stimulant.<ref name="pmid16713924"/><ref>{{cite journal|authors=Quik M, Huang LZ, Parameswaran N, Bordia T, Campos C, Perez XA|title=Multiple roles for nicotine in Parkinson's disease|journal=Biochem Pharmacol|date=1 October 2009|volume=78|issue=7|pages=677–85|pmid=19433069|doi=10.1016/j.bcp.2009.05.003|pmc=2815339}}</ref> Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.<ref>{{cite journal |journal=Neurotoxicology |date=January 2004|volume=25 |issue=1–2 |pages=279–91 |title=Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's disease and neuroprotection; are there links?|authors=Castagnoli K, Murugesan T |pmid=14697903 |doi=10.1016/S0161-813X(03)00107-4}}</ref> However, recently it has been suggested that the negative association with smoking is not protective but is due to an inherent difference in the propensity of patients destined to develop PD to become addicted to nicotine.<ref name="Ritz">Ritz B, Lee PC, Lassen CF, Arah OA. "Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease" ''Neurology'' 2014; 83: 1396–402. PMID: 25217056</ref>

[[Antioxidant]]s, such as vitamins C and E, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven.<ref name="pmid16713924"/> The results regarding fat and [[fatty acid]]s have been contradictory, with various studies reporting protective effects, risk-increasing effects or no effects.<ref name="pmid16713924"/> Also, there have been preliminary indications of a possible protective role of [[estrogen]]s, [[Non-steroidal anti-inflammatory drug|anti-inflammatory]] drugs, certain calcium channel blocking drugs () and higher levels of uric acid ().<ref name="pmid16713924"/>

==Management==
{{Main|Management of Parkinson's disease}}
[[File:Pharmacological treatment of Parkinson's disease.png|thumb|Pharmacological treatment of Parkinson's disease]]
There is no cure for PD, but medications, surgery and physical treatment can provide relief, and are much more effective than those available for other neurological disorders like Alzheimer’s disease, motor neurone disease, the Parkinson plus syndromes and multiple sclerosis. The main families of drugs useful for treating motor symptoms are L-DOPA (now always combined with a [[dopa decarboxylase inhibitor]] which does not cross the [[blood–brain barrier]]), and sometimes combined with a COMT inhibitor, [[dopamine agonist]]s and [[Monoamine oxidase inhibitor|MAO-B inhibitors]].<ref name="Nice-pharma"/> The stage of the disease determines which group is most useful. Three stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability requiring pharmacological treatment, a second stage associated with the development of motor complications related to levodopa usage, and a third stage when non-dopaminergic symptoms (motor and non-motor) may predominate.<ref name="Nice-pharma">{{cite book |chapter= Symptomatic pharmacological therapy in Parkinson’s disease|editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| publisher=Royal College of Physicians|location=London| year=2006| isbn= 1-86016-283-5|pages= 59–100}}</ref> Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from improvement of dopaminergic function. The start of levodopa (or [[L-DOPA]]) treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias.<ref name="Nice-pharma"/> However, levodopa remains the most effective treatment for PD and should not be delayed in patients whose quality of life is impaired. Indeed, dyskinesias correlate more strongly with duration and severity of the disease than duration of levodopa treatment, so delaying this therapy may not really provide much longer dyskinesia-free time than earlier use (). In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed.<ref name="Nice-pharma"/> When medications are not enough to adequately control symptoms, surgery such as deep brain stimulation, and infusion therapies using pumps can be of use.<ref name="pmid20937936"/> The third stage presents many challenging problems requiring a variety of treatments for psychiatric symptoms, orthostatic hypotension, bladder dysfunction, etc..  In the final stages of the disease, [[palliative care]] is provided to improve quality of life.<ref name="Nice-palliative">{{cite book | chapter=Palliative care in Parkinson’s disease | editor=The National Collaborating Centre for Chronic Conditions | title=Parkinson's Disease  | url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English | publisher=Royal College of Physicians | location=London | year=2006 | isbn=1-86016-283-5 | pages=147–51 }}</ref>

===Levodopa===
Levodopa has been the most widely used treatment for over 30 years.<ref name="Nice-pharma"/> L-DOPA is converted into dopamine in the dopaminergic and possibly other (e.g., serotonergic) neurons by [[Aromatic L-amino acid decarboxylase|dopa decarboxylase]].<ref name="Nice-pharma"/> Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.<ref name="Nice-pharma"/>

Only 5–10% of L-DOPA crosses the blood–brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including [[nausea]], vomiting and orthostatic hypotension.<ref name="Nice-pharma"/> [[Carbidopa]] and [[benserazide]] are peripheral [[dopa decarboxylase inhibitor]]s,<ref name="Nice-pharma"/> which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing [[bioavailability]]. They are generally given as combination preparations with levodopa.<ref name="Nice-pharma"/> Existing preparations are [[carbidopa/levodopa]] (co-careldopa) and [[benserazide|benserazide/levodopa]] (co-beneldopa). There are controlled [[Slow-release|release]] versions of levodopa. Older controlled-release levodopa preparations have poor and unreliable absorption and bioavailability and have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.<ref name="Nice-pharma"/><ref name="Jankovic_book-Pharma">{{cite book |authors=Tolosa E, Katzenschlager R|chapter=Pharmacological management of Parkinson's disease|editor=Tolosa E, Jankovic JJ| title=Parkinson's disease and movement disorders|publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |pages= 110–45|isbn=978-0-7817-7881-7}}</ref> A newer extended-release levodopa preparation<ref name="Hauser">Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, Ondo W, O'Connell M, Gupta S; "IPX066 ADVANCE-PD investigators.  Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial." ''Lancet Neurol.'' 2013 Apr;12(4):346-56. doi: 10.1016/S1474-4422(13)70025-5. PMID: 23485610</ref>does seem to be more effective in controlling motor fluctuations but in many patients problems persist. Intestinal infusions of levodopa (Duodopa) can result in striking improvements in motor fluctuations compared to oral levodopa due to insufficient uptake caused by gastroparesis.<ref name="Olanow2">Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman AA, Widnell KL, Robieson WZ, Pritchett Y, Chatamra K, Benesh J, Lenz RA, Antonini A; LCIG Horizon Study Group. "Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study." ''Lancet Neurol.'' 2014 Feb;13(2):141-9. doi: 10.1016/S1474-4422(13)70293-X. PMID: 24361112</ref> Other oral, longer acting formulations are under study currently and other formulations of levodopa (inhaled, transdermal) are under development.

[[Tolcapone]] inhibits the [[COMT]] enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.<ref name="Nice-pharma"/> It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.<ref name="Nice-pharma"/> Another COMT-inhibitor, [[entacapone]], has not been shown to cause significant alterations of liver function but is less efficacious than tolcapone.<ref name="Nice-pharma"/> Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.<ref name="Nice-pharma"/>

Levodopa preparations frequently lead in the long term to the development of motor complications characterized by involuntary movements called [[dyskinesia]]s and fluctuations in the response to medication.<ref name="Nice-pharma"/> When this occurs a person with PD can change from phases with good response to medication and few symptoms ("on" state), to phases with no response to medication and significant motor symptoms ("off" state).<ref name="Nice-pharma"/> For this reason, levodopa doses are kept as low as possible while maintaining functionality.<ref name="Nice-pharma"/> A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now, since it can bring dangerous side effects such as [[neuroleptic malignant syndrome]].<ref name="Nice-pharma"/> Most people with PD will eventually need levodopa and later develop motor side effects.<ref name="Nice-pharma"/>

===Dopamine agonists===
Several [[dopamine agonist]]s that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.<ref name="Nice-pharma"/> These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications.<ref name="Nice-pharma"/><ref>{{cite journal |author=Goldenberg MM |title=Medical management of Parkinson's disease |journal=P & T |volume=33 |issue=10 |pages=590–606 |date=October 2008 |pmid=19750042 |pmc=2730785}}</ref>. Like levodopa, these can improve all of the dopaminergic motor symptoms but they are generally less effective than levodopa.When used in late PD they are useful at reducing the off periods.<ref name="Nice-pharma"/> Dopamine agonists include [[bromocriptine]], [[pergolide]], [[pramipexole]], [[ropinirole]], [[piribedil]], [[cabergoline]], [[apomorphine]], [[lisuride]] and [[rotigotine]]. The most commonly used oral dopamine agonists are pramipexole and ropinerole. Rotigotine is used as a transdermal patch. 

Dopamine agonists can produce significant side effects including [[orthostatic hypotension]], [[somnolence|drowsiness]], hallucinations, insomnia, nausea and constipation.<ref name="Nice-pharma"/> Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.<ref name="Nice-pharma"/> Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.<ref name="Nice-pharma"/> They tend to be more expensive than levodopa.<ref name="pmid15172778"/> Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset.<ref name="pmid15172778"/> Thus dopamine agonists may be preferred as initial treatment in younger-onset patients, as opposed to levodopa for later onset.<ref name="pmid15172778"/> However, recent studies have emphasized little advantage to so-called "levodopa sparing" approaches (e.g., dopamine agonists, MAO-B inhibitors) in early disease.<ref name="Gray>PD Med Collaborative Group, Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, McIntosh E, Wheatley K, Williams A, Clarke CE. "Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial". 
''Lancet''. 2014 Sep 27;384(9949):1196-205. doi: 10.1016/S0140-6736(14)60683-8. PMID: 24928805</ref>
Agonists have been related to impulse control disorders, particularly pathological gambling<ref name="pmid20123548"/> and discontinuing dopamine agonists may be associated with "dopamine agonist withdrawal syndrome",<ref name="Pondal">Pondal M, Marras C, Miyasaki J, Moro E, Armstrong MJ, Strafella AP, Shah BB, Fox S, Prashanth LK, Phielipp N, Lang AE. "Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic" ''J Neurol Neurosurg Psychiatry'' 2013 Feb;84(2):130-5. doi: 10.1136/jnnp-2012-302684 PMID: 22933817</ref> with symptoms similar to withdrawal from narcotics, and apathy.<ref name="Thobois>Thobois S, Lhommée E, Klinger H, Ardouin C, Schmitt E, Bichon A, Kistner A, Castrioto A, Xie J, Fraix V, Pelissier P, Chabardes S, Mertens P, Quesada JL, Bosson JL, Pollak P, Broussolle E, Krack P. "Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil." ''Brain''. 2013 May;136(Pt 5):1568-77. doi: 10.1093/brain/awt067. PMID: 23543483</ref>

=== MAO-B inhibitors ===
[[Monoamine oxidase inhibitor|MAO-B inhibitors]] ([[selegiline]] and [[rasagiline]]) increase the level of dopamine in the basal ganglia by blocking its metabolism. These agents inhibit the enzyme, [[monoamine oxidase B]] (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased L-DOPA in the [[striatum]].<ref name="Nice-pharma"/> Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early disease, but are clearly less effective than levodopa. There are few studies of drug effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods.<ref name="Nice-pharma"/> There remains a question whether these MAO-B inhibitors may slow the progression of the disease. This effect has not been proven and is likely very modest is it exists at all. 

===Other drugs===
Other drugs such as [[amantadine]] and [[anticholinergic]]s may be useful as treatment of motor symptoms. However, because they are old drugs the evidence from modern clinical trials supporting them lacks quality, so they are rarely first choice treatments.<ref name="Nice-pharma"/> Amatadine is now most often used to control dyskinesias in many patients. In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems.<ref name="Nice-NonMotor">{{cite book | chapter=Non-motor features of Parkinson's disease|editor=The National Collaborating Centre for Chronic Conditions | title=Parkinson's Disease  | url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English | publisher=Royal College of Physicians|location=London | year=2006 | isbn=1-86016-283-5 | pages=113–33 }}</ref> Examples are the use of [[clozapine]] and [[quetiapine]] for psychosis, [[cholinesterase inhibitors]] for dementia, and [[modafinil]] for [[excessive daytime sleepiness|daytime sleepiness]].<ref name="Nice-NonMotor"/><ref name="pmid19559160">{{cite journal |authors=Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, Pandurangi AK |title=Pharmacological management of psychosis in elderly patients with parkinsonism |journal=Am. J. Med. |volume=122 |issue=7 |pages=614–22 |date=July 2009 |pmid=19559160 |doi=10.1016/j.amjmed.2009.01.025}}</ref> 

===Surgery===
[[File:Parkinson surgery.jpg|upright|thumb|Placement of an electrode into the brain. The head is stabilised in a frame for [[stereotactic surgery]]. ]]
Treating motor symptoms with surgery was once a common practice, but since the introduction of L-DOPA in 1969, the number of operations declined.<ref name="Nice-surgery">{{cite book |chapter= Surgery for Parkinson’s disease|editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| publisher=Royal College of Physicians|location=London| year=2006| isbn= 1-86016-283-5|pages= 101–11}}</ref> Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy  no longer sufficiently controls symptoms due to motor fluctuations, and increasingly in patients with less advanced disease.<ref name="Nice-surgery"/> Surgery for PD can be divided in two main groups: lesional and [[deep brain stimulation]] (DBS). Target areas for DBS or lesions include the [[thalamus]], the [[globus pallidus]]  or the [[subthalamic nucleus]] and depend on the main clinical symptoms involved.<ref name="Nice-surgery"/> [[Deep brain stimulation]] (DBS) of the subthalamic nucleus is the most commonly used surgical treatment, developed in the 1980s by [[Alim-Louis Benabid]] and others. It involves the implantation of a medical device called a [[neurostimulator]] which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe [[wikt:neuropsychiatric|neuropsychiatric]] problems.<ref name="pmid20937936">{{cite journal |last1=Bronstein|first1=M.|last2=Tagliati|first2=M.|title=Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues |journal=Arch. Neurol. |volume=68 |issue=2 |page=165 |date=February 2011 |pmid=20937936 |doi=10.1001/archneurol.2010.260 |display-authors=1 |last3=Alterman |first3=R. L. |last4=Lozano |last5=Volkmann |last6=Stefani |last7=Horak |last8=Okun |last9=Foote |last10=Krack |last11=Pahwa |last12=Henderson |last13=Hariz |last14=Bakay |last15=Rezai |last16=Marks Jr |last17=Moro |last18=Vitek |last19=Weaver |last20=Gross |last21=Delong |pmc=4523130 }}</ref> Other, less common, surgical therapies involve intentional formation of lesions to suppress overactivity of specific [[wikt:subcortical|subcortical]] areas. For example, [[pallidotomy]] involves surgical destruction (a lesion) of the globus pallidus to control dyskinesia,<ref name="Nice-surgery"/> and [[thalamotomy]] lesions a region in the [[thalamus]] to control tremor. A new technique of lesioning brain areas such as the thalamus without opening the skull uses the technique of focused ultrasound and another uses gamma irradiation (gamma-knife). A major advantage of DBS procedures over these and older lesioning techniques is that they can be applied much more safely to both sides of the brain (bilateral procedures) and is more reversible by switching the device on and off. New developments in DBS include manufacturing closed loop systems in which deep brain electrodes simultaneously pick up local field potentials to respond with the appropriate electrical signal.  

===Rehabilitation===
{{Further|Rehabilitation in Parkinson's disease}}
Exercise programs are recommended in people with Parkinson's disease.<ref name=Neuro2011>{{cite journal|last1=Ahlskog|first1=JE|title=Does vigorous exercise have a neuroprotective effect in Parkinson disease?|journal=Neurology|date=19 July 2011|volume=77|issue=3|pages=288–94|pmid=21768599|doi=10.1212/wnl.0b013e318225ab66|pmc=3136051}}</ref> There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.<ref name="Nice-rehab">{{cite book |chapter= Other key interventions|editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| publisher=Royal College of Physicians|location=London| year=2006| isbn= 1-86016-283-5|pages= 135–46}}</ref><ref name="pmid18181210">{{cite journal |authors=Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL |title=The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis |journal=Mov. Disord. |volume=23 |issue=5 |pages=631–40 |date=April 2008 |pmid=18181210 |doi=10.1002/mds.21922|s2cid=3808899 }}</ref> Regular [[physical exercise]] with or without [[physiotherapy]] can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.<ref name="pmid18181210"/> When an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.<ref>{{cite journal |authors=Dereli EE, Yaliman A |title=Comparison of the effects of a physiotherapist-supervised exercise programme and a self-supervised exercise programme on quality of life in patients with Parkinson's disease |journal=Clin Rehabil |volume=24 |issue=4 |pages=352–62 |date=April 2010 |pmid=20360152 |doi=10.1177/0269215509358933 |s2cid=10947269 |url=http://cre.sagepub.com/cgi/pmidlookup?view=long&pmid=20360152}}</ref> In terms of improving flexibility and range of motion for people experiencing [[Hypokinesia|rigidity]], generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, [[diaphragmatic breathing]], and [[meditation]] techniques.<ref>{{harvnb|O'Sullivan|Schmitz|2007|pp=873, 876}}</ref> As for gait and addressing the challenges associated with the disease such as [[hypokinesia]] (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on but are not limited to improving gait speed, base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).<ref>{{harvnb|O'Sullivan|Schmitz|2007|p=879}}</ref> Strengthening exercises have shown improvements in strength and motor function for people with primary muscular weakness and weakness related to inactivity with mild to moderate PD. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that people with PD should perform exercises 45 minutes to one hour after medications, when they are at their best.<ref>{{harvnb|O'Sullivan|Schmitz|2007|p=877}}</ref> Also, due to the forward flexed posture, and respiratory dysfunctions in advanced PD,  deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.<ref>{{harvnb|O'Sullivan|Schmitz|2007|p=880}}</ref> Exercise may improve constipation.<ref name="pmid19691125"/>

One of the most widely practiced [[Speech therapy|treatments for speech]] disorders associated with Parkinson's disease is the [[Lee Silverman voice treatment]] (LSVT).<ref name="Nice-rehab"/><ref name="pmid17117354">{{cite journal |authors=Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG |title=The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders |journal=Semin. Speech. Lang. |volume=27 |issue=4 |pages=283–99 |date=November 2006 |pmid=17117354 |doi=10.1055/s-2006-955118}}</ref> Speech therapy and specifically LSVT may improve speech.<ref name="Nice-rehab"/> [[Occupational therapy]] (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their [[Daily living skills|daily living activities]] as possible.<ref name="Nice-rehab"/> There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.<ref name="Nice-rehab"/><ref name="pmid17636709">{{cite journal |authors=Dixon L, Duncan D, Johnson P, Kirkby L, O'Connell H, Taylor H, Deane KH|editor1-last=Deane |editor1-first=Katherine |title=Occupational therapy for patients with Parkinson's disease |journal=Cochrane Database of Systematic Reviews |issue=3 |page=CD002813 |year=2007 |pmid=17636709 |doi=10.1002/14651858.CD002813.pub2|pmc=6991932 }}</ref>

===Palliative care===
[[Palliative care]] is specialized medical care for people with serious illnesses, including parkinsonism. The goal of this speciality is to improve quality of life for both the person suffering from PD and the family by providing relief from the symptoms, pain, and stress of illnesses.<ref name="pmid17531914">{{cite journal| authors=Ferrell B, Connor SR, Cordes A, Dahlin CM, Fine PG, Hutton N, Leenay M, Lentz J, Person JL, Meier DE, Zuroski K; National Consensus Project for Quality Palliative Care Task Force Members| title=The national agenda for quality palliative care: the National Consensus Project and the National Quality Forum | journal=J Pain Symptom Manage | year= 2007 | volume= 33 | issue= 6 | pages= 737–44 | pmid=17531914 | doi=10.1016/j.jpainsymman.2007.02.024}}</ref> As PD is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature.<ref name="pmid24182372">{{cite journal| authors=Lorenzl S, Nübling G, Perrar KM, Voltz R| title=Palliative treatment of chronic neurologic disorders | journal=Handb Clin Neurol | year= 2013 | volume= 118 | issue=  | pages= 133–9 | pmid=24182372 | doi=10.1016/B978-0-444-53501-6.00010-X | series=Handbook of Clinical Neurology | isbn=9780444535016 }}</ref>

Palliative care should be involved earlier, rather than later in the disease course.<ref name="pmid22771241">{{cite journal| author=Ghoche R| title=The conceptual framework of palliative care applied to advanced Parkinson's disease. | journal=Parkinsonism Relat Disord | year= 2012 | volume= 18 | issue=Suppl 3 | pages= S2–5 | pmid=22771241 | doi=10.1016/j.parkreldis.2012.06.012}}</ref><ref name="pmid20081638">{{cite journal| author=Wilcox SK| title=Extending palliative care to patients with Parkinson's disease | journal=Br J Hosp Med (Lond) | year= 2010 | volume= 71 | issue= 1 | pages= 26–30 | pmid=20081638 | doi=10.12968/hmed.2010.71.1.45969}}</ref>  Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.<ref name="pmid22771241" /><ref name="pmid20081638"/><ref name="pmid24801658">{{cite journal| authors=Moens K, Higginson IJ, Harding R, EURO IMPACT | title=Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review | journal=J Pain Symptom Manage | year= 2014 | volume=Online first  | issue=  4| pages=  660–677| pmid=24801658 | doi=10.1016/j.jpainsymman.2013.11.009}}</ref>

Along with offering emotional support to both the patient and family, palliative care serves an important role in addressing goals of care. People with parkinsonism may have many difficult decisions to make as the disease progresses such as wishes for [[feeding tube]], [[non-invasive ventilation|non-invasive ventilator]], and [[tracheostomy]]; wishes for or against [[cardiopulmonary resuscitation]]; and when to use [[hospice]] care.<ref name="pmid24182372"/> Palliative care team members can help answer questions and provide guidance around these complex and emotional topics.<ref name="pmid20081638"/><ref name="pmid24195263">{{cite journal| author=Casey G| title=Parkinson's disease: a long and difficult journey. | journal=Nurs N Z | year= 2013 | volume= 19 | issue= 7 | pages= 20–4 | pmid=24195263}}</ref>

=== Other treatments ===
Muscles and nerves that control the digestive process may be affected by PD, resulting in [[constipation]] and [[gastroparesis]] (food remaining in the stomach for a longer period than normal).<ref name="pmid19691125"/> A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction.<ref name="pmid19691125"/> As the disease advances, swallowing difficulties ([[dysphagia]]) may appear. In such cases it may be helpful to use [[thickening agent]]s for liquid intake and an upright posture when eating, both measures reducing the risk of choking. [[Gastrostomy]] to deliver food directly into the stomach is possible in severe cases.<ref name="pmid19691125"/>

L-DOPA and [[protein]]s use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.<ref name="pmid19691125"/> When they are taken together, this results in a reduced effectiveness of the drug.<ref name="pmid19691125"/> Therefore, when L-DOPA is used, excessive [[Protein (nutrient)|protein consumption]] may reduce medication efficacy in some patients. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.<ref name="pmid19691125">{{cite journal |authors=Barichella M, Cereda E, Pezzoli G |title=Major nutritional issues in the management of Parkinson's disease|journal=Mov. Disord. |volume=24 |issue=13 |pages=1881–92 |date=October 2009 |pmid=19691125 |doi=10.1002/mds.22705|hdl=2434/67795 |s2cid=23528416 }}</ref> If dietary protein is determined to reduce levodopa efficacy, strategies to minimize interaction with protein include ingestion of levodopa 60 minutes before meals or 2 hours after meals.<ref name="pmid19691125"/> At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.<ref name="pmid19691125"/> Food in the stomach and constipation both slow stomach emptying which delays or reduces L-DOPA access to the upper small intestine where it is absorbed, resulting in poorer responses to individual doses. 

[[Repetitive transcranial magnetic stimulation]] temporarily  improves levodopa-induced dyskinesias.<ref name="pmid20714078">{{cite journal |author=Koch G |title=rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets |journal=Restor. Neurol. Neurosci. |volume=28 |issue=4 |pages=561–8 |year=2010 |pmid=20714078 |doi=10.3233/RNN-2010-0556}}</ref> Its usefulness in PD is an open research topic,<ref name="pmid20714064">{{cite journal |authors=Platz T, Rothwell JC |title=Brain stimulation and brain repair—rTMS: from animal experiment to clinical trials—what do we know? |journal=Restor. Neurol. Neurosci. |volume=28 |issue=4 |pages=387–98 |year=2010 |pmid=20714064 |doi=10.3233/RNN-2010-0570}}</ref> although recent studies have shown no effect by rTMS.<ref name="pmid20669300">{{cite journal |authors=Arias P, Vivas J, Grieve KL, Cudeiro J |title=Controlled trial on the effect of 10 days low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease |journal=Mov. Disord. |volume=25 |issue=12 |pages=1830–8 |date=September 2010 |pmid=20669300 |doi=10.1002/mds.23055|hdl=2183/14505 |s2cid=2211189 }}</ref> Several [[nutrient]]s have been proposed as possible treatments; however there is no evidence that [[vitamin]]s, [[food additive]]s or orally ingested and intravenous glutathione improve symptoms.<ref name="pmid16606908">{{cite journal |authors=Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ |title=Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology |journal=Neurology |volume=66 |issue=7 |pages=976–82 |date=April 2006 |pmid=16606908 |doi=10.1212/01.wnl.0000206363.57955.1b|s2cid=219207854 }}</ref> There is no evidence to substantiate that [[acupuncture]] and practice of [[Qigong]], or [[T'ai chi ch'uan|T'ai chi]], have any effect on the course of the disease or symptoms.  Further research on the viability of Tai chi for balance or motor skills are necessary.<ref name="pmid18374620">{{cite journal |authors=Lee MS, Lam P, Ernst E |title=Effectiveness of tai chi for Parkinson's disease: a critical review |journal=Parkinsonism Relat. Disord. |volume=14 |issue=8 |pages=589–94 |date=December 2008 |pmid=18374620 |doi=10.1016/j.parkreldis.2008.02.003}}</ref><ref name="pmid18973253">{{cite journal |authors=Lee MS, Ernst E |title=Qigong for movement disorders: A systematic review |journal=Mov. Disord. |volume=24 |issue=2 |pages=301–3 |date=January 2009 |pmid=18973253 |doi=10.1002/mds.22275|s2cid=206239252 }}</ref><ref name="pmid18618661">{{cite journal |authors=Lee MS, Shin BC, Kong JC, Ernst E |title=Effectiveness of acupuncture for Parkinson's disease: a systematic review |journal=Mov. Disord. |volume=23 |issue=11 |pages=1505–15 |date=August 2008 |pmid=18618661 |doi=10.1002/mds.21993|s2cid=24713983 }}</ref> [[Fava bean]]s and the cowhage ([[Mucuna pruriens]]) are natural sources of levodopa and are used by people with PD. While they have shown some effectiveness in clinical trials,<ref>{{cite journal |authors=Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ |title=Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study |journal=J. Neurol. Neurosurg. Psychiatr. |volume=75 |issue=12 |pages=1672–7 |year=2004 |pmid=15548480 |doi=10.1136/jnnp.2003.028761 |pmc=1738871}}</ref> their intake is not free of risks, particularly since the quantities of levodopa received in these formulations are quite variable.<ref name="pmid15719433">{{cite journal |authors=Ladha SS, Walker R, Shill HA |title=Case of neuroleptic malignant-like syndrome precipitated by abrupt fava bean discontinuance |journal=Mov. Disord. |volume=20 |issue=5 |pages=630–1 |date=May 2005 |pmid=15719433 |doi=10.1002/mds.20380|s2cid=37525204 }}</ref><ref name="pmid19678834">{{cite journal |authors=Raguthu L, Varanese S, Flancbaum L, Tayler E, Di Rocco A |title=Fava beans and Parkinson's disease: useful 'natural supplement' or useless risk? |journal=Eur. J. Neurol. |volume=16 |issue=10 |page=e171 |date=October 2009 |pmid=19678834 |doi=10.1111/j.1468-1331.2009.02766.x|s2cid=33221249 }}</ref>

==Prognosis==
{{See also|Unified Parkinson's Disease Rating Scale}}
[[File:Parkinson disease world map - DALY - WHO2004.svg|thumb|Global burden of Parkinson's disease, measured in [[disability-adjusted life year]]s per 100,000&nbsp;inhabitants in 2004
{{Col-begin}}
{{Col-break}}
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|<&nbsp;5}}
{{legend|#fff200|5–12.5}}
{{legend|#ffdc00|12.5–20}}
{{legend|#ffc600|20–27.5}}
{{legend|#ffb000|27.5–35}}
{{legend|#ff9a00|35–42.5}}
{{Col-break}}
{{legend|#ff8400|42.5–50}}
{{legend|#ff6e00|50–57.5}}
{{legend|#ff5800|57.5–65}}
{{legend|#ff4200|65–72.5}}
{{legend|#ff2c00|72.5–80}}
{{legend|#cb0000|>&nbsp;80}}
{{col-end}}]]

PD invariably progresses with time. A severity rating method known as the [[Unified Parkinson's Disease Rating Scale]] (UPDRS) is the most commonly used metric for clinical study. A modified version known as the MDS-UPDRS is incresaingly being used. An older scaling method known as the [[Hoehn and Yahr scale]] (originally published in 1967), and a similar scale known as the Modified Hoehn and Yahr scale, have also been commonly used. The Hoehn and Yahr scale defines five basic stages of progression; it emphasizes gait and posture instability levodopa response, although ratings for the status of on and off medication can be applied.

Motor symptoms, if not treated, advance in linear fashion. Untreated individuals lose independent [[ambulation]] after an average of eight years and are bedbound and dependent on others for everyday activities like dressing feeding and bathing after ten years.<ref name="pmid17131223"/> However, it is uncommon to find untreated people nowadays. Medication has improved quality of life considerably and probably life expectancy by reducing early deaths.<ref name="pmid17131223"/> In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.<ref name="pmid17131223"/> However, it is hard to predict what course the disease will take for a given individual.<ref name="pmid17131223"/> Age is the best predictor of disease progression.<ref name="pmid20495568"/> The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.<ref name="pmid20495568"/>

Since current therapies improve many of the motor symptoms, disability at present is mainly related to non-motor features of the disease as well as the non-dopaminergic motor features.<ref name="pmid20495568"/> Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.<ref name="pmid17131223">{{cite journal |author=Poewe W |title=The natural history of Parkinson's disease |journal=J. Neurol. |volume=253 |issue=Suppl 7 |pages=VII2–6 |date=December 2006 |pmid=17131223 |doi=10.1007/s00415-006-7002-7 |s2cid=35082340 }}</ref> As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems;  and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage.<ref name="pmid17131223"/> Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.<ref name="pmid17131223"/> All of these symptoms, especially cognitive decline, greatly increase disability.<ref name="pmid20495568"/><ref name="pmid17131223"/>

The [[life expectancy]] of people with PD is reduced.<ref name="pmid17131223"/> [[Standardized mortality ratio|Mortality ratios]] are around twice those of unaffected people.<ref name="pmid17131223"/> Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality [[risk factor]]s.  On the other hand, a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival.<ref name="pmid17131223"/> Death from [[aspiration pneumonia]] is twice as common in individuals with PD as in the healthy population.<ref name="pmid17131223"/>

In 2013 PD resulted in about 103,000 deaths globally, up from 44,000 deaths in 1990.<ref name=GDB2013>{{cite journal|last1=GBD 2013 Mortality and Causes of Death|first1=Collaborators|title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.|journal=Lancet|date=17 December 2014|pmid=25530442|doi=10.1016/S0140-6736(14)61682-2|volume=385|issue=9963 |pages=117–71|pmc=4340604}}</ref> The death rate increased from an average of 1.5 to 1.8 per 100,000 during that time.<ref name=GDB2013/>

==Epidemiology==
PD is the second most common [[neurodegeneration|neurodegenerative disorder]] after [[Alzheimer's disease]] and affects approximately seven million people globally and one million people in the United States.<ref name="OFP">{{cite journal |last1=Yao|first1=S.C.|last2=Hart|first2=A.D.|last3=Terzella|first3=M.J.|title=An evidence-based osteopathic approach to Parkinson disease |journal=Osteopathic Family Physician |volume=5 |issue=3 |pages=96–101 |date=May 2013 |pmid= |doi=10.1016/j.osfp.2013.01.003 }}</ref><ref name="pmid16713924">{{cite journal |authors=de Lau LM, Breteler MM |title=Epidemiology of Parkinson's disease |journal=Lancet Neurol. |volume=5 |issue=6 |pages=525–35 |date=June 2006 |pmid=16713924 |doi=10.1016/S1474-4422(06)70471-9|s2cid=39310242 }}</ref> The [[prevalence|proportion in a population at a given time]] is about 0.3% in industrialized countries. PD is more common in the elderly and rates rises from 1% in those over 60 years of age to 4% of the population over 80.<ref name="pmid16713924"/> The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset PD, begin between the ages of 20 and 50.<ref name="pmid15172778"/> There is also some evidence that the incidence of the disease reduces in the ninth decade of life. PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.<ref name="pmid16713924"/> Most, but not all, studies show that it is more common in men than women, but others failed to detect any differences between the two sexes.<ref name="pmid16713924"/> The [[incidence (epidemiology)|number of new cases per year]] of PD is between 8 and 18 per 100,000 person–years.<ref name="pmid16713924"/>

==History==
{{Main|History of Parkinson's disease}}
[[File:Charcot1893.jpg|thumb|upright|left|An 1893 photograph of [[Jean-Martin Charcot]], who made important contributions to the understanding of the disease and proposed its current name honoring [[James Parkinson]]]]
Several early sources, including an [[Ancient Egypt|Egyptian]] [[papyrus]], an [[ayurveda|Ayurvedic]] medical treatise, the [[Bible]], and [[Galen]]'s [[Leonardo da Vinci]]'s writings, describe symptoms suggestive of PD.<ref name="pmid15568171">{{cite journal |author=García Ruiz PJ|title=Prehistoria de la enfermedad de Parkinson |trans-title=[Prehistory of Parkinson's disease] |language=Spanish|journal=Neurologia |volume=19 |issue=10 |pages=735–7 |date=December 2004 |pmid=15568171 }}</ref> After Galen there are no references unambiguously related to PD until the 17th century.<ref name="pmid15568171"/> In the 17th and 18th centuries, several authors wrote about elements of the disease, including [[Franciscus Sylvius|Sylvius]], [[Hieronymus David Gaubius|Gaubius]], [[John Hunter (surgeon)|Hunter]] and [[Auguste François Chomel|Chomel]].<ref name="pmid15568171"/><ref name="pmid19892136">{{cite journal |author=Lanska DJ |title=Chapter 33: the history of movement disorders |journal=Handb. Clin. Neurol. |volume=95 |pages=501–46 |year=2010 |pmid=19892136 |doi=10.1016/S0072-9752(08)02133-7 |series=Handbook of Clinical Neurology |isbn=9780444520098 }}</ref><ref name="pmid9380070">{{cite journal |authors=Koehler PJ, Keyser A |title=Tremor in Latin texts of Dutch physicians: 16th–18th centuries |journal=Mov. Disord. |volume=12 |issue=5 |pages=798–806 |date=September 1997 |pmid=9380070 |doi=10.1002/mds.870120531|s2cid=310819 }}</ref>

In 1817 an English doctor, [[James Parkinson]], published his essay reporting six cases of paralysis agitans.<ref name="pmid18175393">{{cite journal |author=Lees AJ |title=Unresolved issues relating to the shaking palsy on the celebration of James Parkinson's 250th birthday |journal=Mov. Disord. |volume=22 |issue=Suppl 17 |pages=S327–34 |date=September 2007 |pmid=18175393 |doi=10.1002/mds.21684 |s2cid=9471754 |url=}}</ref> ''An Essay on the Shaking Palsy'' described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.<ref name="An Essay on the Shaking Palsy"/><ref name="pmid9399240">{{cite journal |author=Louis ED |title=The shaking palsy, the first forty-five years: a journey through the British literature |journal=Mov. Disord. |volume=12 |issue=6 |pages=1068–72 |date=November 1997 |pmid=9399240 |doi=10.1002/mds.870120638 |s2cid=34630080 |url=}}</ref> Early neurologists who made further additions to the knowledge of the disease include [[Armand Trousseau|Trousseau]], [[William Richard Gowers|Gowers]], [[Samuel Alexander Kinnier Wilson|Kinnier Wilson]] and [[Wilhelm Heinrich Erb|Erb]], and [[Jean-Martin Charcot]] whose studies between 1868 and 1881 were a landmark in the understanding of the disease.<ref name="pmid18175393"/> Among other advances, he made the distinction between rigidity, weakness and bradykinesia.<ref name="pmid18175393"/> He also championed the renaming of the disease in honor of James Parkinson.<ref name="pmid18175393"/>

In 1912 [[Frederic Lewy]] described microscopic particles in affected brains, later named "[[Lewy body|Lewy bodies]]".<ref name="pmid18175393"/> In 1919 [[Konstantin Tretiakoff]] reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by [[Rolf Hassler]] in 1938.<ref name="pmid18175393"/> The underlying [[biochemical]] changes in the [[brain]] were identified in the 1950s, due largely to the work of [[Arvid Carlsson]] on the neurotransmitter dopamine and [[Oleh Hornykiewicz]] on its role on PD.<ref name="pmid18781671"/> In 1997, alpha-synuclein was found to be the main component of Lewy bodies by [[Maria Grazia Spillantini|Spillantini]], [[John Q. Trojanowski|Trojanowski]], [[Michel Goedert|Goedert]] and others.<ref name="pmid20563819"/>

Anticholinergics and surgery (lesioning of the [[corticospinal pathway]] or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically.<ref name="pmid19892136"/><ref name="pmid9361073">{{cite journal |authors=Guridi J, Lozano AM |title=A brief history of pallidotomy |journal=Neurosurgery |volume=41 |issue=5 |pages=1169–80; discussion 1180–3 |date=November 1997 |pmid=9361073 |doi= 10.1097/00006123-199711000-00029}}</ref> [[Levodopa]] was first synthesized in 1911 by [[Casimir Funk]], but it received little attention until the mid 20th century.<ref name="pmid18781671"/> It entered clinical practice in 1967 and brought about a revolution in the management of PD.<ref name="pmid18781671">{{cite journal |author=Fahn S |title=The history of dopamine and levodopa in the treatment of Parkinson's disease |journal=Mov. Disord. |volume=23 |issue=Suppl 3 |pages=S497–508 |year=2008 |pmid=18781671 |doi=10.1002/mds.22028 |s2cid=45572523 |url=}}</ref><ref>{{cite journal |author=Hornykiewicz O |title=L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent |journal=Amino Acids |volume=23 |issue=1–3 |pages=65–70 |year=2002 |pmid=12373520 |doi=10.1007/s00726-001-0111-9|s2cid=25117208 }}</ref> 

==Society and culture==

===Cost===
[[File:Pdtulip-aware3-72dpi.jpg|thumb|125px|"Parkinson's awareness" logo with red tulip symbol.]]
The costs of PD to society are high, but precise calculations are difficult due to methodological issues in research and differences between countries.<ref name="pmid17702630">{{cite journal |author=Findley LJ |title=The economic impact of Parkinson's disease |journal=Parkinsonism Relat. Disord. |volume=13 |issue=Suppl  |pages=S8–S12 |date=September 2007 |pmid=17702630 |doi=10.1016/j.parkreldis.2007.06.003 |url=}}</ref>  The annual cost in the UK is estimated to be between 449 million and 3.3 billion pounds, while the cost per patient per year in the U.S. is probably around $10,000 and the total burden around 23 billion dollars.<ref name="pmid17702630"/> The largest share of direct cost comes from [[inpatient care]] and nursing homes, while the share coming from medication is substantially lower.<ref name="pmid17702630"/> Indirect costs are high, due to reduced productivity and the burden on caregivers.<ref name="pmid17702630"/> In addition to economic costs, PD reduces [[quality of life]] of those with the disease and their caregivers.<ref name="pmid17702630"/>

===Advocacy===
11 April, the birthday of James Parkinson, has been designated as Parkinson's disease day.<ref name="pmid18175393"/><ref name="tulip"/> A red tulip was chosen by international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip [[cultivar]], registered in 1981 by a Dutch horticulturalist.<ref name="tulip">{{cite web| url=http://www.gsk.com/infocus/parkinsons.htm| title=Parkinson's – 'the shaking palsy'| date=1 April 2009|publisher=GlaxoSmithKline}}</ref> Advocacy organizations include the [[National Parkinson Foundation]], which has provided more than $180 million in care, research and support services since 1982,<ref name="urlNational Parkinson Foundation – Mission">{{cite web |url=http://www.parkinson.org/About-Us/Mission |title=National Parkinson Foundation – Mission |accessdate=28 March 2011}}</ref> [[Parkinson's Disease Foundation]], which has distributed nearly $110 million for research and nearly $47 million for education and advocacy programs since its founding in 1957 by William Black;<ref>{{cite magazine|magazine=Time|url=http://www.time.com/time/magazine/article/0,9171,828597,00.html |title=Education: Joy in Giving| date=18 January 1960|accessdate=2 April 2011}}</ref><ref>{{cite web|url=http://www.pdf.org/en/about_pdf|title=About PDF |publisher=Parkinson's Disease Foundation|accessdate=22 July 2015}}</ref> the [[American Parkinson Disease Association]], founded in 1961;<ref>{{cite web|url=http://www.apdaparkinson.org/userND/index.asp|title= American Parkinson Disease Association: Home |publisher=American Parkinson Disease Association |accessdate=9 August 2010}}</ref> Parkinson’s UK, which has been helping people with Parkinson’s in the UK for over 40 years, and the [[European Parkinson's Disease Association]], founded in 1992.<ref>{{cite web|url=http://www.epda.eu.com/about-us/|title=About EPDA|year=2010|publisher= European Parkinson's Disease Association |accessdate=9 August 2010}}</ref>

===Notable cases===
{{main|List of people diagnosed with Parkinson's disease}}
[[File:Muhammad Ali, Davos.jpg|thumb|upright|right|[[Muhammad Ali]] at the [[World Economic Forum]] in [[Davos]], at the age of 64. He has shown signs of parkinsonism since the age of 38.]]
<!--

Parkinson's is a common disease, so lots of notable people have it.  Please only add people here who have played a MAJOR role in supporting research or public understanding of the disease.  All others can be listed at the main article about people diagnosed with Parkinson's disease.

 -->Actor [[Michael J. Fox]] has PD and has greatly increased the public awareness of the disease.<ref name="MJF_TIME">{{cite news| url=http://www.time.com/time/specials/2007/time100/article/0,28804,1595326_1615754_1615882,00.html | title=Michael J. Fox| date=3 May 2007| author=Davis P|work=The TIME 100|publisher=[[Time (magazine)|Time]]|accessdate=2 April 2011}}</ref> After diagnosis, Fox embraced his Parkinson's in television roles, sometimes acting without medication, in order to further illustrate the effects of the condition. He has written two autobiographies in which his fight against the disease plays a major role,<ref name="MJF_guardian">{{cite news| url=http://www.guardian.co.uk/lifeandstyle/2009/apr/11/michael-j-fox-parkinsons | title='It's the gift that keeps on taking'| date=11 April 2009| author=Brockes E|work=The Guardian|accessdate=25 October 2010}}</ref> and appeared before the [[United States Congress]] without medication to illustrate the effects of the disease.<ref name="MJF_guardian" /> [[The Michael J. Fox Foundation]] aims to develop a cure for Parkinson's disease.<ref name="MJF_guardian" /> Fox received an [[honorary doctorate]] in medicine from [[Karolinska Institutet]] for his contributions to research in Parkinson's disease.<ref name="doctorate_Fox">{{cite news| url=http://ki.se/ki/jsp/polopoly.jsp?d=25844&a=96573&l=en&newsdep=25844 | title=Michael J. Fox to be made honorary doctor at Karolinska Institutet| date=5 March 2010| publisher=Karolinska Institutet|accessdate=2 April 2011 }}</ref>

Professional cyclist and Olympic medalist [[Davis Phinney]], who was diagnosed with young onset Parkinson's at age 40, started the [[Davis Phinney Foundation]] in 2004 to support Parkinson's research, focusing on quality of life for people with the disease.<ref>{{cite web|last=Macur|first=Juliet|title=For the Phinney Family, a Dream and a Challenge|url=http://www.nytimes.com/2008/03/26/sports/othersports/26cycling.html?pagewanted=all&_r=0|work=The New York Times|accessdate=25 May 2013|date=26 March 2008|quote=About 1.5 million Americans have received a diagnosis of Parkinson’s disease, but only 5 to 10 percent learn of it before age 40, according to the National Parkinson Foundation. Davis Phinney was among the few.}}</ref><ref name="DPF">{{cite web|url=http://davisphinneyfoundation.org/dpf/who-we-are/ |title=Who We Are |publisher=Davis Phinney Foundation |accessdate=18 January 2012}}</ref><ref name="Phinney2">{{cite press release| url=http://www.davisphinneyfoundation.org/atf/cf/%7B79AE86BA-CFD7-437E-A98E-2A5F5429BA65%7D/Exercise%20Video%20Release%20FNL.pdf| title=Davis Phinney foundation launches exercise-focused tools to help people live well with Parkinson's | date=19 October 2010|publisher=Davis Phinney foundation|author= Emanuel, W|accessdate=2 April 2011 }}</ref>

[[Muhammad Ali]] showed signs of Parkinson's when he was 38, but was not diagnosed until he was 42, and has been called the "world's most famous Parkinson's patient".<ref name="Ali_NN_comment">{{cite journal| url=http://www.aan.com/elibrary/neurologynow/?event=home.showArticle&id=ovid.com:/bib/ovftdb/01222928-200602020-00003| title=Muhammad Ali's Message: Keep Moving Forward| date=April 2006|journal=Neurology Now |publisher=American Academy of Neurology|author=Brey RL|volume=2|issue=2|page=8|accessdate=2 April 2011| doi=10.1097/01222928-200602020-00003}}</ref> Whether he has PD or a [[parkinsonism]] [[Dementia pugilistica|related to boxing]] is unresolved.<ref name="Ali_NN">{{cite journal| url=http://journals.lww.com/neurologynow/Fulltext/2006/02020/Ali_s_Fighting_Spirit.4.aspx| title=Ali's Fighting Spirit| date=April 2006|journal=Neurology Now |publisher=American Academy of Neurology|author=Matthews W|volume=2|issue=2|pages=10–23|accessdate=2 April 2011| doi=10.1097/01222928-200602020-00004| s2cid=181104230}}</ref><ref name="Ali_NYT">{{cite news| url=http://www.nytimes.com/1988/07/17/magazine/ali-still-magic.html| title=Ali: Still Magic| date=17 July 1988| author= Tauber P|work=New York Times|accessdate=2 April 2011}}</ref> Ray Kennedy the Arsenal and Liverpool football player developed PD towards the end of his professional football career at the age of 35. Retrospective examination of television footage confirmed that he had physical signs in one arm while he was still playing football at a high level(Lees 1992).  

==Research==
{{See also|Parkinson's disease clinical research}}
There is little prospect of dramatic new PD treatments expected in the next 5 years.<ref name=Dimond/> Currently active research directions include the search for new [[animal model]]s of the disease and studies of the potential usefulness of [[gene therapy]], [[stem cell]] transplants and [[neuroprotective]] agents.<ref name="pmid20495568"/>

===Animal models===
PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The neurotoxin 6-hydroxydopamine, also known as 6-OHDA, creates a model of PD in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra or the striatum.<ref>{{cite journal|last1=Blum|first1=D|last2=Torch|first2=S|title=Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease|journal=Progress in Neurobiology|date=October 2001|volume=65|issue=2|pages=135–172|doi=10.1016/S0301-0082(01)00003-X|pmid=11403877|last3=Lambeng|first3=N|last4=Nissou|first4=M|last5=Benabid|first5=AL|last6=Sadoul|first6=R|last7=Verna|first7=JM|s2cid=19095092}}</ref> The appearance of parkinsonian symptoms in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic [[opiate]] [[MPPP]] led to the discovery of the chemical [[MPTP]] as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans.<ref name="pmid6823561">{{cite journal |authors=Langston JW, Ballard P, Tetrud JW, Irwin I |title=Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis |journal=Science |volume=219 |issue=4587 |pages=979–80|date=February 1983 |pmid=6823561 |doi= 10.1126/science.6823561|bibcode=1983Sci...219..979L }}</ref> Other predominant toxin-based models employ the insecticide [[rotenone]], the herbicide [[paraquat]] and the fungicide [[maneb]].<ref name="pmid19729209">{{cite journal|authors=Cicchetti F, Drouin-Ouellet J, Gross RE |title=Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? |journal=Trends Pharmacol. Sci. |volume=30 |issue=9 |pages=475–83 |date=September 2009|pmid=19729209 |doi=10.1016/j.tips.2009.06.005 }}</ref> Models based on toxins are most commonly used in [[primate]]s. [[Transgenic]] rodent models that replicate various aspects of PD have been developed.<ref name="pmid18642640">{{cite journal |authors=Harvey BK, Wang Y, Hoffer BJ |title=Transgenic rodent models of Parkinson's disease |journal=Acta Neurochir. Suppl. |volume=101 |pages=89–92 |year=2008 |pmid=18642640 |pmc=2613245 |doi= 10.1007/978-3-211-78205-7_15|url= |series=Acta Neurochirurgica Supplementum |isbn=978-3-211-78204-0}}</ref>

===Gene therapy===
Gene therapy typically involves the use of a non-infectious [[virus]] (i.e., a [[viral vector]] such as the [[adeno-associated virus]]) to shuttle genetic material into a part of the brain. The gene used leads to the production of proteins that could affect symptoms of PD in a variety of ways including increasing dopamine production, stimulating the sprouting or regeneration of remaining dopamine cells by trophic factors, or causing neurons to change their transmitter function in hopes of normalizing basal ganglia network activity.<ref name="pmid20495568"/><ref name="pmid20155994">{{cite journal |authors=Feng, LR, Maguire-Zeiss KA |title=Gene Therapy in Parkinson's Disease: Rationale and Current Status |journal=CNS Drugs |volume=24 |issue=3|pages=177–92 |year=2010|pmid=20155994 |pmc=2886503|doi=10.2165/11533740-000000000-00000}}</ref> In 2010 there were four clinical trials using gene therapy in PD.<ref name="pmid20495568"/> There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.<ref name="pmid20495568"/> One of these reported positive results in 2011,<ref name="pmid21419704">{{cite journal |authors=Lewitt PA, Rezai AR, Leehey MA|title=AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial |journal=Lancet Neurol |volume=10 |issue=4 |pages=309–19|date=April 2011 |pmid=21419704 |doi=10.1016/S1474-4422(11)70039-4|s2cid=37154043 }}</ref> but the company filed for bankruptcy in March 2012.<ref>{{cite web |url=http://www.bloomberg.com/news/2012-03-16/neurologix-files-to-liquidate-under-chapter-7-bankruptcy-1-.html |title=Neurologix Files to Liquidate Under Chapter 7 Bankruptcy|website=[[Bloomberg News]] }}</ref> More recently, gene therapy for the trophic factor neurturin, injected into both the striatum and substantia nigra, failed to show benefit in a well-designed randomized controlled clinical trial.<ref name="Warren">Warren Olanow C, Bartus RT, Baumann TL, Factor S, Boulis N, Stacy M, Turner DA, Marks W, Larson P, Starr PA, Jankovic J, Simpson R, Watts R, Guthrie B, Poston K, Henderson JM, Stern M, Baltuch G, Goetz CG, Herzog C, Kordower JH, Alterman R, Lozano AM, Lang AE. "Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial." ''Ann Neurol.'' 2015 Aug;78(2):248-57. doi: 10.1002/ana.24436. PMID: 26061140</ref>


=== Neuroprotective treatments ===
[[File:GDNF.jpg|thumb|Several chemical compounds such as [[GDNF]] (chemical structure pictured) have been proposed as neuroprotectors in PD, but their effectiveness has not been proven.]]
Investigations on [[neuroprotective|neuroprotection]] are at the forefront of PD research. Several molecules have been proposed as potential treatments.<ref name="pmid20495568"/> However, none of them have been conclusively demonstrated to reduce degeneration.<ref name="pmid20495568"/> Agents currently under investigation include, [[calcium channel blocker]]s ([[isradipine]]) and [[growth factor]]s ([[GDNF]]).<ref name="pmid20495568"/> Preclinical research also targets [[alpha-synuclein]].<ref name=Dimond>{{cite web|url=http://www.genengnews.com/analysis-and-insight/no-new-parkinson-disease-drug-expected-anytime-soon/77899336/|title=No New Parkinson Disease Drug Expected Anytime Soon |author=Dimond PF|date=16 August 2010|work=GEN news highlights |publisher=GEN-Genetic Engineering & Biotechnology News }}</ref> Both active and passive methods of immunizing against [[alpha-synuclein]] are being actively pursued.<ref name=NS1>{{cite web|url=http://www.newscientist.com/article/mg21428682.000-worlds-first-parkinsons-vaccine-is-trialled.html |title=World's first Parkinson's vaccine is trialled |date=7 June 2012 |publisher=New Scientist }}</ref>

=== Neural transplantation ===
Since early in the 1980s, [[fetus|fetal]], [[pig|porcine]], [[Common carotid artery|carotid]] or [[retina]]l tissues have been used in cell transplants, in which cells are injected into the [[striatum]] in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.<ref name="pmid20495568"/>
Although there was initial evidence of [[Mesencephalon|mesencephalic]] dopamine-producing cell transplants being beneficial, [[Double-blind#Double-blind trials|double-blind trials]] to date indicate that cell transplants fail to provide adequate benefit in the majority of patients, particularly in these trials, although individual patients (often younger and with milder disease) have shown marked prolonged improvement.<ref name="pmid20495568">{{cite journal |authors=Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G |title=Missing pieces in the Parkinson's disease puzzle |journal=Nat. Med. |volume= 16|issue= 6|pages= 653–61|date=May 2010 |pmid=20495568 |doi=10.1038/nm.2165|s2cid=3146438 }}</ref> An additional significant problem was the development of graft-induced dyskinesias that did not require levodopa or other dopaminergic medications to be maintained.<ref>{{cite journal |author=Redmond DE |title=Cellular replacement therapy for Parkinson's disease—where we are today? |journal=The Neuroscientist|volume=8 |issue=5 |pages=457–88 |date=October 2002 |pmid=12374430|doi=10.1177/107385802237703}}</ref> [[Stem cell]] transplants are a recent research target, because stem cells are easy to manipulate and stem cells transplanted into the brains of rodents and monkeys have been found to survive and reduce behavioral abnormalities.<ref name="pmid20495568"/><ref name="Science Daily">{{cite web|url=http://www.sciencedaily.com/releases/2006/12/061204123212.htm |title=Stem Cell Research Aims to Tackle Parkinson's Disease |accessdate=16 April 2010}}</ref> Nevertheless, use of fetal stem cells is [[Stem cell controversy|controversial]].<ref name="pmid20495568"/> It has been proposed that effective treatments may be developed in a less controversial way by use of [[induced pluripotent stem cell]]s taken from adults.<ref name="pmid20495568"/> It remains uncertain whether early ‘physiological’ replacement of the damaged nigrostriatal dopamine pathway will correct all the symptoms and signs of Parkinson’s disease.<ref name="Olanow">Olanow CW, Kordower JH, Lang AE, Obeso JA. "Dopaminergic transplantation for Parkinson's disease: current status and future prospects." ''Ann Neurol.'' 2009 Nov;66(5):591-6. doi: 10.1002/ana.21778. PMID: 19938101</ref>

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==References==
{{Reflist|30em}}
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