Parkinson's disease (PD) is a long-term degenerative disorder of the
central nervous system that mainly affects the motor system. The
symptoms generally come on slowly over time. Early in the disease,
the most obvious are shaking, rigidity, slowness of movement, and
difficulty with walking. Thinking and behavioral problems may also
Dementia becomes common in the advanced stages of the
disease. Depression and anxiety are also common occurring in more
than a third of people with PD. Other symptoms include sensory,
sleep, and emotional problems. The main motor symptoms are
collectively called "parkinsonism", or a "parkinsonian
The cause of
Parkinson's disease is generally unknown, but believed to
involve both genetic and environmental factors. Those with a family
member affected are more likely to get the disease themselves.
There is also an increased risk in people exposed to certain
pesticides and among those who have had prior head injuries, while
there is a reduced risk in tobacco smokers and those who drink coffee
or tea. The motor symptoms of the disease result from the death
of cells in the substantia nigra, a region of the midbrain. This
results in not enough dopamine in these areas. The reason for this
cell death is poorly understood, but involves the build-up of proteins
into Lewy bodies in the neurons. Diagnosis of typical cases is
mainly based on symptoms, with tests such as neuroimaging being used
to rule out other diseases.
There is no cure for Parkinson's disease, with treatment directed at
improving symptoms. Initial treatment is typically with the
antiparkinson medication levodopa (L-DOPA), with dopamine agonists
being used once levodopa becomes less effective. As the disease
progresses and neurons continue to be lost, these medications become
less effective while at the same time they produce a complication
marked by involuntary writhing movements. Diet and some forms of
rehabilitation have shown some effectiveness at improving
symptoms. Surgery to place microelectrodes for deep brain
stimulation has been used to reduce motor symptoms in severe cases
where drugs are ineffective. Evidence for treatments for the
non-movement-related symptoms of PD, such as sleep disturbances and
emotional problems, is less strong.
In 2015, PD affected 6.2 million people and resulted in about 117,400
Parkinson's disease typically occurs in people
over the age of 60, of which about one percent are affected.
Males are more often affected than females at a ratio of around
3:2. When it is seen in people before the age of 50, it is called
young-onset PD. The average life expectancy following diagnosis is
between 7 and 14 years. 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. Public awareness
campaigns include World Parkinson's 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, and late professional boxer Muhammad
2 Signs and symptoms
3.1 Environmental factors
Brain cell death
7.1.2 COMT inhibitors
7.1.4 MAO-B inhibitors
7.1.5 Other drugs
7.4 Palliative care
11 Society and culture
11.3 Notable cases
12.1 Animal models
12.2 Gene therapy
12.4 Neural transplantation
13 See also
15 External links
The movement difficulties found in PD are called parkinsonism and a
number of different disorders feature parkinsonism. "Parkinsonism" is
defined as bradykinesia (slowness in initiating voluntary movements,
with progressive reduction in speed and range of repetitive actions
such as voluntary finger-tapping) in combination with one of three
other physical signs: muscular (lead-pipe or cogwheel) rigidity,
tremor at rest, and postural instability.
Parkinson's disease is the most common form of parkinsonism and is
sometimes called "idiopathic parkinsonism", meaning parkinsonism with
no identifiable cause. Identifiable causes of parkinsonism
include toxins, infections, side effects of drugs, metabolic
derangement, and brain lesions such as strokes. Several
neurodegenerative disorders also may present with parkinsonism and are
sometimes referred to as "atypical parkinsonism" or "Parkinson plus"
syndromes (illnesses with parkinsonism plus some other features
distinguishing them from PD). They include multiple system atrophy,
progressive supranuclear palsy, corticobasal degeneration, and
dementia with Lewy bodies (DLB).
Scientists sometimes refer to Parkinson’s disease as a
synucleiopathy (due to an abnormal accumulation of alpha-synuclein
protein in the brain) to distinguish it from other neurodegenerative
diseases, such as
Alzheimer's disease where the brain accumulates tau
protein. Considerable clinical and pathological overlap exists
between tauopathies and synucleinopathies. In contrast to Parkinson's
Alzheimer's disease presents most commonly with memory loss,
and the cardinal signs of
Parkinson's disease (slowness, tremor,
stiffness, and postural instability) are not normal features of
Dementia with Lewy bodies is another synucleinopathy and it has close
pathological similarities with PD, especially with the subset of PD
cases with dementia. The relationship between PD and DLB is complex
and incompletely understood. They may represent parts of a
continuum with variable distinguishing clinical and pathological
features or they may prove to be separate diseases.
Signs and symptoms
A man with
Parkinson's disease displaying a flexed walking posture
pictured in 1892
Handwriting of a person affected by PD
Main article: Signs and symptoms of Parkinson's disease
The most recognizable symptoms in
Parkinson's disease are movement
("motor") related. Non-motor symptoms, which include autonomic
dysfunction, 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 may be present at the time of diagnosis.
Further information: Parkinsonian gait
Four motor symptoms are considered cardinal in PD: tremor, slowness of
movement (bradykinesia), rigidity, and postural instability.
The most common presenting sign is a coarse slow tremor of the hand at
rest which disappears during voluntary movement of the affected arm
and in the deeper stages of sleep. It typically appears in only
one hand, eventually affecting both hands as the disease
progresses. 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 and thumb to touch and perform together a circular
movement. The term derives from the similarity between the
movement of people with PD and the early pharmaceutical technique of
manually making pills.
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 to execution of a movement.
Performance of sequential and simultaneous movement is impaired.
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 concurrent illnesses. Paradoxically patients with
Parkinson's 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.
Rigidity is stiffness and resistance to limb movement caused by
increased muscle tone, an excessive and continuous contraction of
muscles. In parkinsonism the rigidity can be uniform ("lead-pipe
rigidity") or ratchety ("cogwheel rigidity"). The
combination of tremor and increased tone is considered to be at the
origin of cogwheel rigidity. Rigidity may be associated with joint
pain; such pain being a frequent initial manifestation of the
disease. 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. With the
progression of the disease, rigidity typically affects the whole body
and reduces the ability to move.
Postural instability is typical in the later stages of the disease,
leading to impaired balance and frequent falls, and secondarily to
bone fractures, 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. Up to 40% of people diagnosed with PD may experience
falls and around 10% may have falls weekly, with the number of falls
being related to the severity of PD.
Other recognized motor signs and symptoms include gait and posture
disturbances such as festination (rapid shuffling steps and a
forward-flexed posture when walking with no flexed arm swing).
Freezing of gait (brief arrests when the feet seem to get stuck to the
floor, especially on turning or changing direction), a slurred
monotonous quiet voice, mask-like facial expression, and handwriting
that gets smaller and smaller are other common signs.
Parkinson's disease can cause neuropsychiatric disturbances, which can
range from mild to severe. This includes disorders of cognition, mood,
behavior, and thought.
Cognitive disturbances can occur in the early stages of the disease
and sometimes prior to diagnosis, and increase in prevalence with
duration of the disease. The most common cognitive deficit in
PD is executive dysfunction, which can include problems with planning,
cognitive flexibility, abstract thinking, rule acquisition, inhibiting
inappropriate actions, initiating appropriate actions, working memory,
and control of attention. Other cognitive difficulties include
slowed cognitive processing speed, impaired recall and impaired
perception and estimation of time. 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. A person with PD has two to six
times the risk of dementia compared to the general population.
The prevalence of dementia increases with age and, to a lesser degree,
duration of the disease.
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.
Impulse control disorders including pathological gambling, compulsive
sexual behavior, 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 levodopa use (Giovannoni, et al. 2000).
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. Establishing the diagnosis of depression is
complicated by the fact that the body language of depression may
masquerade as PD including a sad expressionless anxious face, a hang
dog appearance, slow movement, and monotonous speech. Up to 30% of
people with PD may experience symptoms of anxiety, ranging from a
generalized anxiety disorder to social phobia, 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.
Punding in which complicated repetitive aimless stereotyped behaviors
occur for many hours is another disturbance caused by anti-Parkinson
Hallucinations or delusions occur in approximately 50% of people with
PD over the course of the illness, and may herald the emergence of
dementia. These range from minor hallucinations – "sense of passage"
(something quickly passing beside the person) or "sense of 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. Auditory hallucinations are
uncommon in PD, and are rarely described as voices. It is now believed
that psychosis is an integral part of the disease. A psychosis with
delusions and associated delirium is a recognized complication of
anti-Parkinson drug treatment and may also be caused by urinary tract
infections (as frequently occurs in the fragile elderly), but drugs
and infection are not the only factors, and underlying brain pathology
or changes in neurotransmitters or their receptors (e.g.,
acetylcholine, serotonin) are also thought to play a role in psychosis
In addition to neuropsychiatric and motor symptoms, PD can impair
Sleep problems are a feature of the disease and can be worsened by
medications. Symptoms can manifest as daytime drowsiness
(including sudden sleep attacks resembling narcolepsy), disturbances
in REM sleep, or insomnia. 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), oily skin and
excessive sweating, urinary incontinence, and altered sexual
Constipation and impaired stomach emptying (gastric
dysmotility) can be severe enough to cause discomfort and even
endanger health. Changes in perception may include an impaired
sense of smell, disturbed vision, pain, and paresthesia (tingling and
numbness). All of these symptoms can occur years before diagnosis
of the disease.
Main article: Causes of Parkinson's disease
Exposure to pesticides and a history of head injury have each been
linked with Parkinson disease (PD), but the risks are modest. Never
having smoked cigarettes, and never drinking caffeinated beverages,
are also associated with small increases in risk of developing PD.
Low concentrations of urate in the blood serum is associated with an
increased risk of PD.
Parkin crystal structure
Research indicates that PD is the product of a complex interaction of
genetic and environmental factors. Around 15% of individuals with
PD have a first-degree relative who has the disease, and 5–10%
of people with PD are known to have forms of the disease that occur
because of a mutation in one of several specific genes. Harboring
one of these gene mutations may not lead to the disease;
susceptibility factors put the individual at an increased risk, often
in combination with other risk factors, which also affect age of
onset, severity and progression.
Genes implicated in the development of PD include SNCA, LRRK2, GBA,
PRKN, PINK1, PARK7, VPS35, EIF4G1,
DNAJC13 and CHCHD2.
SNCA gene mutations are important in PD because the protein that gene
encodes, alpha-synuclein, is the main component of the Lewy bodies
that accumulate in the brains of people with PD. Mutations in some
genes, including SNCA,
LRRK2 and GBA, have been found to be risk
factors for "sporadic" (non-familial) PD. Mutations in the gene
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. A mutation in GBA
presents the greatest genetic risk of developing Parkinsons
Several Parkinson-related genes are involved in the function of
lysosomes, organelles that digest cellular waste products. It has been
suggested that some cases of PD may be caused by lysosome dysfunctions
that reduce the ability of cells to break down alpha-synuclein.
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.
Main article: Pathophysiology of Parkinson's disease
The main pathological characteristics of PD are cell death in the
brain's basal ganglia (affecting up to 70% of the dopamine secreting
neurons in the substantia nigra pars compacta by the end of life)
and the presence of Lewy bodies (accumulations of the protein
alpha-synuclein) in many of the remaining neurons. This loss of
neurons is accompanied by the death of astrocytes (star-shaped glial
cells) and a significant increase in the number of microglia (another
type of glial cell) in the substantia nigra.
Schematic initial progression of
Lewy body deposits in the first
stages of Parkinson's disease, as proposed by Braak and colleagues
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 brainstem damage may be
the first identifiable stage of PD neuropathology
There are five major pathways in the brain connecting other brain
areas with the basal ganglia. These are known as the motor,
oculo-motor, associative, limbic and orbitofrontal circuits, with
names indicating the main projection area of each circuit. 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.
Scientifically, the motor circuit has been examined the most
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.
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. 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.
Brain cell death
There is speculation of several mechanisms by which the brain cells
could be lost. 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. According to the Braak staging,
a classification of the disease based on pathological findings
proposed by Heiko Braak, Lewy bodies first appear in the olfactory
bulb, medulla oblongata and pontine tegmentum; individuals at this
stage may be asymptomatic or may have early non-motor symptoms (such
as loss of sense of smell, or some sleep or automatic dysfunction). As
the disease progresses, Lewy bodies develop in the substantia nigra,
areas of the midbrain and basal forebrain and, finally, the
neocortex. 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). 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 plaques, characteristic of
Alzheimer's disease, are not common unless the person is demented.
Other cell-death mechanisms include proteasomal and lysosomal system
dysfunction and reduced mitochondrial activity. 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
A physician will initially assess for
Parkinson's disease with a
careful medical history and neurological examination. People may
be given levodopa, with any resulting improvement in motor impairment
helping to confirm the PD diagnosis. The finding of Lewy bodies in the
midbrain on autopsy is usually considered final proof that the person
had PD. The clinical course of the illness over time may reveal it is
not Parkinson's disease, requiring that the clinical presentation be
periodically reviewed to confirm accuracy of the diagnosis.
Other causes that can secondarily produce parkinsonism are stroke and
drugs. Parkinson plus syndromes such as progressive supranuclear
palsy and multiple system atrophy must be ruled out.
Anti-Parkinson's medications are typically less effective at
controlling symptoms in Parkinson plus syndromes. 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. Genetic forms with
an autosomal dominant or recessive pattern of inheritance are
sometimes referred to as familial
Parkinson's disease or familial
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
Brain Bank for Neurological Disorders and the U.S. National
Institute of Neurological Disorders and Stroke. The Queen Square Brain
Bank criteria require slowness of movement (bradykinesia) plus either
rigidity, resting tremor, or postural instability. Other possible
causes of 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
dyskinesias induced by the intake of excessive levodopa.
When PD diagnoses are checked by autopsy, movement disorders experts
are found on average to be 79.6% accurate at initial assessment and
83.9% accurate after they have refined their diagnosis at a follow-up
examination. When clinical diagnoses performed mainly by nonexperts
are checked by autopsy, average accuracy is 73.8%. Overall, 80.6% of
PD diagnoses are accurate, and 82.7% of diagnoses using the
criteria are accurate.
A task force of the International Parkinson and Movement Disorder
Society (MDS) has proposed diagnostic criteria for Parkinson’s
disease as well as research criteria for the diagnosis of prodromal
disease, but these will require validation against the more
Computed tomography (CT) scans of people with PD usually appear
normal. MRI has become more accurate in diagnosis of the disease
over time, specifically through iron-sensitive T2* and SWI sequences
at a magnetic field strength of at least 3T, both of which can
demonstrate absence of the characteristic 'swallow tail' imaging
pattern in the dorsolateral substantia nigra. In a meta-analysis,
absence of this pattern was 98% sensitive and 95% specific for the
Diffusion MRI has shown potential in distinguishing
between PD and Parkinson plus syndromes, though its diagnostic value
is still under investigation. CT and MRI are also used to rule out
other diseases that can be secondary causes of parkinsonism, most
commonly encephalitis and chronic ischemic insults, as well as less
frequent entities such as basal ganglia tumors and hydrocephalus.
Dopamine-related activity in the basal ganglia can be directly
measured with PET and SPECT scans. A finding of reduced
dopamine-related activity in the basal ganglia can rule out
drug-induced parkinsonism, but reduced basal ganglia dopamine-related
activity is seen in both PD and the Parkinson-plus disorders so these
scans are not reliable in distinguishing PD from other
neurodegenerative causes of parkinsonism.
Exercise in middle age may reduce the risk of Parkinson's disease
later in life.
Caffeine also appears protective with a greater
decrease in risk occurring with a larger intake of caffeinated
beverages such as coffee. People who smoke cigarettes or use
smokeless tobacco are less likely than non-smokers to develop PD, and
the more they have used tobacco, the less likely they are to develop
PD. It is not known what underlies this effect. Tobacco use may
actually protect against PD, or it may be that an unknown factor both
increases the risk of PD and causes an aversion to tobacco or makes it
easier to quit using tobacco.
Antioxidants, 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. The results regarding fat
and fatty acids have been contradictory, with various studies
reporting protective effects, risk-increasing effects or no
effects. There have been preliminary indications that the use of
anti-inflammatory drugs and calcium channel blockers may be
protective. A 2010 meta-analysis found that nonsteroidal
anti-inflammatory drugs (apart from aspirin), have been associated
with at least a 15 percent (higher in long-term and regular users)
reduction of incidence of the development of Parkinson's disease.
Main article: Management of Parkinson's disease
Pharmacological treatment of Parkinson's disease
There is no cure for Parkinson's disease, but medications, surgery,
and physical treatment can provide relief and are much more effective
than treatments available for other neurological disorders like
Alzheimer’s disease, motor neuron disease, and Parkinson plus
syndromes. The main families of drugs useful for treating motor
symptoms are levodopa (always combined with a dopa decarboxylase
inhibitor and sometimes also with a COMT inhibitor), dopamine agonists
and MAO-B inhibitors. The stage of the disease and the age at disease
onset determine which group is most useful.
Three stages may be 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 complications related to levodopa usage, and a third
stage when symptoms unrelated to dopamine deficiency or levodopa
treatment may predominate.
Treatment in the first stage aims for an optimal trade off between
symptom control and treatment side-effects. The start of levodopa
treatment may be postponed by initially using other medications such
as MAO-B inhibitors and dopamine agonists instead, in the hope of
delaying the onset of complications due to levodopa use. However,
levodopa is still the most effective treatment for the motor symptoms
of PD and should not be delayed in patients whose quality of life is
impaired by those symptoms. Levodopa-related 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 early use.
In the second stage the aim is to reduce PD symptoms while controlling
fluctuations in the effect of the medication. Sudden withdrawals from
medication or overuse have to be managed. When oral medications
are not enough to control symptoms, surgery, deep brain stimulation,
subcutaneous waking day apomorphine infusion and enteral dopa pumps
can be of use. 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
The motor symptoms of PD are the result of reduced dopamine production
in the brain's basal ganglia.
Dopamine does not cross the blood-brain
barrier, so it cannot be taken as a medicine to boost the brain's
depleted levels of dopamine. However a precursor of dopamine,
levodopa, can pass through to the brain where it is readily converted
to dopamine, and administration of levodopa temporarily diminishes the
motor symptoms of PD.
Levodopa has been the most widely used PD
treatment for over 40 years.
Only 5–10% of levodopa crosses the blood–brain barrier. Much of
the remainder is metabolized to dopamine elsewhere in the body,
causing a variety of side effects including nausea, vomiting and
Carbidopa and benserazide are dopa
decarboxylase inhibitors which do not cross the blood-brain barrier
and inhibit the conversion of levodopa to dopamine outside the brain,
reducing side effects and improving the availability of levodopa for
passage into the brain. One of these drugs is usually taken along with
levodopa, often combined with levodopa in the same pill.
Levodopa use leads in the long term to the development of
complications: involuntary movements called dyskinesias, and
fluctuations in the effectiveness of the medication. When
fluctuations occur, a person can cycle through phases with good
response to medication and reduced PD symptoms ("on" state), and
phases with poor response to medication and significant PD symptoms
("off" state). Using lower doses of levodopa may reduce the risk
and severity of these levodopa-induced complications. A former
strategy to reduce levodopa-related dyskinesia and fluctuations was to
withdraw levodopa medication for some time. This is now discouraged
since it can bring on dangerous side effects such as neuroleptic
malignant syndrome. Most people with PD will eventually need
levodopa and will later develop levodopa-induced fluctuations and
There are controlled-release versions of levodopa. Older
controlled-release levodopa preparations have poor and unreliable
absorption and bioavailability and have not demonstrated improved
control of PD motor symptoms or a reduction in levodopa-related
complications when compared to immediate release preparations. A newer
extended-release levodopa preparation does seem to be more effective
in reducing fluctuations but in many patients problems persist.
Intestinal infusions of levodopa (Duodopa) can result in striking
improvements in fluctuations compared to oral levodopa when the
fluctuations are due to insufficient uptake caused by gastroparesis.
Other oral, longer acting formulations are under study and other modes
of delivery (inhaled, transdermal) are being developed.
Tolcapone inhibits the activity COMT, an enzyme which degrades
dopamine. It has been used to complement levodopa; however, its
usefulness is limited by possible complications such as liver
damage. A similarly effective drug, entacapone, has not been shown
to cause significant alterations of liver function. Licensed
preparations of entacapone contain entacapone alone or in combination
with carbidopa and levodopa.
Several dopamine agonists that bind to dopamine receptors in the brain
have similar effects to levodopa. These were initially used as a
complementary therapy to levodopa for individuals experiencing
levodopa complications (on-off fluctuations and dyskinesias); they are
now mainly used on their own as first therapy for the motor symptoms
of PD with the aim of delaying the initiation of levodopa therapy and
so delaying the onset of levodopa's complications. Dopamine
agonists include bromocriptine, pergolide, pramipexole, ropinirole,
piribedil, cabergoline, apomorphine and lisuride.
Though dopamine agonists are less effective than levodopa at
controlling PD motor symptoms, they are usually effective enough to
manage these symptoms in the first years of treatment. Dyskinesias
due to dopamine agonists are rare in younger people who have PD but,
along with other complications, become more common with older age at
onset. Thus dopamine agonists are the preferred initial treatment
for younger onset PD, and levodopa is preferred for older onset
Dopamine agonists produce significant, although usually mild, side
effects including drowsiness, hallucinations, insomnia, nausea, and
constipation. Sometimes side effects appear even at a minimal
clinically effective dose, leading the physician to search for a
different drug. Agonists have been related to impulse control
disorders (such as compulsive sexual activity, eating, gambling and
shopping) even more strongly than levodopa. They tend to be more
expensive than levodopa.
Apomorphine, a non-orally administered dopamine agonist, may be used
to reduce off periods and dyskinesia in late PD. It is
administered by intermittent injections or continuous subcutaneous
infusions. Since secondary effects such as confusion and
hallucinations are common, individuals receiving apomorphine treatment
should be closely monitored. Two dopamine agonists that are
administered through skin patches (lisuride and rotigotine) and are
useful for people in the initial stages and possibly to control off
states in those in the advanced state.
MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the
amount of dopamine in the basal ganglia by inhibiting the activity of
monoamine oxidase B (MAO-B), an enzyme which breaks down dopamine.
Like dopamine agonists, their use may delay the commencement of
levodopa therapy in early disease, but MAO-B inhibitors produce more
adverse effects and are less effective than levodopa at controlling PD
motor symptoms. 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. An initial study
indicated that selegiline in combination with levodopa increased the
risk of death, but this was later disproven.
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. 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. Examples are the use of quetiapine for psychosis,
cholinesterase inhibitors for dementia, and modafinil for daytime
Doxepin and rasagline may reduce physical fatigue in PD.
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 discovery of levodopa, the number of operations has
declined. 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. 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
Deep brain stimulation
Deep brain stimulation is the most commonly used surgical
treatment, developed in the 1980s by
Alim Louis Benabid
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 neuropsychiatric problems. Other, less common, surgical
therapies involve intentional formation of lesions to suppress
overactivity of specific subcortical areas. For example, pallidotomy
involves surgical destruction of the globus pallidus to control
Further information: Rehabilitation in Parkinson's disease
Exercise programs are recommended in people with Parkinson's
disease. There is some evidence that speech or mobility problems
can improve with rehabilitation, although studies are scarce and of
low quality. Regular physical exercise with or without
physical therapy can be beneficial to maintain and improve mobility,
flexibility, strength, gait speed, and quality of life. 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. In terms
of improving flexibility and range of motion for people 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. 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, the 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). 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 Parkinson's disease. 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. 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. Exercise may improve
constipation. It is unclear if exercise reduces physical fatigue
One of the most widely practiced treatments for speech disorders
Parkinson's disease is the Lee Silverman voice
Speech therapy and specifically LSVT may
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. 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.
Palliative care is specialized medical care for people with serious
illnesses, including Parkinson's. The goal of this speciality is to
improve quality of life for both the person suffering from Parkinson's
and the family by providing relief from the symptoms, pain, and stress
of illnesses. As Parkinson's is not a curable disease, all
treatments are focused on slowing decline and improving quality of
life, and are therefore palliative in nature.
Palliative care should be involved earlier, rather than later in the
Palliative care specialists can help with
physical symptoms, emotional factors such as loss of function and
jobs, depression, fear, and existential concerns.
Along with offering emotional support to both the patient and family,
palliative care serves an important role in addressing goals of care.
People with Parkinson's may have many difficult decisions to make as
the disease progresses such as wishes for feeding tube, non-invasive
ventilator, and tracheostomy; wishes for or against cardiopulmonary
resuscitation; and when to use hospice care.
Palliative care team
members can help answer questions and guide people with Parkinson's on
these complex and emotional topics to help them make the best decision
based on their own values.
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). 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. 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.
deliver food directly into the stomach is possible in severe
Levodopa and proteins use the same transportation system in the
intestine and the blood–brain barrier, thereby competing for
access. When they are taken together, this results in a reduced
effectiveness of the drug. 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. To minimize interaction with proteins,
levodopa should be taken 30 minutes before meals. At the same
time, regimens for PD restrict proteins during breakfast and lunch,
allowing protein intake in the evening.
See also: Unified
Parkinson's disease rating scale
Global burden of Parkinson's disease, measured in disability-adjusted
life years per 100,000 inhabitants in 2004
PD invariably progresses with time. A severity rating method known as
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 also sometimes used. An older scaling method known as
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
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. 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. In people taking levodopa, the progression time of
symptoms to a stage of high dependency from caregivers may be over 15
years. However, it is hard to predict what course the disease
will take for a given individual. Age is the best predictor of
disease progression. 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
Since current therapies improve motor symptoms, disability at present
is mainly related to non-motor features of the disease.
Nevertheless, the relationship between disease progression and
disability is not linear. Disability is initially related to motor
symptoms. 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
levodopa-induced complications, which appear in up to 50% of
individuals after 5 years of levodopa usage. Finally, after ten
years most people with the disease have autonomic disturbances, sleep
problems, mood alterations and cognitive decline. All of these
symptoms, especially cognitive decline, greatly increase
The life expectancy of people with PD is reduced. Mortality
ratios are around twice those of unaffected people. 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. Death from
aspiration pneumonia is twice as common in individuals with PD as in
the healthy population.
In 2013 PD resulted in about 103,000 deaths globally, up from 44,000
deaths in 1990. The death rate increased from an average of 1.5
to 1.8 per 100,000 during that time.
Deaths from Parkinson disease per million persons in 2012
PD is the second most common neurodegenerative disorder after
Alzheimer's disease and affects approximately seven million people
globally and one million people in the United States. The
proportion in a population at a given time is about 0.3% in
industrialized countries. PD is more common in the elderly and rates
rise from 1% in those over 60 years of age to 4% of the population
over 80. 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. Males are more often affected than females at a
ratio of around 3:2. PD may be less prevalent in those of African
and Asian ancestry, although this finding is disputed. Some
studies have proposed that it is more common in men than women, but
others failed to detect any differences between the two sexes. The
number of new cases per year of PD is between 8 and 18 per 100,000
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. The most frequently replicated relationships are an
increased risk of PD in those exposed to pesticides, and a reduced
risk in smokers.
Main article: History of Parkinson's disease
Jean-Martin Charcot, who made important contributions to the
understanding of the disease and proposed its current name honoring
Several early sources, including an Egyptian papyrus, an Ayurvedic
medical treatise, the Bible, and Galen's writings, describe symptoms
resembling those of PD. After
Galen there are no references
unambiguously related to PD until the 17th century. In the 17th
and 18th centuries, several authors wrote about elements of the
disease, including Sylvius, Gaubius, Hunter and Chomel.
In 1817 an English doctor, James Parkinson, published his essay
reporting six cases of paralysis agitans. 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. 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. Among other advances, he made the
distinction between rigidity, weakness and bradykinesia. He also
championed the renaming of the disease in honor of James
Frederic Lewy described microscopic particles in affected
brains, later named "Lewy bodies". 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.
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. In 1997, alpha-synuclein was found to be the main component
of Lewy bodies by Spillantini, Trojanowski, Goedert and others.
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
Levodopa was first synthesized in 1911 by
Casimir Funk, but it received little attention until the mid 20th
century. It entered clinical practice in 1967 and brought about a
revolution in the management of PD. By the late 1980s deep
brain stimulation introduced by
Alim Louis Benabid
Alim Louis Benabid and colleagues at
Grenoble, France, emerged as a possible treatment.
Society and culture
"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. 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. The largest share of direct cost comes
from inpatient care and nursing homes, while the share coming from
medication is substantially lower. Indirect costs are high, due
to reduced productivity and the burden on caregivers. In addition
to economic costs, PD reduces quality of life of those with the
disease and their caregivers.
11 April, the birthday of James Parkinson, has been designated as
World Parkinson's Day. A red tulip was chosen by international
organizations as the symbol of the disease in 2005: it represents the
Tulip cultivar, registered in 1981 by a Dutch
horticulturalist. Advocacy organizations include the National
Parkinson Foundation, which has provided more than $180 million in
care, research and support services since 1982, Parkinson's
Disease Foundation, which has distributed more than $115 million for
research and nearly $50 million for education and advocacy programs
since its founding in 1957 by William Black; the American
Parkinson Disease Association, founded in 1961; and the European
Parkinson's Disease Association, founded in 1992.
Main article: List of people diagnosed with Parkinson's disease
Muhammad Ali at the
World Economic Forum
World Economic Forum in Davos, at the age of 64.
He had shown signs of parkinsonism from the age of 38 until his death.
Michael J. Fox
Michael J. Fox has PD and has greatly increased the public
awareness of the disease. 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, and appeared before the United States
Congress without medication to illustrate the effects of the
Michael J. Fox
Michael J. Fox Foundation aims to develop a cure for
Parkinson's disease. Fox received an honorary doctorate in
Karolinska Institutet for his contributions to research
in Parkinson's disease.
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.
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". Whether he had PD or parkinsonism
related to boxing is unresolved.
Parkinson's disease clinical research
There is little prospect of significant new PD treatments in the near
future. 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
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 parkinsonism 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 parkinsonism in non-human primates as well as in
humans. Other predominant toxin-based models employ the
insecticide rotenone, the herbicide paraquat and the fungicide
maneb. Models based on toxins are most commonly used in primates.
Transgenic rodent models that replicate various aspects of PD have
been developed. Using the neurotoxin 6-hydroxydopamine, also
known as 6-OHDA, it creates a model of
Parkinson's disease in rats by
targeting and destroying dopaminergic neurons in the nigrostriatal
pathway when injected into the substantia nigra.
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 an enzyme that helps to manage PD symptoms or protects
the brain from further damage. In 2010 there were four
clinical trials using gene therapy in PD. There have not been
important adverse effects in these trials although the clinical
usefulness of gene therapy is still unknown. One of these reported
positive results in 2011, but the company filed for bankruptcy in
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 neuroprotection are at the forefront of PD research.
Several molecules have been proposed as potential treatments.
However, none of them have been conclusively demonstrated to reduce
degeneration. Agents currently under investigation include
anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine
oxidase inhibitors (selegiline, rasagiline), promitochondrials
(coenzyme Q10, creatine), calcium channel blockers (isradipine) and
growth factors (GDNF). Preclinical research also targets
alpha-synuclein. A vaccine that primes the human immune system to
destroy alpha-synuclein, PD01A (developed by Austrian company,
Affiris), has entered clinical trials in humans.
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. 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. An additional
significant problem was the excess release of dopamine by the
transplanted tissue, leading to dystonias.
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. Nevertheless, use of fetal stem cells is
controversial. 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.
Repetitive transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation temporarily improves
levodopa-induced dyskinesias. Its usefulness in PD is an open
research topic, Several nutrients have been proposed as possible
treatments; however there is no evidence that vitamins or food
additives improve symptoms. There is no evidence to substantiate
that acupuncture and practice of Qigong, or T'ai chi, have any effect
on the course of the disease or symptoms. Fava beans
and velvet beans are natural sources of levodopa and are eaten by many
people with PD; their intake is not free of risks as life-threatening
adverse reactions have been described, such as the neuroleptic
Parkinson's disease dementia
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V · T · D
ICD-10: G20, F02.3
OMIM: 168600 556500
eMedicine: neuro/304 neuro/635 in young
GeneReviews: Parkinson Disease Overview
Find more aboutParkinson's diseaseat's sister projects
Definitions from Wiktionary
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Textbooks from Wikibooks
Learning resources from Wikiversity
Data from Wikidata
Parkinson's Disease at Curlie (based on DMOZ)
Parkinson's Disease: Hope Through Research (National Institute of
Neurological Disorders and Stroke)
World Parkinson Disease Association
PDGENE – Database for Parkinson's Disease genetic association
Mental and behavioral disorders (F00–F99 & 290–319)
Mild cognitive impairment
AIDS dementia complex
Organic brain syndrome
Psychoactive substances, substance abuse, drug abuse and
Schizophrenia, schizotypal and delusional
Psychosis and schizophrenia-like disorders
Brief reactive psychosis
Disorganized (hebephrenic) schizophrenia
Folie à deux
(Major depressive disorder
Seasonal affective disorder
Neurotic, stress-related and somatoform
Specific social phobia
Generalized anxiety disorder
(Acute stress reaction
Adjustment disorder with depressed mood
Body dysmorphic disorder
Da Costa's syndrome
Mass psychogenic illness
Dissociative identity disorder
(REM sleep behavior disorder
(Hypoactive sexual desire disorder
(Female sexual arousal disorder)
Adult personality and behavior
Sexual maturation disorder
Ego-dystonic sexual orientation
Sexual relationship disorder
Impulse control disorder
Disorders typically diagnosed in childhood
X-linked intellectual disability
Emotional and behavioral
(Separation anxiety disorder)
Symptoms and uncategorized
Intermittent explosive disorder
Psychogenic non-epileptic seizures
Diseases of the nervous system, primarily CNS (G04–G47, 323–349)
Cavernous sinus thrombosis
Tropical spastic paraparesis
Basal ganglia disease
Primary progressive aphasia
Frontotemporal dementia/Frontotemporal lobar degeneration
Dementia with Lewy bodies
Posterior cortical atrophy
Central pontine myelinolysis
Transient global amnesia
Congenital central hypoventilation syndrome
Circadian rhythm sleep disorder
Advanced sleep phase disorder
Delayed sleep phase disorder
Non-24-hour sleep–wake disorder
Choroid plexus papilloma
Idiopathic intracranial hypertension
Spinal cord compression
Primary lateral sclerosis
Hereditary spastic paraplegia
Distal hereditary motor neuronopathies
Spinal muscular atrophies
Progressive muscular atrophy
Progressive bulbar palsy
Infantile progressive bulbar palsy
Amyotrophic lateral sclerosis
Antiparkinson agents (N04)
DA receptor agonists
Methylxanthines (e.g., caffeine)
‡Withdrawn from market
§Never to phase III