Parkinson's disease - Wikipedia, the free encyclopedia · Parkinson's, idiopathic parkinsonism , primary parkinsonism , PD , or paralysis agitans) is a degenerative disorder of the

Parkinson's disease

Classification and external resources

Illustration of Parkinson's disease by William

Richard Gowers, which was first published in A

Manual of Diseases of the �ervous System (1886)

ICD-10 G20. (http://apps.who.int

/classifications/apps/icd/icd10online

/?gg20.htm+g20) , F02.3

(http://apps.who.int/classifications

/apps/icd/icd10online

/?gf00.htm+f023)

ICD-9 332 (http://www.icd9data.com

/getICD9Code.ashx?icd9=332)

OMIM 168600 (http://omim.org/entry

/168600) 556500 (http://omim.org

/entry/556500)

DiseasesDB 9651

(http://www.diseasesdatabase.com

/ddb9651.htm)

MedlinePlus 000755 (http://www.nlm.nih.gov

/medlineplus/ency/article

/000755.htm)

eMedicine neuro/304

(http://www.emedicine.com/neuro

/topic304.htm) neuro/635

(http://www.emedicine.com/neuro

/topic635.htm#) in young

pmr/99 (http://www.emedicine.com

/pmr/topic99.htm#) rehab

Parkinson's diseaseFrom Wikipedia, the free encyclopedia

Parkinson's disease (also known as Parkinson disease,

Parkinson's, idiopathic parkinsonism, primary

parkinsonism, PD, or paralysis agitans) is a

degenerative disorder of the central nervous system. It

results from the death of dopamine-containing cells in the

substantia nigra, a region of the midbrain; the cause of

cell-death is unknown. Early in the course of the disease,

the most obvious symptoms are movement-related,

including shaking, rigidity, slowness of movement and

difficulty with walking and gait. Later, cognitive and

behavioural problems may arise, with dementia commonly

occurring in the advanced stages of the disease. Other

symptoms include sensory, sleep and emotional problems.

PD is more common in the elderly with most cases

occurring after the age of 50.

The main motor symptoms are collectively called

parkinsonism, or a "parkinsonian syndrome". Parkinson's

disease is often defined as a parkinsonian syndrome that is

idiopathic (having no known cause), although some

atypical cases have a genetic origin. Many risk and

protective factors have been investigated: the clearest

evidence is for an increased risk of PD in people exposed

to certain pesticides and a reduced risk in tobacco

smokers. The pathology of the disease is characterized by

the accumulation of a protein called alpha-synuclein into

inclusions called Lewy bodies in neurons, and from

insufficient formation and activity of dopamine produced

in certain neurons of parts of the midbrain. Diagnosis of

typical cases is mainly based on symptoms, with tests

such as neuroimaging being used for confirmation.

Modern treatments are effective at managing the early

motor symptoms of the disease, mainly through the use of

levodopa and dopamine agonists. As the disease

progresses and dopamine neurons continue to be lost, a

point eventually arrives at which these drugs become

ineffective at treating the symptoms and at the same time

produce a complication called dyskinesia, marked by

involuntary writhing movements. Diet and some forms of

rehabilitation have shown some effectiveness at

alleviating symptoms. Surgery and deep brain stimulation

have been used to reduce motor symptoms as a last resort

in severe cases where drugs are ineffective. Research

directions include a search of new animal models of the

disease and investigations of the potential usefulness of

gene therapy, stem cell transplants and neuroprotective

agents. Medications to treat non-movement-related

symptoms of PD, such as sleep disturbances and

emotional problems, also exist.

1 of 23

GeneReviews Parkinson Disease Overview

(http://www.ncbi.nlm.nih.gov

/bookshelf/br.fcgi?book=gene&

part=parkinson-overview)

The disease is named after the English doctor James

Parkinson, who published the first detailed description in

An Essay on the Shaking Palsy in 1817. 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, April 11, and the

use of a red tulip as the symbol of the disease. People with parkinsonism who have enhanced the public's

awareness include Michael J. Fox and Muhammad Ali.

Contents

1 Classification

2 Signs and symptoms2.1 Motor

2.2 Neuropsychiatric

2.3 Other

3 Causes

4 Pathology

4.1 Anatomical pathology4.2 Pathophysiology

4.3 Brain cell death

5 Diagnosis6 Management

6.1 Levodopa

6.2 Dopamine agonists6.3 MAO-B inhibitors

6.4 Other drugs

6.5 Surgery and deep brain stimulation6.6 Rehabilitation

6.7 Diet

6.8 Palliative care6.9 Other treatments

7 Prognosis

8 Epidemiology8.1 Risk factors

8.2 Protective factors

9 History10 Research directions

10.1 Animal models

10.2 Gene therapy10.3 Neuroprotective treatments

10.4 Neural transplantation

11 Society and culture11.1 Cost

11.2 Advocacy

11.3 Notable cases

12 Support groups

13 References

2 of 23

Handwriting of a person affected by

PD in Lectures on the diseases of the

nervous system by Charcot (1879).

The original description of the text

states "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

14 External links14.1 Videos

Classification

The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness,

slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes

according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and

parkinson plus syndromes or multiple system degeneration.[1] Parkinson's disease is the most common form

of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external

identifiable cause.[2][3] In recent years several genes that are directly related to some cases of Parkinson's

disease have been discovered. As much as this can go against the definition of Parkinson's disease as an

idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included

under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's

disease" can be used to differentiate genetic from truly idiopathic forms of the disease.[4]

PD is usually classified as a movement disorder, although it also gives rise to several non-motor types of

symptoms such as sensory deficits,[5] cognitive difficulties or sleep problems. Parkinson plus diseases are

primary parkinsonisms which present additional features.[2] They include multiple system atrophy,

progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies.[2]

In terms of pathophysiology, PD is considered a synucleinopathy due to an abnormal accumulation of alpha-

synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer's

disease where the brain accumulates tau protein in the form of neurofibrillary tangles.[6] Nevertheless, there

is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of

Alzheimer's disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary

tangles in brains affected by PD.[6]

Dementia with Lewy bodies (DLB) is another synucleinopathy that has 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.[7] They may represent parts of a continuum or they may be separate diseases.[7]

Signs and symptoms

Main article: Signs and symptoms of Parkinson's disease

Parkinson's disease affects movement, producing motor symptoms.[1]

Non-motor symptoms, which include autonomic dysfunction,

neuropsychiatric problems (mood, cognition, behavior or thought

alterations), and sensory and sleep difficulties, are also common.[1]

Motor

Further information: Parkinsonian gait

Four motor symptoms are considered cardinal in PD: tremor, rigidity,

slowness of movement, and postural instability.[1]

Tremor is the most apparent and well-known symptom.[1] It is the

3 of 23

comparative firmness and are, in fact,

nearly normal — the finer up-strokes,

on the contrary, are all tremulous in

appearance (...)."

A man with Parkinson's

disease displaying a flexed

walking posture pictured in

1892. Photo appeared in

�ouvelle Iconographie de la

Salpètrière, vol. 5.

most common; though around 30% of individuals with PD do not

have tremor at disease onset, most develop it as the disease

progresses.[1] It is usually a rest tremor: maximal when the limb is at

rest and disappearing with voluntary movement and sleep.[1] It

affects to a greater extent the most distal part of the limb and at onset

typically appears in only a single arm or leg, becoming bilateral later.[1]

Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A

feature of tremor is "pill-rolling", a term used to describe the tendency of the

index finger of the hand to get into contact with the thumb and perform

together a circular movement.[1][8] The term derives from the similarity

between the movement in PD patients and the earlier pharmaceutical

technique of manually making pills.[8]

Bradykinesia (slowness of movement) is another characteristic feature of

PD, and is associated with difficulties along the whole course of the

movement process, from planning to initiation and finally execution of a

movement.[1] Performance of sequential and simultaneous movement is

hindered.[1] Bradykinesia is the most disabling symptom in the early stages

of the disease.[2] Initial manifestations are problems when performing daily

tasks which require fine motor control such as writing, sewing or getting

dressed.[1] Clinical evaluation is based in similar tasks such as alternating

movements between both hands or both feet.[2] Bradykinesia is not equal for

all movements or times. It is modified by the activity or emotional state of

the subject, to the point that some patients are barely able to walk yet can

still ride a bicycle.[1] Generally patients have less difficulty when some sort

of external cue is provided.[1][9]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and

continuous contraction of muscles.[1] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or

ratchety (cogwheel rigidity).[1][2][10][11] The combination of tremor and increased tone is considered to be

at the origin of cogwheel rigidity.[12] Rigidity may be associated with joint pain; such pain being a frequent

initial manifestation of the disease.[1] In early stages of Parkinson's disease, rigidity is often asymmetrical

and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[13]

With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls,

and secondarily to bone fractures.[1] Instability is often absent in the initial stages, especially in younger

people.[2] Up to 40% of the patients may experience falls and around 10% may have falls weekly, with

number of falls being related to the severity of PD.[1]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid

shuffling steps and a forward-flexed posture when walking),[1] speech and swallowing disturbances

including voice disorders,[14] mask-like face expression or small handwriting, although the range of possible

motor problems that can appear is large.[1]

&europsychiatric

Parkinson's disease can cause neuropsychiatric disturbances which can range from mild to severe. This

includes disorders of speech, cognition, mood, behaviour, and thought.[1]

4 of 23

PDB rendering of Parkin (ligase)

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.[1][15] 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 slowed cognitive speed are among other cognitive

difficulties. Memory is affected, specifically in 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.[15]

A person with PD has two to six times the risk of suffering dementia compared to the general population.[1][15] The prevalence of dementia increases with duration of the disease. [15] Dementia is associated with a

reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability

of needing nursing home care.[15]

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,

apathy and anxiety.[1] Impulse control behaviors such as medication overuse and craving, binge eating,

hypersexuality, or pathological gambling can appear in PD and have been related to the medications used to

manage the disease.[1][16] Psychotic symptoms—hallucinations or delusions—occur in 4% of patients, and it

is assumed that the main precipitant of psychotic phenomena in Parkinson’s disease is dopaminergic excess

secondary to treatment; it therefore becomes more common with increasing age and levodopa intake.[17][18]

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.[1] Symptoms can manifest in daytime

drowsiness, disturbances in REM sleep, or insomnia.[1] Alterations in the autonomic nervous system can

lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary

incontinence and altered sexual function.[1] Constipation and gastric dysmotility can be severe enough to

cause discomfort and even endanger health.[19] PD is related to several eye and vision abnormalities such as

decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast

automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred

or double vision.[1][20] Changes in perception may include an impaired sense of smell, sensation of pain and

paresthesia (skin tingling and numbness).[1] All of these symptoms can occur years before diagnosis of the

disease.[1]

Causes

Most people with Parkinson's disease have idiopathic Parkinson's

disease (having no specific known cause). A small proportion of

cases, however, can be attributed to known genetic factors. Other

factors have been associated with the risk of developing PD, but no

causal relationship has been proven.

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.[2] At least 5% of people are now known

to have forms of the disease that occur because of a mutation of one

of several specific genes.[21]

5 of 23

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.

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-

synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), parkin (PRKN), leucine-rich repeat

kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[4][21] 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.[4] 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. Mutations in GBA are known to cause Gaucher's disease.[21]

Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases,

have yielded few positive results, but such studies have been few in number and their size small.[21]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of

Lewy bodies.[21] Missense mutations of the gene (in which a single nucleotide is changed), and duplications

and triplications of the locus containing it have been found in different groups with familial PD.[21] Missense

mutations are rare.[21] On the other hand, multiplications of the SNCA locus account for around 2% of

familial cases.[21] Multiplications have been found in asymptomatic carriers, which indicate that penetrance

is incomplete or age-dependent.[21]

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a

Basque word for tremor, because this gene was first identified in families from England and the north of

Spain.[4] Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting

for up to 10% of individuals with a family history of the disease and 3% of sporadic cases.[4][21] More than

40 different mutations of the gene have been found to be related to PD.[21]

Pathology

Anatomical pathology

The basal ganglia, a group of "brain structures" innervated by the

dopaminergic system, are the most seriously affected brain areas in

PD.[22] The main pathological characteristic of PD 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.[4]

Macroscopic alterations can be noticed on cut surfaces of the

brainstem, where neuronal loss can be inferred from a reduction of

melanin pigmentation in the substantia nigra and locus coeruleus.[23]

The histopathology (microscopic anatomy) of the substantia nigra

and several other brain regions shows neuronal loss and Lewy bodies

in many of the remaining nerve cells. Neuronal loss is accompanied

by death of astrocytes (star-shaped glial cells) and activation of the

microglia (another type of glial cell). Lewy bodies are a key

pathological feature of PD.[23]

Pathophysiology

The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine-secreting

cells caused by cell death in the pars compacta region of the substantia nigra.[22]

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are

6 of 23

A. Schematic initial progression of

Lewy body deposits in the first stages

of Parkinson's disease, as proposed by

Braak and colleagues

B. Localization of the area of

significant brain 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[24]

known as the motor, oculo-motor, associative, limbic and

orbitofrontal circuits, with names indicating the main projection area

of each circuit.[22] 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.[22] Scientifically, the motor circuit

has been examined the most intensively.[22]

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.[22] 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, 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.[22] 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 dyskinesias.[22]

Brain cell death

There is speculation of several mechanisms by which the brain cells could be lost.[25] 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.[4][26] 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, with individuals at this stage being

asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the

midbrain and basal forebrain, and in a last step the neocortex.[4] 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.[25][26] In patients with dementia, a generalized presence of Lewy bodies is common in cortical areas.

Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the

person is demented.[23]

Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced

mitochondrial activity.[25] 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.[27]

Diagnosis

A physician will diagnose Parkinson's disease from the medical history and a neurological examination.[1]

There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out

disorders that could give rise to similar symptoms. Patients may be given levodopa and resulting relief of

7 of 23

Fludeoxyglucose (18F)

(FDG)] 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.

motor impairment tends to confirm diagnosis. The finding of Lewy bodies in

the midbrain on autopsy is usually considered proof that the patient suffered

from Parkinson's disease. The progress of the illness over time may reveal it

is not Parkinson's disease, and some authorities recommend that the

diagnosis be periodically reviewed.[1][28]

Other causes that can secondarily produce a parkinsonian syndrome are

Alzheimer's disease, multiple cerebral infarction and drug-induced

parkinsonism.[28] Parkinson plus syndromes such as progressive supranuclear

palsy and multiple system atrophy must be ruled out.[1] Anti-Parkinson's

medications are typically less effective at controlling symptoms in Parkinson

plus syndromes.[1] 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.[29] Genetic forms are usually

classified as PD, although the terms familial Parkinson's disease and

familial parkinsonism are used for disease entities with an autosomal

dominant or recessive pattern of inheritance.[2]

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 Parkinson's Disease Society Brain Bank and the US National Institute of

Neurological Disorders and Stroke.[1] The PD Society 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 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 dyskinesias induced

by the intake of excessive levodopa.[1] Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with

specialists such as neurologists having the highest rates.[1]

Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually

appear normal.[30] These techniques are nevertheless useful to rule out other diseases that can be secondary

causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus.[30] 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.[30] Dopaminergic

function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are

ioflupane (123I) (trade name DaTSCA�) and iometopane (Dopascan) for SPECT or fludeoxyglucose (18F)

for PET.[30] A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.[30]

Management

Main article: Treatment of Parkinson's disease

There is no cure for Parkinson's disease, but medications, surgery and multidisciplinary management can

provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are

levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists and

MAO-B inhibitors.[31] The stage of the disease determines which group is most useful. Two stages are

usually distinguished: an initial stage in which the individual with PD has already developed some disability

for which he needs pharmacological treatment, then a second stage in which an individual develops motor

complications related to levodopa usage.[31] Treatment in the initial stage aims for an optimal tradeoff

between good symptom control and side-effects resulting from enhancement of dopaminergic function. The

8 of 23

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.[31] 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.[31] When medications are not enough to

control symptoms, surgery and deep brain stimulation can be of use.[32] In the final stages of the disease,

palliative care is provided to enhance quality of life.[33]

Levodopa

Levodopa has been the most widely used treatment for over 30 years.[31] L-DOPA is converted into

dopamine in the dopaminergic neurons by dopa decarboxylase.[31] Since motor symptoms are produced by a

lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor

symptoms.[31]

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, dyskinesias and joint stiffness.[31] Carbidopa

and benserazide are peripheral dopa decarboxylase inhibitors,[31] 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.[31] Existing

preparations are carbidopa/levodopa (co-careldopa) and benserazide/levodopa (co-beneldopa). Levodopa

has been related to dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and

punding.[16] There are controlled release versions of levodopa in the form intravenous and intestinal

infusions that spread out the effect of the medication. These slow-release levodopa preparations have not

shown an increased control of motor symptoms or motor complications when compared to immediate release

preparations.[31][34]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of

levodopa.[31] It has been used to complement levodopa; however, its usefulness is limited by possible side

effects such as liver damage.[31] A similarly effective drug, entacapone, has not been shown to cause

significant alterations of liver function.[31] Licensed preparations of entacapone contain entacapone alone or

in combination with carbidopa and levodopa.[31]

Levodopa preparations lead in the long term to the development of motor complications characterized by

involuntary movements called dyskinesias and fluctuations in the response to medication.[31] 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).[31] For this

reason, levodopa doses are kept as low as possible while maintaining functionality.[31] Delaying the initiation

of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common

practice.[31] 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.[31] Most people with PD will eventually need levodopa and later develop motor side effects.[31]

Dopamine agonists

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects

to levodopa.[31] 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.[31][35] When used in late PD they are useful at

reducing the off periods.[31] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole,

9 of 23

piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness,

hallucinations, insomnia, nausea and constipation.[31] Sometimes side effects appear even at a minimal

clinically effective dose, leading the physician to search for a different drug.[31] Compared with levodopa,

dopamine agonists may delay motor complications of medication use but are less effective at controlling

symptoms.[31] Nevertheless, they are usually effective enough to manage symptoms in the initial years.[2]

They tend to be more expensive than levodopa.[2] 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.[2] Thus

dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later

onset.[2] Agonists have been related to a impulse control disorders (such as compulsive sexual activity and

eating, and pathological gambling and shopping) even more strongly than levodopa.[16]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and

dyskinesia in late PD.[31] It is administered by intermittent injections or continuous subcutaneous

infusions.[31] Since secondary effects such as confusion and hallucinations are common, individuals

receiving apomorphine treatment should be closely monitored.[31] Two dopamine agonists that are

administered through skin patches (lisuride and rotigotine) have been recently found to be useful for patients

in initial stages and preliminary positive results has been published on the control of off states in patients in

the advanced state.[34]

MAO-B inhibitors

MAO-B inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking

its metabolism. They inhibit 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.[31]

Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the

need for levodopa in early disease, but produce more adverse effects and are less effective than levodopa.

There are few studies of their effectiveness in the advanced stage, although results suggest that they are

useful to reduce fluctuations between on and off periods.[31] An initial study indicated that selegiline in

combination with levodopa increased the risk of death, but this was later disproven.[31]

Other drugs

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms.

However, the evidence supporting them lacks quality, so they are not first choice treatments.[31] 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.[36] Examples are the use of clozapine for psychosis, cholinesterase

inhibitors for dementia, and modafinil for daytime sleepiness.[36][37]

Surgery and deep brain stimulation

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa,

the number of operations declined.[38] 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

is no longer sufficient.[38] 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.[38] Deep brain stimulation (DBS) is the most commonly used surgical treatment. It

involves the implantation of a medical device called a brain pacemaker, which sends electrical impulses to

specific parts of the brain. DBS is recommended for people who have PD who suffer from motor

10 of 23

Placement of an electrode

into the brain. The head is

stabilised in a frame for

stereotactic surgery.

fluctuations and tremor inadequately controlled by medication, or to those

who are intolerant to medication, as long as they do not have severe

neuropsychiatric problems.[32] Other, less common, surgical therapies

involve the formation of lesions in specific subcortical areas (a technique

known as pallidotomy in the case of the lesion being produced in the globus

pallidus).[38]

Rehabilitation

There is some evidence that speech or mobility problems can improve with

rehabilitation, although studies are scarce and of low quality.[39][40] Regular

physical exercise with or without physiotherapy can be beneficial to maintain

and improve mobility, flexibility, strength, gait speed, and quality of life.[40]

However, 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. [41] In terms of improving

flexibility and range of motion for patients experiencing 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. [42]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).[43] Strengthening exercises have shown improvements in strength and

motor function for patients with primary muscular weakness and weakness related to inactivity with mild to

moderate Parkinson’s disease. However, reports show a significant interaction between strength and the time

the medications was taken. Therefore, it is recommended that patients should perform exercises 45 minutes

to one hour after medications, when the patient is at their best.[44] Also, due to the forward flexed posture,

and respiratory dysfunctions in advanced Parkinson’s disease, deep diaphragmatic breathing exercises are

beneficial in improving chest wall mobility and vital capacity. [45] Exercise may improve constipation.[19]

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the

Lee Silverman voice treatment (LSVT).[39][46] Speech therapy and specifically LSVT may improve

speech.[39] 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 activities as possible.[39] 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.[39][47]

Diet

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 of time than normal).[19] 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.[19] As the disease advances, swallowing

difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake

and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food

11 of 23

Global burden of Parkinson's disease,

measured in disability-adjusted life

years per 100,000 inhabitants in 2004

no

data

< 5

5–12.5

12.5–20

20–27.5

27.5–35

35–42.5

42.5–50

50–57.5

directly into the stomach is possible in severe cases.[19]

Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier,

thereby competing for access.[19] When they are taken together, this results in a reduced effectiveness of the

drug.[19] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well

balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products

such as bread or pasta is recommended for similar reasons.[19] To minimize interaction with proteins,

levodopa should be taken 30 minutes before meals.[19] At the same time, regimens for PD restrict proteins

during breakfast and lunch, allowing protein intake in the evening.[19]

Palliative care

Palliative care is often required in the final stages of the disease when all other treatment strategies have

become ineffective. The aim of palliative care is to maximize the quality of life for the person with the

disease and those surrounding him or her. Some central issues of palliative care are: care in the community

while adequate care can be given there, reducing or withdrawing drug intake to reduce drug side effects,

preventing pressure ulcers by management of pressure areas of inactive patients, and facilitating end-of-life

decisions for the patient as well as involved friends and relatives.[33]

Other treatments

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[48] Its

usefulness in PD is an open research topic,[49] although recent studies have shown no effect by rTMS.[50]

Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or

food additives improve symptoms.[51] There is no evidence to substantiate that acupuncture and practice of

Qigong, or Tai 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.[52][53][54] Fava beans and velvet beans are

natural sources of levodopa and are eaten by many people with PD. While they have shown some

effectiveness in clinical trials,[55] their intake is not free of risks. Life-threatening adverse reactions have

been described, such as the neuroleptic malignant syndrome.[56][57]

Prognosis

See also: Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale

PD invariably progresses with time. Motor symptoms, if not treated,

advance aggressively in the early stages of the disease and more

slowly later. Untreated, individuals are expected to lose independent

ambulation after an average of eight years and be bedridden after ten

years.[58] However, it is uncommon to find untreated people

nowadays. Medication has improved the prognosis of motor

symptoms, while at the same time it is a new source of disability

because of the undesired effects of levodopa after years of use.[58] In

people taking levodopa, the progression time of symptoms to a stage

of high dependency from caregivers may be over 15 years.[58]

However, it is hard to predict what course the disease will take for a

given individual.[58] Age is the best predictor of disease

progression.[25] 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

12 of 23

57.5–65

65–72.5

72.5–80

> 80

U.S. Army helicopter spraying Agent

Orange over Vietnamese agricultural

land during the Vietnam war. Agent

onset.[25]

Since current therapies improve motor symptoms, disability at

present is mainly related to non-motor features of the disease.[25]

Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially

related to motor symptoms.[58] 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.[58] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems,

mood alterations and cognitive decline.[58] All of these symptoms, especially cognitive decline, greatly

increase disability.[25][58]

The life expectancy of people with PD is reduced.[58] Mortality ratios are around twice those of unaffected

people.[58] Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of

swallowing problems are all mortality risk factors. On the other hand a disease pattern mainly characterized

by tremor as opposed to rigidity predicts an improved survival.[58] Death from aspiration pneumonia is twice

as common in individuals with PD as in the healthy population.[58]

Epidemiology

PD is the second most common neurodegenerative disorder after Alzheimer's disease.[59] The prevalence

(proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized

countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to

4% of the population over 80.[59] The mean age of onset is around 60 years, although 5–10% of cases,

classified as young onset, begin between the ages of 20 and 50.[2] PD may be less prevalent in those of

African and Asian ancestry, although this finding is disputed.[59] Some studies have proposed that it is more

common in men than women, but others failed to detect any differences between the two sexes.[59] The

incidence of PD is between 8 and 18 per 100,000 person–years.[59]

Many risk factors and protective factors have been proposed, sometimes in relation to theories concerning

possible mechanisms of the disease, however none have been conclusively related to PD by empirical

evidence. When epidemiological studies have been carried out in order to test the relationship between a

given factor and PD, they have often been flawed and their results have in some cases been

contradictory.[59] The most frequently replicated relationships are an increased risk of PD in those exposed

to pesticides, and a reduced risk in smokers.[59]

Risk factors

Injections of the synthetic neurotoxin MPTP produce a range of

symptoms similar to those of PD as well as selective damage to the

dopaminergic neurons in the substantia nigra. This observation has

led to theorizing that exposure to some environmental toxins may

increase the risk of having PD.[59] Exposure to toxins that have been

consistently related to the disease can double the risk of PD, and

include certain pesticides, such as rotenone or paraquat, and

herbicides, such as Agent Orange.[59][60][61] Indirect measures of

exposure, such as living in rural environments, have been found to

increase the risk of PD.[61] Heavy metals exposure has been

proposed to be a risk factor, through possible accumulation in the

13 of 23

Orange has been associated with PD.

A 1893 photograph of

Jean-Martin Charcot, who

made important contributions

to the understanding of the

disease and proposed its

current name honoring James

Parkinson

substantia nigra; however, studies on the issue have been

inconclusive.[59]

Protective factors

Smoking has been related to a reduced risk of having PD. Smokers' risk of having PD may be reduced down

to a third when compared to non-smokers.[59] The basis for this effect is not known, but possibilities include

an effect of nicotine as a dopamine stimulant.[59] Tobacco smoke contains compounds that act as MAO

inhibitors that also might contribute to this effect.[62] Caffeine consumption also protects against PD.[63]

Antioxidants, such as vitamins C and D, have been proposed to protect against the disease but results of

studies have been contradictory and no positive effect has been proven.[59] The results regarding fat and

fatty acids have been contradictory, with various studies reporting protective effects, risk-enhancing effects

or no effects.[59] Finally there have been preliminary indications of a possible protective role of estrogens

and anti-inflammatory drugs.[59]

History

Main article: History of Parkinson's disease

Several early sources, including an Egyptian papyrus, an Ayurvedic medical

treatise, the Bible, or Galen's writings, describe symptoms resembling those

of PD.[64] After Galen there are no references unambiguously related to PD

until the 17th century.[64] In the 17th and 18th centuries, several authors

wrote about elements of the disease, including Sylvius, Gaubius, Hunter and

Chomel.[64][65][66]

In 1817 an English doctor, James Parkinson, published his essay reporting six

cases of paralysis agitans.[67] 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.[67][68] Early neurologists who made further additions to the knowledge

of the disease include Trousseau, Gowers, Kinnier Wilson and Erb, and most

notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a

landmark in the understanding of the disease.[67] Among other advances, he

made the distinction between rigidity, weakness and bradykinesia.[67] He

also championed the renaming of the disease in honor of James

Parkinson.[67]

In 1912 Frederic Lewy described microscopic particles in affected brains,

later named "Lewy bodies".[67] 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.[67] 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 its role on PD.[69] In 1997, alpha-synuclein was found to be

the main component of Lewy bodies.[26]

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.[65][70]

Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th

14 of 23

While several chemical compounds

such as GDNF (chemical structure

pictured) have been proposed as

neuroprotectors in PD, none have

proven efficacy.

century.[69] It entered clinical practice in 1967 and brought about a revolution in the management of

PD.[69][71] By the late 1980s deep brain stimulation emerged as a possible treatment.[72]

Research directions

See also: Parkinson's disease clinical research

There is little prospect of dramatic new PD treatments expected in a short time frame.[73] Currently active

research directions include the search for new animal models of the disease and studies of the potential

usefulness of gene therapy, stem cell transplants and neuroprotective agents.[25]

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 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.[74] Other predominant toxin-based models employ the insecticide rotenone, the herbicide

paraquat and the fungicide maneb.[75] Models based on toxins are most commonly used in primates.

Transgenic rodent models that replicate various aspects of PD have been developed.[76]

Gene therapy

Gene therapy involves the use of a non-infectious virus to shuttle a gene into a part of the brain. The gene

used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from

further damage.[25][77] In 2010 there were four clinical trials using gene therapy in PD.[25] There have not

been important adverse effects in these trials although the clinical usefulness of gene therapy is still

unknown.[25] One of these reported positive results in 2011.[78]

&europrotective treatments

Investigations on neuroprotection are at the forefront of PD research.

Several molecules have been proposed as potential treatments.[25]

However, none of them have been conclusively demonstrated to

reduce degeneration.[25] Agents currently under investigation include

anti-apoptotics (TCH346, CEP-1347), antiglutamatergics,

monoamine oxidase inhibitors (selegiline, rasagiline),

promitochondrials (coenzyme Q10, creatine), calcium channel

blockers (isradipine) and growth factors (GDNF).[25] Preclinical

research also targets alpha-synuclein.[73]

&eural transplantation

Since early in the 1980s, fetal, porcine, carotid or retinal tissues have

been used in cell transplants, in which dissociated cells are injected

into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that

replaces the dopamine-producing cells that have been lost.[25] Although there was initial evidence of

mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that

cell transplants produce no long-term benefit.[25] An additional significant problem was the excess release of

dopamine by the transplanted tissue, leading to dystonias.[79] Stem cell transplants are a recent research

15 of 23

Muhammad Ali at the age of

64 in 2006. He has shown

signs of parkinsonism since

the age of 38.

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.[25][80] Nevertheless, use of fetal

stem cells is controversial.[25] It has been proposed that effective treatments may be developed in a less

controversial way by use of induced pluripotent stem cells taken from adults.[25]

Society and culture

Cost

The costs of PD to society are high, but difficult to calculate exactly due to

methodological difficulties in research and differences between countries.[81]

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 US is probably

around $10,000 and the total burden around 23 billion dollars.[81] The largest

share of direct cost comes from inpatient care and nursing homes, while the

share coming from medications is substantially lower.[81] Indirect costs are

high, due to reduced productivity and the burden on caregivers.[81] In

addition to economic costs, PD reduces quality of life of those with the

disease and their caregivers.[81]

Advocacy

April 11, the birthday of James Parkinson, has been designated as the world's

Parkinson's disease day.[67][82] A red tulip was chosen by several

international organizations as the symbol of the disease in 2005: it represents

the James Parkinson Tulip cultivar, registered in 1981 by a Dutch

horticulturalist.[82] Advocacy organizations on the disease include the

National Parkinson Foundation, which has provided more than $155 million

in care, research and support services since 1982,[83] Parkinson's Disease

Foundation, which has provided more than $85 million for research and $34

million for education and advocacy programs since its foundation in 1957 by William Black;[84][85] the

American Parkinson Disease Association, founded in 1961;[86] and the European Parkinson's Disease

Association, founded in 1992.[87]

&otable cases

Main article: List of people diagnosed with Parkinson's disease

Among the many famous people with PD, one who has greatly increased the public awareness of the disease

is the actor Michael J. Fox. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from

the public for seven years.[88] He has written two autobiographic books in which his fight against the disease

plays a major role,[89] and appeared before the United States Congress without medication to illustrate the

effects of the disease.[89] The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. In

recent years it has been the major Parkinson's fundraiser in the US, providing 140 million dollars in research

funding between 2001 and 2008.[89] Fox's work led him to be named one of the 100 people "whose power,

talent or moral example is transforming the world" in 2007 by Time magazine,[88] and he received an

honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's

disease.[90] Another foundation that supports Parkinson's research was established by professional cyclist

Davis Phinney.[91] The Davis Phinney Foundation strives to improve the lives of those living with

16 of 23

Gerald Ganglbauer's Parkins(on)line

Parkinson's disease by providing them with information and tools.[92] Muhammad Ali has been called the

"world's most famous Parkinson's patient".[93] He was 42 at diagnosis although he already showed signs of

Parkinson's when he was 38.[94] Nevertheless, whether he has PD or a parkinsonian syndrome caused by

boxing is still an open question.[94][95]

Support groups

One of Parkinson's organisations around the world most valuable and

popular services is the development and coordination of a network of

Parkinson's support groups.[96] A support group, or self-help group is

an informal gathering of people who share similar experiences,

situations or problems. Parkinson's support group members can offer

each other emotional and practical support. Getting together with other people who are facing similar

challenges allows everyone to share feelings, resources and experiences. Active participation provides

benefits from the exchange of practical information, as well as motivation and inspiration to help members

deal positively with the changes to their lifestyle. Support groups also offer a chance to meet new people,

which helps to break down any feelings of isolation associated with the disease. Support groups meet in the

real world for group discussions, educational sessions by guest speakers, social outings, and, with the

popularity of the internet, also in virtual support groups, such as Parkins(on)line.[97]

References

^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am

Jankovic J (April 2008).

"Parkinson's disease: clinical features and diagnosis" (http://jnnp.bmj.com/content/79/4/368.full) . J. �eurol.

�eurosurg. Psychiatr. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045 (http://dx.doi.org

/10.1136%2Fjnnp.2007.131045) . PMID 18344392 (http://www.ncbi.nlm.nih.gov/pubmed/18344392) .

http://jnnp.bmj.com/content/79/4/368.full.

1.

^ a b c d e f g h i j k l m n Samii A, Nutt JG, Ransom BR (May 2004). "Parkinson's disease". Lancet 363 (9423):

1783–93. doi:10.1016/S0140-6736(04)16305-8 (http://dx.doi.org/10.1016%2FS0140-6736%2804%2916305-8)

. PMID 15172778 (http://www.ncbi.nlm.nih.gov/pubmed/15172778) .

2.

^ Schrag A (2007). "Epidemiology of movement disorders". In Tolosa E, Jankovic JJ. Parkinson's disease and

movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 50–66. ISBN 0-7817-7881-6.

3.

^ a b c d e f g h Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27.

doi:10.1093/bmb/ldn013 (http://dx.doi.org/10.1093%2Fbmb%2Fldn013) . PMID 18398010

(http://www.ncbi.nlm.nih.gov/pubmed/18398010) .

4.

^ Barnett-Cowan M, Dyde RT, Foxe SH, Moro E, Hutchison WD, Harris LR (June 2010). "Multisensory

determinants of orientation perception in Parkinson's disease". �euroscience 167 (4): 1138–50.

doi:10.1016/j.neuroscience.2010.02.065 (http://dx.doi.org/10.1016%2Fj.neuroscience.2010.02.065) .

PMID 20206672 (http://www.ncbi.nlm.nih.gov/pubmed/20206672) .

5.

^ a b Galpern WR, Lang AE (March 2006). "Interface between tauopathies and synucleinopathies: a tale of two

proteins". Ann. �eurol. 59 (3): 449–58. doi:10.1002/ana.20819 (http://dx.doi.org/10.1002%2Fana.20819) .


6.

^ a b Aarsland D, Londos E, Ballard C (April 2009). "Parkinson's disease dementia and dementia with Lewy

bodies: different aspects of one entity". Int. Psychogeriatr. 21 (2): 216–9. doi:10.1017/S1041610208008612

(http://dx.doi.org/10.1017%2FS1041610208008612) . PMID 19173762 (http://www.ncbi.nlm.nih.gov/pubmed

/19173762) .

7.

^ a b Cooper G, Eichhorn G, Rodnitzky RL (2008). "Parkinson's disease". In Conn PM. �euroscience in

medicine. Totowa, NJ: Humana Press. pp. 508–512. ISBN 978-1-60327-454-8.

8.

^ Rodriguez-Oroz MC, Jahanshahi M, Krack P, et al. (December 2009). "Initial clinical manifestations of

Parkinson's disease: features and pathophysiological mechanisms". Lancet �eurol. 8 (12): 1128–39.

doi:10.1016/S1474-4422(09)70293-5 (http://dx.doi.org/10.1016%2FS1474-4422%2809%2970293-5) .


9.

^ Banich MT, Compton RJ (2011). "Motor control". Cognitive neuroscience. Belmont, CA: Wadsworth,10.

17 of 23

Cengage learning. pp. 108–44. ISBN 0-8400-3298-6.

^ Longmore, Murray; Wilkinson, Ian B.; Turmezei, Tom; Cheung, Chee Kay (2007-01-04). Oxford Handbook

of Clinical Medicine. Oxford University Press. p. 486. ISBN 978-0-19-856837-7.

11.

^ Fung VSC, Thompson PD (2007). "Rigidity and spasticity". In Tolosa E, Jankovic JJ. Parkinson's disease

and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 504–13. ISBN 0-7817-7881-6.

12.

^ O'Sullivan, Susan B, Schmitz, Thomas J (2007). Physical Rehabilitation (5th Ed.) "Parkinson's Disease".

Philidephia: F.A. Davis. pp. 856–857.

13.

^ Russell JA, Ciucci MR, Connor NP, Schallert T. (2010 Jun 23). "Targeted exercise therapy for voice and

swallow in persons with Parkinson's disease". Brain Res. 1341: 3-11. PMC 2908992

(http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=2908992) . PMID 20233583


14.

^ a b c d e Caballol N, Martí MJ, Tolosa E (September 2007). "Cognitive dysfunction and dementia in Parkinson

disease". Mov. Disord.. 22 Suppl 17 (S17): S358–66. doi:10.1002/mds.21677 (http://dx.doi.org

/10.1002%2Fmds.21677) . PMID 18175397 (http://www.ncbi.nlm.nih.gov/pubmed/18175397) .

15.

^ a b c Ceravolo R, Frosini D, Rossi C, Bonuccelli U (December 2009). "Impulse control disorders in

Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management". Parkinsonism Relat.

Disord.. 15 Suppl 4: S111–5. doi:10.1016/S1353-8020(09)70847-8 (http://dx.doi.org

/10.1016%2FS1353-8020%2809%2970847-8) . PMID 20123548 (http://www.ncbi.nlm.nih.gov/pubmed

/20123548) .

16.

^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170290/pdf/v065p00610.pdf17.

^ Friedman JH (June 2010). "Parkinson's disease psychosis 2010: A review article". Parkinsonism Relat.

Disord. 16 (9): 553–60. doi:10.1016/j.parkreldis.2010.05.004 (http://dx.doi.org

/10.1016%2Fj.parkreldis.2010.05.004) . PMID 20538500 (http://www.ncbi.nlm.nih.gov/pubmed/20538500) .

18.

^ a b c d e f g h i j Barichella M, Cereda E, Pezzoli G (October 2009). "Major nutritional issues in the

management of Parkinson's disease". Mov. Disord. 24 (13): 1881–92. doi:10.1002/mds.22705 (http://dx.doi.org


19.

^ Armstrong RA (March 2008). "Visual signs and symptoms of Parkinson's disease". Clin. Exp. Optom. 91 (2):

129–38. doi:10.1111/j.1444-0938.2007.00211.x (http://dx.doi.org/10.1111%2Fj.1444-0938.2007.00211.x) .


20.

^ a b c d e f g h i j k Lesage S, Brice A (April 2009). "Parkinson's disease: from monogenic forms to genetic

susceptibility factors". Hum. Mol. Genet. 18 (R1): R48–59. doi:10.1093/hmg/ddp012 (http://dx.doi.org

/10.1093%2Fhmg%2Fddp012) . PMID 19297401 (http://www.ncbi.nlm.nih.gov/pubmed/19297401) .

21.

^ a b c d e f g h Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, et al. (2008). "Functional organization of the

basal ganglia: therapeutic implications for Parkinson's disease". Mov. Disord.. 23 Suppl 3 (S3): S548–59.

doi:10.1002/mds.22062 (http://dx.doi.org/10.1002%2Fmds.22062) . PMID 18781672


22.

^ a b c Dickson DV (2007). "Neuropathology of movement disorders". In Tolosa E, Jankovic JJ. Parkinson's

disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 271–83.

ISBN 0-7817-7881-6.

23.

^ Jubault T, Brambati SM, Degroot C, et al. (2009). Gendelman, Howard E.. ed. "Regional brain stem atrophy

in idiopathic Parkinson's disease detected by anatomical MRI". PLoS O�E 4 (12): e8247.

doi:10.1371/journal.pone.0008247 (http://dx.doi.org/10.1371%2Fjournal.pone.0008247) . PMC 2784293



24.

^ a b c d e f g h i j k l m n o p q r s Obeso JA, Rodriguez-Oroz MC, Goetz CG, et al. (May 2010). "Missing pieces

in the Parkinson's disease puzzle". �at. Med. 16 (6): 653–61. doi:10.1038/nm.2165 (http://dx.doi.org

/10.1038%2Fnm.2165) . PMID 20495568 (http://www.ncbi.nlm.nih.gov/pubmed/20495568) .

25.

^ a b c Schulz-Schaeffer WJ (August 2010). "The synaptic pathology of alpha-synuclein aggregation in dementia

with Lewy bodies, Parkinson's disease and Parkinson's disease dementia". Acta �europathol. 120 (2): 131–43.

doi:10.1007/s00401-010-0711-0 (http://dx.doi.org/10.1007%2Fs00401-010-0711-0) . PMC 2892607



26.

^ Hirsch EC (December 2009). "Iron transport in Parkinson's disease". Parkinsonism Relat. Disord.. 15 Suppl

3: S209–11. doi:10.1016/S1353-8020(09)70816-8 (http://dx.doi.org


/20082992) .

27.

^ a b The National Collaborating Centre for Chronic Conditions, ed (2006). "Diagnosing Parkinson's Disease".

Parkinson's Disease (http://guidance.nice.org.uk/CG35/Guidance/pdf/English) . London: Royal College of

28.

18 of 23

Physicians. pp. 29–47. ISBN 1-86016-283-5.

^ Poewe W, Wenning G (November 2002). "The differential diagnosis of Parkinson's disease". Eur. J. �eurol..

9 Suppl 3: 23–30. PMID 12464118 (http://www.ncbi.nlm.nih.gov/pubmed/12464118) .

29.

^ a b c d e Brooks DJ (April 2010). "Imaging approaches to Parkinson disease". J. �ucl. Med. 51 (4): 596–609.

doi:10.2967/jnumed.108.059998 (http://dx.doi.org/10.2967%2Fjnumed.108.059998) . PMID 20351351


30.

^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah The National Collaborating Centre for Chronic

Conditions, ed (2006). "Symptomatic pharmacological therapy in Parkinson’s disease". Parkinson's Disease

(http://guidance.nice.org.uk/CG35/Guidance/pdf/English) . London: Royal College of Physicians. pp. 59–100.

ISBN 1-86016-283-5.

31.

^ a b Bronstein JM, Tagliati M, Alterman RL, et al. (February 2011). "Deep brain stimulation for Parkinson

disease: an expert consensus and review of key issues". Arch. �eurol. 68 (2): 165.

doi:10.1001/archneurol.2010.260 (http://dx.doi.org/10.1001%2Farchneurol.2010.260) . PMID 20937936


32.

^ a b The National Collaborating Centre for Chronic Conditions, ed (2006). "Palliative care in Parkinson’s

disease". Parkinson's Disease (http://guidance.nice.org.uk/CG35/Guidance/pdf/English) . London: Royal

College of Physicians. pp. 147–51. ISBN 1-86016-283-5.

33.

^ a b Tolosa E, Katzenschlager R (2007). "Pharmacological management of Parkinson's disease". In Tolosa E,

Jankovic JJ. Parkinson's disease and movement disorders. Hagerstwon, MD: Lippincott Williams & Wilkins.

pp. 110–45. ISBN 0-7817-7881-6.

34.

^ Goldenberg MM (October 2008). "Medical management of Parkinson's disease". P & T 33 (10): 590–606.

PMC 2730785 (http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=2730785) .


35.

^ a b The National Collaborating Centre for Chronic Conditions, ed (2006). "Non-motor features of Parkinson’s



36.

^ Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, Pandurangi AK (July 2009).

"Pharmacological management of psychosis in elderly patients with parkinsonism". Am. J. Med. 122 (7):

614–22. doi:10.1016/j.amjmed.2009.01.025 (http://dx.doi.org/10.1016%2Fj.amjmed.2009.01.025) .


37.

^ a b c d The National Collaborating Centre for Chronic Conditions, ed (2006). "Surgery for Parkinson’s



38.

^ a b c d e The National Collaborating Centre for Chronic Conditions, ed (2006). "Other key interventions".

Parkinson's Disease (http://guidance.nice.org.uk/CG35/Guidance/pdf/English) . London: Royal College of

Physicians. pp. 135–46. ISBN 1-86016-283-5.

39.

^ a b Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL (April 2008). "The effectiveness of

exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis". Mov.

Disord. 23 (5): 631–40. doi:10.1002/mds.21922 (http://dx.doi.org/10.1002%2Fmds.21922) . PMID 18181210


40.

^ Dereli, E. E., & Yaliman, A. (2010). Comparison of the effects of a physiotherapist-supervised exercise

programme and a self-supervised exercise program on quality of life in patients with Parkinson's disease.

Clinical Rehabilitation, 24(4), 352-362.

41.


Philidephia: F.A. Davis. pp. 873 & 876.

42.

^ O'Sullivan, Susan, B.,. In O'Sullivan and Schmitz (2007). Physical Rehabilitation (5th Ed.). Philadelphia: F.A

Davis. pp. 879.

43.


Philidephia: F.A. Davis. pp. 877.

44.


Philidephia: F.A. Davis. pp. 880.

45.

^ Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG (November 2006). "The science and

practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease

and other neurological disorders". Semin. Speech. Lang. 27 (4): 283–99. doi:10.1055/s-2006-955118

(http://dx.doi.org/10.1055%2Fs-2006-955118) . PMID 17117354 (http://www.ncbi.nlm.nih.gov/pubmed

/17117354) .

46.

^ Dixon L, Duncan D, Johnson P, et al. (2007). Deane, Katherine. ed. "Occupational therapy for patients with

Parkinson's disease". Cochrane Database Syst. Rev. (3): CD002813. doi:10.1002/14651858.CD002813.pub2

47.

19 of 23

(http://dx.doi.org/10.1002%2F14651858.CD002813.pub2) . PMID 17636709 (http://www.ncbi.nlm.nih.gov

/pubmed/17636709) .

^ Koch G (2010). "rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for

effective cortical targets". Restor. �eurol. �eurosci. 28 (4): 561–8. doi:10.3233/RNN-2010-0556

(http://dx.doi.org/10.3233%2FRNN-2010-0556) . PMID 20714078 (http://www.ncbi.nlm.nih.gov/pubmed

/20714078) .

48.

^ Platz T, Rothwell JC (2010). "Brain stimulation and brain repair—rTMS: from animal experiment to clinical

trials—what do we know?". Restor. �eurol. �eurosci. 28 (4): 387–98. doi:10.3233/RNN-2010-0570

(http://dx.doi.org/10.3233%2FRNN-2010-0570) . PMID 20714064 (http://www.ncbi.nlm.nih.gov/pubmed

/20714064) .

49.

^ Arias P, Vivas J, Grieve KL, Cudeiro J (September 2010). "Controlled trial on the effect of 10 days

low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease"

(http://dx.doi.org/10.1002/mds.23055) . Mov. Disord. 25 (12): 1830–8. doi:10.1002/mds.23055

(http://dx.doi.org/10.1002%2Fmds.23055) . PMID 20669300 (http://www.ncbi.nlm.nih.gov/pubmed/20669300) .

http://dx.doi.org/10.1002/mds.23055. Retrieved 2011-04-02.

50.

^ Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ (April 2006). "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". �eurology 66

(7): 976–82. doi:10.1212/01.wnl.0000206363.57955.1b (http://dx.doi.org

/10.1212%2F01.wnl.0000206363.57955.1b) . PMID 16606908 (http://www.ncbi.nlm.nih.gov/pubmed

/16606908) .

51.

^ Lee MS, Lam P, Ernst E (December 2008). "Effectiveness of tai chi for Parkinson's disease: a critical

review". Parkinsonism Relat. Disord. 14 (8): 589–94. doi:10.1016/j.parkreldis.2008.02.003 (http://dx.doi.org


52.

^ Lee MS, Ernst E (January 2009). "Qigong for movement disorders: A systematic review". Mov. Disord. 24

(2): 301–3. doi:10.1002/mds.22275 (http://dx.doi.org/10.1002%2Fmds.22275) . PMID 18973253


53.

^ Lee MS, Shin BC, Kong JC, Ernst E (August 2008). "Effectiveness of acupuncture for Parkinson's disease: a

systematic review". Mov. Disord. 23 (11): 1505–15. doi:10.1002/mds.21993 (http://dx.doi.org


54.

^ Katzenschlager R, Evans A, Manson A, et al (2004). "Mucuna pruriens in Parkinson's disease: a double blind

clinical and pharmacological study". J. �eurol. �eurosurg. Psychiatr. 75 (12): 1672–7.

doi:10.1136/jnnp.2003.028761 (http://dx.doi.org/10.1136%2Fjnnp.2003.028761) . PMC 1738871



55.

^ Ladha SS, Walker R, Shill HA (May 2005). "Case of neuroleptic malignant-like syndrome precipitated by

abrupt fava bean discontinuance". Mov. Disord. 20 (5): 630–1. doi:10.1002/mds.20380 (http://dx.doi.org


56.

^ Raguthu L, Varanese S, Flancbaum L, Tayler E, Di Rocco A (October 2009). "Fava beans and Parkinson's

disease: useful 'natural supplement' or useless risk?". Eur. J. �eurol. 16 (10): e171.

doi:10.1111/j.1468-1331.2009.02766.x (http://dx.doi.org/10.1111%2Fj.1468-1331.2009.02766.x) .


57.

^ a b c d e f g h i j k l Poewe W (December 2006). "The natural history of Parkinson's disease". J. �eurol.. 253

Suppl 7 (S7): VII2–6. doi:10.1007/s00415-006-7002-7 (http://dx.doi.org/10.1007%2Fs00415-006-7002-7) .


58.

^ a b c d e f g h i j k l m n o de Lau LM, Breteler MM (June 2006). "Epidemiology of Parkinson's disease". Lancet

�eurol. 5 (6): 525–35. doi:10.1016/S1474-4422(06)70471-9 (http://dx.doi.org


/16713924) .

59.

^ Tanner CM, Kamel F, Ross GW, et al. (January 2011). "Rotenone, Paraquat and Parkinson's Disease".

Environ. Health Perspect. doi:10.1289/ehp.1002839 (http://dx.doi.org/10.1289%2Fehp.1002839) .


60.

^ a b IOM (Institute of Medicine), ed (2009). "Neurologic disorders". Veterans and Agent Orange: Update

2008 (http://www.nap.edu/catalog.php?record_id=12662) . Washington D.C.: The National Academies press.

pp. 510–45. ISBN 0-309-13884-1.

61.

^ Castagnoli K, Murugesan T (2004 Jan). "Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's

disease and neuroprotection; are there links?". �eurotoxicology 25 (1–2): 279–91.

doi:10.1016/S0161-813X(03)00107-4 (http://dx.doi.org/10.1016%2FS0161-813X%2803%2900107-4) .

62.

20 of 23


^ Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A (2010). "Caffeine exposure and the risk of Parkinson's

disease: a systematic review and meta-analysis of observational studies". J. Alzheimers Dis.. 20 Suppl 1:

S221–38. doi:10.3233/JAD-2010-091525 (http://dx.doi.org/10.3233%2FJAD-2010-091525) . PMID 20182023


63.

^ a b c García Ruiz PJ (December 2004). "Prehistoria de la enfermedad de Parkinson [[Prehistory of Parkinson's

disease]]" (in Spanish; Castilian). �eurologia 19 (10): 735–7. PMID 15568171 (http://www.ncbi.nlm.nih.gov

/pubmed/15568171) .

64.

^ a b Lanska DJ (2010). "Chapter 33: the history of movement disorders". Handb. Clin. �eurol. 95: 501–46.



65.

^ Koehler PJ, Keyser A (September 1997). "Tremor in Latin texts of Dutch physicians: 16th–18th centuries".

Mov. Disord. 12 (5): 798–806. doi:10.1002/mds.870120531 (http://dx.doi.org/10.1002%2Fmds.870120531) .


66.

^ a b c d e f g h Lees AJ (September 2007). "Unresolved issues relating to the shaking palsy on the celebration of

James Parkinson's 250th birthday". Mov. Disord.. 22 Suppl 17 (S17): S327–34. doi:10.1002/mds.21684

(http://dx.doi.org/10.1002%2Fmds.21684) . PMID 18175393 (http://www.ncbi.nlm.nih.gov/pubmed/18175393) .

67.

^ Louis ED (November 1997). "The shaking palsy, the first forty-five years: a journey through the British

literature". Mov. Disord. 12 (6): 1068–72. doi:10.1002/mds.870120638 (http://dx.doi.org


68.

^ a b c Fahn S (2008). "The history of dopamine and levodopa in the treatment of Parkinson's disease". Mov.

Disord.. 23 Suppl 3 (S3): S497–508. doi:10.1002/mds.22028 (http://dx.doi.org/10.1002%2Fmds.22028) .


69.

^ Guridi J, Lozano AM (November 1997). "A brief history of pallidotomy". �eurosurgery 41 (5): 1169–80;

discussion 1180–3. doi:10.1097/00006123-199711000-00029 (http://dx.doi.org

/10.1097%2F00006123-199711000-00029) . PMID 9361073 (http://www.ncbi.nlm.nih.gov/pubmed/9361073) .

70.

^ Hornykiewicz O (2002). "L-DOPA: from a biologically inactive amino acid to a successful therapeutic

agent". Amino Acids 23 (1–3): 65–70. doi:10.1007/s00726-001-0111-9 (http://dx.doi.org

/10.1007%2Fs00726-001-0111-9) . PMID 12373520 (http://www.ncbi.nlm.nih.gov/pubmed/12373520) .

71.

^ Coffey RJ (March 2009). "Deep brain stimulation devices: a brief technical history and review". Artif.

Organs 33 (3): 208–20. doi:10.1111/j.1525-1594.2008.00620.x (http://dx.doi.org

/10.1111%2Fj.1525-1594.2008.00620.x) . PMID 18684199 (http://www.ncbi.nlm.nih.gov/pubmed/18684199) .

72.

^ a b Dimond PF (2010-08-16). "No New Parkinson Disease Drug Expected Anytime Soon"

(http://www.genengnews.com/analysis-and-insight/no-new-parkinson-disease-drug-expected-anytime-

soon/77899336/) . GE� news highlights. GEN-Genetic Engineering & Biotechnology News.

http://www.genengnews.com/analysis-and-insight/no-new-parkinson-disease-drug-expected-anytime-

soon/77899336/.

73.

^ Langston JW, Ballard P, Tetrud JW, Irwin I (February 1983). "Chronic Parkinsonism in humans due to a

product of meperidine-analog synthesis". Science 219 (4587): 979–80. doi:10.1126/science.6823561

(http://dx.doi.org/10.1126%2Fscience.6823561) . PMID 6823561 (http://www.ncbi.nlm.nih.gov/pubmed

/6823561) .

74.

^ Cicchetti F, Drouin-Ouellet J, Gross RE (September 2009). "Environmental toxins and Parkinson's disease:

what have we learned from pesticide-induced animal models?". Trends Pharmacol. Sci. 30 (9): 475–83.

doi:10.1016/j.tips.2009.06.005 (http://dx.doi.org/10.1016%2Fj.tips.2009.06.005) . PMID 19729209


75.

^ Harvey BK, Wang Y, Hoffer BJ (2008). "Transgenic rodent models of Parkinson's disease". Acta �eurochir.

Suppl. 101: 89–92. doi:10.1007/978-3-211-78205-7_15 (http://dx.doi.org/10.1007%2F978-3-211-78205-7_15) .

PMC 2613245 (http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=2613245) .


76.

^ Feng, LR, Maguire-Zeiss KA (2010). "Gene Therapy in Parkinson's Disease: Rationale and Current Status".

C�S Drugs 24 (3): 177–92. doi:10.2165/11533740-000000000-00000 (http://dx.doi.org

/10.2165%2F11533740-000000000-00000) . PMC 2886503 (http://www.pubmedcentral.gov

/articlerender.fcgi?tool=pmcentrez&artid=2886503) . PMID 20155994 (http://www.ncbi.nlm.nih.gov/pubmed

/20155994) .

77.

^ Lewitt PA, Rezai AR, Leehey MA, et al. (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's

disease: a double-blind, sham-surgery controlled, randomised trial". Lancet �eurol 10 (4): 309–19.



78.

21 of 23

^ Redmond DE (October 2002). "Cellular replacement therapy for Parkinson's disease—where we are today?".

The �euroscientist 8 (5): 457–88. doi:10.1177/107385802237703 (http://dx.doi.org

/10.1177%2F107385802237703) . PMID 12374430 (http://www.ncbi.nlm.nih.gov/pubmed/12374430) .

79.

^ "Stem Cell Research Aims to Tackle Parkinson's Disease" (http://www.sciencedaily.com/releases/2006/12

/061204123212.htm) . http://www.sciencedaily.com/releases/2006/12/061204123212.htm. Retrieved

2010-04-16.

80.

^ a b c d e Findley LJ (September 2007). "The economic impact of Parkinson's disease". Parkinsonism Relat.

Disord.. 13 Suppl: S8–S12. doi:10.1016/j.parkreldis.2007.06.003 (http://dx.doi.org


81.

^ a b "Parkinson's – 'the shaking palsy'" (http://www.gsk.com/infocus/parkinsons.htm) . GlaxoSmithKline.

2009-04-01. http://www.gsk.com/infocus/parkinsons.htm.

82.

^ "National Parkinson Foundation - Mission" (http://www.parkinson.org/About-Us/Mission) .

http://www.parkinson.org/About-Us/Mission. Retrieved 2011-03-28.

83.

^ "Education: Joy in Giving" (http://www.time.com/time/magazine/article/0,9171,828597,00.html) . Time.

1960-01-18. http://www.time.com/time/magazine/article/0,9171,828597,00.html. Retrieved 2011-04-02.

84.

^ "About PDF" (http://www.pdf.org/en/about_pdf) . Parkinson's Disease Foundation. http://www.pdf.org

/en/about_pdf. Retrieved 2010-12-21.

85.

^ "American Parkinson Disease Association: Home" (http://www.apdaparkinson.org/userND/index.asp) .

American Parkinson Disease Association, Inc. http://www.apdaparkinson.org/userND/index.asp. Retrieved

2010-08-09.

86.

^ "About EPDA" (http://www.epda.eu.com/about-us/) . European Parkinson's Disease Association. 2010.

http://www.epda.eu.com/about-us/. Retrieved 2010-08-09.

87.

^ a b Davis P (2007-05-03). "Michael J. Fox" (http://www.time.com/time/specials/2007/time100/article

/0,28804,1595326_1615754_1615882,00.html) . The TIME 100 (Time). http://www.time.com/time/specials

/2007/time100/article/0,28804,1595326_1615754_1615882,00.html. Retrieved 2011-04-02.

88.

^ a b c Brockes E (2009-04-11). "'It's the gift that keeps on taking'" (http://www.guardian.co.uk/lifeandstyle

/2009/apr/11/michael-j-fox-parkinsons) . The Guardian. http://www.guardian.co.uk/lifeandstyle/2009/apr

/11/michael-j-fox-parkinsons. Retrieved 2010-10-25.

89.

^ "Michael J. Fox to be made honorary doctor at Karolinska Institutet" (http://ki.se/ki/jsp

/polopoly.jsp?d=25844&a=96573&l=en&newsdep=25844) . Karolinska Institutet. 2010-03-05. http://ki.se

/ki/jsp/polopoly.jsp?d=25844&a=96573&l=en&newsdep=25844. Retrieved 2011-04-02.

90.

^ Roelofs T (2010-05-10). "Tour de France bicyclist Davis Phinney talks about life with Parkinson's Disease"

(http://www.mlive.com/news/grand-rapids/index.ssf/2010/05/tour_de_france_bicyclist_davis.html) . The Grand

Rapids Press. http://www.mlive.com/news/grand-rapids/index.ssf/2010/05/tour_de_france_bicyclist_davis.html.

Retrieved 2010-10-25.

91.

^ Davis Phinney foundation (2010-10-19). "Davis Phinney foundation launches exercise-focused tools to help

people live well with Parkinson's" (http://www.davisphinneyfoundation.org/atf/cf/%7B79AE86BA-CFD7-437E-

A98E-2A5F5429BA65%7D/Exercise%20Video%20Release%20FNL.pdf) . Press release.

http://www.davisphinneyfoundation.org/atf/cf/%7B79AE86BA-CFD7-437E-A98E-2A5F5429BA65%7D

/Exercise%20Video%20Release%20FNL.pdf. Retrieved 2011-04-02.

92.

^ Brey RL (April 2006). "Muhammad Ali's Message: Keep Moving Forward" (http://www.aan.com/elibrary

/neurologynow/?event=home.showArticle&id=ovid.com:/bib/ovftdb/01222928-200602020-00003) . �eurology

�ow (American Academy of Neurology) 2 (2): 8. http://www.aan.com/elibrary/neurologynow

/?event=home.showArticle&id=ovid.com:/bib/ovftdb/01222928-200602020-00003. Retrieved 2011-04-02.

93.

^ a b Matthews W (April 2006). "Ali's Fighting Spirit" (http://journals.lww.com/neurologynow/Fulltext

/2006/02020/Ali_s_Fighting_Spirit.4.aspx) . �eurology �ow (American Academy of Neurology) 2 (2): 10–23.

http://journals.lww.com/neurologynow/Fulltext/2006/02020/Ali_s_Fighting_Spirit.4.aspx. Retrieved

2011-04-02.

94.

^ Tauber P (1988-07-17). "Ali: Still Magic" (http://www.nytimes.com/1988/07/17/magazine/ali-still-

magic.html) . �ew York Times. http://www.nytimes.com/1988/07/17/magazine/ali-still-magic.html. Retrieved

2011-04-02.

95.

^ Parkinson's NSW Inc. Support Groups (http://www.parkinsonsnsw.org.au/services/support-groups/)96.

^ Parkins(on)line Virtual Support Groups (http://www.parkinsonline.info)97.

External links

Parkinson's Disease (http://www.dmoz.org/Health/Conditions_and_Diseases

22 of 23

/Neurological_Disorders/Parkinson's_Disease//) at the Open Directory ProjectParkinson's Disease: Hope Through Research (National Institute of Neurological Disorders and

Stroke) (http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm)

GeneReview/NIH/UW entry on LRRK2-Related Parkinson Disease (http://www.ncbi.nlm.nih.gov/books/NBK1208/)

European Parkinson's Disease Association (http://www.epda.eu.com/)

Videos

Clinical case video on the effect of subthalamic stimulation on a patient.

(http://www.neuro.jhmi.edu/DBS/cases.htm)Video by the Lloyd Tan Parkinson's Trust Fund showing a patient's tremor, gait, freezing and

dyskinesias (http://www.lloydtan-trust.com/index.php?page=living_sub&type=videos&id=20)

Video by the Lloyd Tan Parkinson's Trust Fund showing a patient's tremor (http://www.lloydtan-trust.com/index.php?page=living_sub&type=videos&id=7)

Retrieved from "http://en.wikipedia.org/wiki/Parkinson%27s_disease"

Categories: Aging-associated diseases | Geriatrics | Parkinson's disease | Cytoskeletal defects

This page was last modified on 28 July 2011 at 20:10.Text is available under the Creative Commons Attribution-ShareAlike License; additional terms

may apply. See Terms of use for details.

Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profitorganization.

23 of 23

Documents

Parkinson's disease - Wikipedia, the free encyclopedia · Parkinson's, idiopathic parkinsonism , primary parkinsonism , PD , or paralysis agitans) is a degenerative disorder of the